The Association between Music Preferences and Psychiatric

Transkript

47
Review / Derleme
DOI: 10.5472/MMJ.2012.02130.1
The Association between Music Preferences and Psychiatric
Problems in Adolescents
Ergenlerde Müzik Tercihi ile Psikiyatrik Sorunlar Arasındaki İlişki
Özalp EKİNCİ1, Volkan TOPÇUOĞLU2, Özgür Bilgin TOPÇUOĞLU3, Osman SABUNCUOĞLU4, Meral BERKEM4
1Child Psychiatry Clinic, Antakya Childrens’ Hospital, Hatay, Turkey
2Department of Psychiatry, School of Medicine, Marmara University, İstanbul, Turkey
3Department of Neurology, Erenköy Psychiatric and Neurological Disorders Hospital, İstanbul,Turkey
4Department of Child and Adolescent Psychiatry, School of Medicine, Marmara University, İstanbul, Turkey
Abstract
Özet
Despite the well-known importance of music in adolescent life, the relationship
between music preferences and the psychological profiles of adolescents has
not been completely clarified. The preference for some music types, especially
heavy metal and rap (heavy music types), has been found to be associated
with depressive symptoms, antisocial behavior and alcohol/drug usage. The
lyrics of these music types and music videos also appear to contribute to these
conditions. Although the bidirectional relationship between music preferences
and psychiatric problems has not been well understood, the available research
data suggest that the preferred music type represents already existing
behavioural tendencies and emotional vulnerability towards psychiatric
problems. (Marmara Medical Journal 2012;25:47-52)
Key Words: Music preference, Adolescents, Heavy metal, Rap
Müziğin ergenlerin hayatındaki önemi gösterilmiş olmasına rağmen müzik
tercihleri ile ergenlerin psikolojik profilleri arasındaki ilişki henüz tam olarak
aydınlatılamamıştır. Bazı müzik türlerinin, özellikle “Ağır müzik türleri” olarak
tanımlanan Heavy metal ve Rap müziğin, tercih edilmesinin depresif belirtilerle,
antisosyal davranışlarla ve alkol/madde kullanımı ile ilişkili olduğu bulunmuştur.
Bu müzik türlerinde şarkı sözleri ve şarkıların video klipleri de bu ilişkilere katkı
yapıyor gibi görünmektedir. Müzik tercihleri ile psikiyatrik sorunlar arasındaki
ilişki tam olarak anlaşılamamış olsa da, mevcut literatürdeki çalışmalar tercih
edilen müzik türünün önceden var olan davranışsal özellikleri ve emosyonel
eğilimleri gösterdiğini işaret etmektedir. (Marmara Üniversitesi Tıp Fakültesi
Dergisi 2012;25:47-52)
Anahtar Kelimeler: Müzik tercihi, Ergen, Heavy metal, Rap
Introduction
Music undoubtedly has an important impact on adolescents’
life. It’s a way of living and reflecting feelings, values, needs and
conflicts. For some of the adolescents, music is a part of
socialization and even personality development1-3. Music can also
provide a background for romance and serve as the basis for
establishing relationships in diverse settings4. It is estimated that
an ordinary adolescent spends over two hours listening to music
everyday5,6. The daily time spent in listening to music music may
be even more than that of watching television for adolescents4.
In recent years, with the huge increase in the popularity of
internet use and the free availability of MP3 songs on the internet,
music has become even more essential in the life of adolescents.
The relationship between music preferences and the
psychological profiles of adolescents has not been completely
clarified. Regarding music types, heavy metal and rap music has
always derived more attention. Heavy metal was found to be
Correspondence to/İletişim: : Özalp Ekinci, M.D., Child Psychiatry Clinic, Antakya Childrens’ Hospital, Hatay, Turkey
E-mail: [email protected]
Submitted/Başvuru Tarihi: 02.01.2012 Accepted/Kabul Tarihi: 27.02.2012
© Marmara Medical Journal, Published by Galenos Publishing. / © Marmara Üniversitesi Tıp Fakültesi Dergisi, Galenos Yayınevi tarafından basılmıştır.
48
Ekinci et al.
Music Preferences and Psychiatric Problems in Adolescents
related to suicidality, self harm, depression, drug abuse,
recklessness, antisocial behavior, school problems, arrests and
family dysfunction3,7-9 while rap was shown to be linked with
alcohol abuse, illegal-drug use, aggressive behavior and
arrests8,10,11. Dance, hip-hop, techno and reggae music were
reported to be related mainly to alcohol and illegal drug use10,12.
A newer music style, emo music, was also suggested to be
associated with psychiatric problems in youth. In 2007, Australian
media linked the double suicide of two teenage girls with the
lyrical themes of emo music13.
This article aims to review the current literature on the
relationship between music preferences and psychiatric problems
in adolescents. The limited research on the topic in non-Western
countries and in Turkey will also be discussed.
Classification of Music Preferences in Adolescents
Some researchers suggested useing broad classification
systems to categorize music types into main categories,
classifying similar types under one broad category in order to find
more general results. Schwarts and Fouts in their study used the
terms heavy and light music types which refer to hard rock,
classical rock, heavy metal, rap and pop, teen pop and dance
music respectively3. This classification has also been used by
others2,14. However, there are still definition problems in this
system. For instance, grouping the fans of rock, hard rock and
heavy metal music under the same category may not be an
appropriate approach. In a former research paper, it is indicated
that, in the U.S., adolescent heavy metal fans consist of a more
extreme group, with more pronounced negative characteristics,
compared with both mainstream rock and hard rock fans15. Rap
music, at least for the songs produced in the 2000s, also seems to
be different from heavy metal music in some aspects. In their
comprehensive review, Reddick and Beresin suggested that a rap
audience is more unified around race, inner-city life and resistance
against the oppressor, especially the police16. Indeed, compared
to that of heavy metal, a rap audience seems to be associated
more with external violence, such as gang and gun violence,
rather than suicide16. Newer music styles have been on the
market since the year 2000. Emo music, an abbreviation for
emotional music, is defined as a musical outpouring of emotions,
usually associated with relationship break-ups or other tragic
events4. Except for those with certain music preferences, there is
a group of adolescents who state that they do not have strong
preferences for any style of music. This type of music preference is
referred to as eclectic3. However, although these adolescents do
not declare a preferred music type, they still may have answers for
which types of music they enjoy listening. Therefore, it may be
more accurate to explore both the favourite music type and the
overall listening habits of adolescents for a more clear picture of
their music preferences.
Music Preferences and Personality Traits in Youth
Studies from the 80s to date investigated the relationship
between music preferences and personality traits in youth. An
Marmara Medical Journal 2012;25:47-52
early study showed that the preference for heavy metal music
correlated with assertiveness, aggressiveness, indifference to the
feelings of others, moodiness, pessimism, and increased likelihood
to act on impulses17. Other studies also showed that adolescents
preferring heavy metal music have an increased tendency to
homicide18, experience more psychological turmoil8, and exhibit
more anger and emotional problems19 than those without such a
preference. Personality traits of youth preferring pop music were
also studied. Swartz and Fouts3 found pop music preference to be
linked to being overly responsible, and struggling with issues of
sexuality, peer acceptance, and negotiation of the balance
between dependence and independence. The results of these
studies, however, must be considered in the context of the
evolution of popular music and other dynamics of adolescents’
lives. Adolescents’ perceptions, attributions and reflections on
music may also be influenced by social, cultural and enviromental
factors.
Demographic findings
Studies have revealed some gender and age differences in
music preferences and involvement with music20-23. Female
adolescents usually feel themselves more close to light music than
do males, since such music reflects their social tendencies (e.g.,
emotional expressiveness, relationships)24,25. In contrast, male
adolescents seem more likely than females to prefer heavy music,
as these music types, in turn, reflect their social tendencies (e.g.,
themes of independence and dominance)26. Male adolescents’
preference for rock and metal music may partly reflect the fact
that male adolescents identify more with the rock musicians, 94%
of who are young males27. Indeed, aggresiveness, moral relativity,
hypermasculinity and the anti-authority in both the lyrics and
loud tones of heavy music types also match with the typical
idealizations and externalizing behavior of male adolescents. A
recent study supported these findings for light music types but
not for heavy music preferences. In this study, females preferred
light music more than males but there was no significant
difference between males and females in their preferences for
heavy music3. The risk for psychopathology may also differ
between genders. According to the study performed by Martin et
al, the majority of female adolescents found rock/heavy metal
unacceptable. However, the minority of female adolescents who
preferred rock/heavy metal were found to be a group with a high
risk of suicidal acts and thoughts, depression, delinquency and
family problems9.
Music and Emotional Symptoms: Bidirectional Relationship
and Additional Factors
The effects of music on the life and mental health of
adolescents may be related with time, context, culture and many
unidentified and confounding factors. One important clue for this
may be the change itself in music and music subculture over the
past 20 years4. For instance, the music and lyrics of heavy metal
music in the 80s and 90s have changed extensively from the
90s to the late 2000s with subdividions into different categories
and even a different outlook and life style. Approximately one
decade ago, two famous heavy metal bands; Judas Priest and
Ozzie Osbourne were unsuccesfully sued by the parents of suicide
victim adolescents because their music was being played while
the adolescents died9. In the case of rap music, a change in the
lyrics/themes of songs may be argued from the 80s to the present
time. There has been a remarkable increase in lyrics about drugs
and alcohol use in this genre throughout the past thirty years10.
Another important issue is the bidirectional relationship
between music preferences and psychiatric problems. Preference
for certain types of music may be interpreted as red flags for
psychiatric problems. However, it may also be true that preferring
these music types reflects the underlying vulnerability which may
be the real cause of psychiatric problems. It has previously been
shown that adolescents’ music preferences reflect their
developmental needs, individualism level, family and friend
relations, dependence-independence, perceptions of self and
various other domains of self and environment1,2,28,29. All of these
subdomains are well known correlates of vulnerabity to psychiatric
problems including emotional symptoms.
The available research on the association of depression risk and
suicidality and music preferences revealed mixed results. Martin et
al found heavy metal preference associated with suicidal thoughts
and depression in 10 year old students9. Another study involving
university students found that those who listened to rock music or
watched rock music videos with suicidal content wrote scenarios
with suicide-related themes more often than those who were
exposed to music with non-suicide-related themes30. In contrast
to the findings of these studies, Lacourse et al.31, found no
relation between heavy metal preference and suicide risk. Ballard
and Coates reported no significant association between music
preference and suicidal tendencies32. Becknell et al.33 recently
indicated that youngsters with a heavy metal preference use this
music to treat their depressive feelings, rather than becoming
depressed as a result of listening to it. There is evidence that one
of the most important indicators of vulnerability to emotional
symptoms is not how you feel before listening but how you feel
after listening to music. It’s been shown that for the majority of
adolescents, independent of the music type, listening to music
had a positive effect on mood7. As for heavy metal preference;
there is evidence that most of the heavy metal fans are typically
in a negative, especially angry, mood before listening to and
experiencing the positive effects of heavy metal music9,34,35.
Martin et al., in their preliminary study linking heavy metal
music to psychopathology, identified a relatively small subgroup
of rock/heavy metal fans who reported feeling worse after
listening. In their study, the most disturbed group of adolescents
presented with suicidal thoughts, self-harm, and depression9. It
may also be true for not only heavy metal but also other types of
music preferences that; feeling negative emotions like sadness,
anxiety and/or feeling worse after listening may be the main
indicator of psychopathology. We speculate that, it may be
reasonable to extend this hyphothesis to “using music as an
adaptation to life or not”. In other words; even for the
problematic music types, including rap and heavy metal, it may
be true that some adolescents may not “hurt” but “heal”
themselves with music and use music to adapt to life. Being an
Ekinci et al.
49
important part of a music subculture, such as being a member of
a popular music band, a successful disc jockey or popular among
the opposite sex may contribute to using music functionally.
Music Preferences and Alcohol/Drug Usage
There is evidence that certain music preferences are linked to
alcohol and drug usage. A handful of studies showed that
preferring loud and energetic types of music, such as heavy metal,
rap, and dance music (heavy music), co-occurs with increased
levels of alcohol, cannabis, and tobacco consumption, compared
to preferring light music genres including pop12,34,36. The
association of heavy music preference and alcohol, cannabis and
tobacco usage have been shown widely in Western countries
including US28,30, Australia9 and European countries10,12,37.
Several explanations were proposed for this association. It is
suggested that both the behavior of admired music artists in the
community and the lyrics of the songs may have a modeling
effect through mentioning, using or even celebrating smoking
and alcohol usage as desirable behavior38-41. Another explanation
points out the presence of some behavioral traits both in heavy
music preference and substance usage. Rebelliousness and
sensation seeking, commonly known behavioral correlates of risktaking behaviors and substance usage, were also linked with the
preference of heavy music styles38,42-45.
Music Preferences and Deviant, Reckless and
Anti-social Behaviors
The relationship between music preferences and antisocial
behaviors has been addressed in the available literature. Listening
to violent songs, regardless of the music type, is linked with being
more hostile and aggressive34. In a US study on adolescents,
preference for heavy metal or rock music was found to be
associated with higher rates of reckless behaviour (e.g. drinkdriving, unprotected sex, shoplifting and vandalism) than those
with a preference for other types of music15. Another study
among university students also showed that the preference for rap
and heavy metal music was associated with significant hostile
attitudes46. In correlation with the previous studies, a recent study
found strong links between rap music and deviant behaviours
including violence, theft and membership of street gangs36.
Music Videos
Research on the relationship between music preferences with
adolescent mental health has detected another dimension of
current popular music: the music videos4. By the 2000s, music
videos address the youth not only in the Western countries but
also in the whole world. A recent study revealed that a sample of
12 to 15-year-olds watched music videos on an average of 4.3
days per week4,47. Music videos may be classified into two types,
performance and concept videos. While the performance videos
consist of an artist or a group filmed during a performance of the
song, concept videos show the viewer a theme and/or a story
which is usually related to the song’s lyrics. This story may
sometimes add content to the lyrics and provide a particular
interpretation that is reinforced every time the viewer hears the
song. The content of music videos has been studied in a number
of studies. A comprehensive study in the US found that rap videos
50
Ekinci et al.
had the highest portrayal of violence (20.4%), followed by rock
videos (19.8%)4,48. Another study showed that rap music videos
had a higher content of alcohol or tobacco use when compared
with the other types of music videos49. The content of music
videos appears to be related with adolescent behavior. Former
studies showed that adolescents exposed to violent videos
reported an increased probability of being engaged in violence
and a greater acceptance of the use of violence47,50,51.
Case-Control Clinical Studies
Only a limited number of studies are available investigating
the relationship between music preferences and psychopathology.
The results of these studies are complicated. Weidinger and
Demi52 investigated the relationship between music preferences
and the preadmission dysfunctional psychosocial behavior (PDPB)
of 60 adolescents who were hospitalized in a psychiatric unit.
Findings revealed that hospitalized adolescents who primarily
listened to music with negative lyrics/themes had a history of
more PDPB than those who primarily listened to music without
negative lyrics/themes. Heavy metal music listeners were found to
have a history of more PDPB than the ones who primarily listened
to other types of music52. Rosenbaum and Prinsky53 reported that
a high incidence of adolescents with preference for heavy metal
music were hospitalized for psychiatric problems. Doak54 also
found that adolescents diagnosed with mood disorder tended to
like rap, classic rock, hard rock, heavy metal and alternative music.
Another study, in which 35 adolescents (aged 12-18 yrs) from a
psychiatric facility were included, short-term fluctuations in mood
were measured before and after music listening, and music
preference was assessed with a rating sheet completed during
testing. When grouped according to music preferences, heavy
metal music listeners were found to have a significant increase in
positive attitude after listening to the music they prefer. In this
study, primary psychiatric diagnoses of adolescents had showed
that music had only a little effect on mood35. Future studies are
needed to draw a comprehensive conclusion on the relationship
between music preferences and psychopathology in clinical trials
of adolescents.
Popular Music Types in Turkey
Despite the extensive literature in Western countries, research
on the relationship between music preferences and psyhiatric
profiles of youth is limited in non-Western countries. Beside the
international Western oriented music types, every country has its
own specific music types according to the society’s sociodemographic properties, beliefs, problems, needs and conflicts.
Turkey, with its unique geographical location between Europe
and Asia, consists of different cultures and music types. Both the
above-mentioned Western-oriented music types and indigenous
Turkish music styles in Turkish are popular in Turkey, depending
on the the socio-economic status, cultural origin and age of the
people. Indigenous Turkish music styles, however, appear to be
more popular in the general population. For instance, arabesque
is a musical style which combines aspects of folk music and
traditional Turkish music with the musical styles of Egyptian and
Indian music. Its popularity reached peak in the 1980s and it
still has listeners, especially in the lower socioeconomic levels
which suffer from adaptation problems caused by rapid
urbanization and by migration from rural areas to large
cities55,56. Stokes indicated that arabesque, with its lyrics about
protests on lost lives and unjust fate, seems to represent a
rejected social identity in these poorly educated individuals
without hope or the power to control their lives55. Another
popular style, Turkish Folk music, has more positive themes and
seems to be linked to the expression of identity and nationality56.
Beside these indigenous music styles, above-mentioned Westernoriented styles like rock, heavy metal, rap, pop and dance/techno
are also popular in Turkey, especially in the young generation
belonging to the middle and upper socio-economic class. With
the globalization of the world and the music industry, these music
styles originally born in Western countries are accepted
internationally and undoubtedly have a great influence on the
youth of the whole world including Turkey. Levine indicated that
the popularity of heavy metal tends to increase among youth in
Muslim societies including Turkey57. Turkish rap in the 2000s also
deserves attention. Among Turkish adolescents, Turkish rap is far
more popular than American rap music. Turkish rap, which is still
underground in nature, was first produced by Turkish immigrants
in Germany. Currently, Turkish rap musicians from Turkey have
come to dominate Turkey’s popular rap field. The lyrical themes
of Turkish rap may be defined as similar to the ones of American
rap in terms of aggression towards authority and a rejection of
the rules of the law58.
Regarding the relationship between Western-oriented music
preferences and psychiatric problems, there is limited data on
Turkish adolescents. In a study about the social activity patterns in
Turkish high school students who use drugs, Ogel et al.59 showed
that most of the adolescents with at least one experience with
drugs had a preference for pop music. However, the majority of
the whole sample also had pop music preference while rock music
was second. On the other hand, the adolescents who use more
than one substance and use marihuanna, frequently prefered rap,
hip hop, techno and dance music types. Going to concerts was
found to be an indicator for substance usage among
adolescents59. One recent study focused on young adult heavy
metal patrons in Istanbul and showed associations between being
a heavy metal patron and having social anxiety disorder, attention
deficit hyperacitivty disorder (ADHD) and depression60.
The Lyrics of Songs in Non-Western Countries
The sound of the music styles, i.e., the exaggerated volume,
bass, and rhythm commonly heard in heavy metal and rap songs,
appear to be universal. However, it is unclear to what extent youth
from non-English speaking and non-Western countries
understand the lyrics of music types like heavy metal and rap. The
violence, drugs and sex content in the lyrics of these genres may
not be understood by the adolescents in non-Western countries to
the same degree in Western countries where English is natively
spoken. On the other hand, some authors hold the notion that
lyrics of the individual songs, compared to music, has less
influence on the adolescents’ behavior, mood and cognition.
Prinsky and Rosenbaum61 suggested that adolescents do not
interpret correctly or comprehend the messages of the songs’
lyrics, and they feel that the lyrics are the least important reason
for liking a song. Ballard and Dodson62 proposed that, when
compared to the actual lyrics, the expectations and of
adolescents created by a particular music seem to have an effect
on their mood.
Conclusion
The researches in the past 30 years indicate that the music
preferences of adolescents may be associated with their
psychological profile. In addition, music preference appears to be
an indicator of an underlying emotional disturbance or
vulnerability to psychopathology. The American Academy of
Pediatrics recommends both to parents and to the professionals
working with adolescents, that they should explore adolescents’
music preferences and the music videos that they watch. The
professionals should also become familiar with the role of the
music in the life of the adolescents, and identify the music
preferences of their patients as clues to their emotional conflict or
problems4. The complex relation between music preferences and
psychopathology in adolescents will be clarified in future studies.
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53
Derleme / Review
DOI: 10.5472/MMJ.2012.01921.1
Wnt/Beta-Katenin Sinyal Yolunda Görev Alan Hedef Hücre
Zarı Biyomolekülleri
Biomolecules of Target Cell Membrane Involved in the Wnt/Beta-Catenin
Signaling Pathway
Hanife Güler TANIR1, Şayeste DEMİREZEN1, Mehmet Sinan BEKSAÇ2
1Biyoloji Bilim Dalı, Genel Biyoloji Anabilim Dalı, Fen Fakültesi, Hacettepe Üniversitesi, Ankara, Türkiye
2Kadın Hastalıkları ve Doğum Anabilim Dalı, Tıp Fakültesi, Hacettepe Üniversitesi, Ankara, Türkiye
Özet
Abstract
Wnt/β-katenin sinyal yolu hücre proliferasyonu ve farklılaşması, hücre siklusunun
düzenlenmesi, hücre-hücre ve hücre-matriks etkileşimleri, anjiogenez, apoptozis
ve adipogenez gibi çeşitli biyolojik olaylarda önemli rol oynar. Wnt/β-katenin
sinyal yolu, Wnt proteininin hedef hücre zarındaki reseptörlerine bağlanmasıyla
başlar ve bu bağlanma ile ekstraselüler bir sinyal, hücre zarından sitoplazmaya
oradan da çekirdeğe kadar iletilir. Sinyal yolunun bu şekildeki aktivasyonu ile
birçok genin transkripsiyonu da aktive edilmiş olur. Ancak Wnt, Fz ve LRP5/6 gibi
proteinleri kodlayan genlerde meydana gelen mutasyonlar, hem Wnt/β-katenin
sinyal yolunun kontrolsüz aktivasyonuna, hem de kanser başta olmak üzere
birçok ciddi hastalıkların oluşmasına neden olabilmektedir. Dolayısıyla bu sinyal
yolu ve bu yolda görev alan biyomoleküllerin aydınlatılması hem oluşumlarında
rol oynadıkları hastalıkların etiyolojilerinin ayrıntılı biçimde ortaya konulmasında
hem de bu hastalıkların tedavisi için yeni hedef moleküllerin belirlenmesinde
oldukça önemlidir. Bu sebeple Wnt/β-katenin sinyalinin hedef hücre zarındaki
başlangıç mekanizması ve bu mekanizmada görev yapan biyomoleküllerin
tartışılması ve bu şekilde sinyal yolunun tam olarak aydınlatılması amaçlanmıştır.
(Marmara Üniversitesi Tıp Fakültesi Dergisi 2012;25:53-7)
Anahtar Kelimeler: Wnt proteinleri, Beta-katenin, Fz, LRP5/6, Erişkin kök
hücreler, Kanser
The Wnt/β-catenin signaling pathway plays crucial roles in various
biological processes, including; cell proliferation and differentiation,
regulation of cell cycle, cell-cell and cell-matrix interactions,
angiogenesis, apoptosis and adipogenesis. The Wnt/β-catenin signaling
pathway starts with the binding of the Wnt protein to its cell surface
receptors, and an extracellular signal is transferred to the cytoplasm and
nucleus from the cell membrane. Transcription of various genes is
activated by the activation of the signaling pathway in the nucleus.
However, mutations of genes, which encode Wnts, Fz and LRP5/6
proteins, may cause aberrant activation of Wnt/β-catenin signaling and
also many severe diseases, especially cancer. Therefore, clarifying this
pathway and its biomolecules is quite important for determining both
the etiologies of the diseases, and novel target molecules that can be
used for treatment. Thus, we aimed to discuss the initial step of the
Wnt/β-catenin signaling mechanism on the target cell membrane, and
biomolecules such as Wnt, Fz and LRP5/6 involved in this mechanism,
and in this manner we intended to clarify fully the signaling mechanism.
(Marmara Medical Journal 2012;25:53-7)
Key Words: Wnt proteins, Beta-catenin, Fz, LRP5/6, Adult stem cells, Cancer
Giriş
Organizmalarda hem embriyonik hem de erişkin dönemdeki
birçok önemli biyolojik süreçte aktivite gösteren üç adet Wnt sinyal
yolu tanımlanmıştır1. Bu yollardan ilki embriyonik dönemde hücre
iskeletinin düzenlenmesinde ve dolayısıyla hücre polaritesinin
sağlanmasında görev alır. O nedenle bu Wnt sinyal yoluna “Hücre
polaritesinin sağlanmasında görev alan sinyal yolu [The Planar Cell
İletişim/Correspondence to: Dr. Şayeste Demirezen, Biyoloji Bilim Dalı, Genel Biyoloji Anabilim Dalı, Fen Fakültesi, Hacettepe Üniversitesi, Ankara, Türkiye
E-posta: [email protected]
Başvuru Tarihi/Submitted: 20.11.2011 Kabul Tarihi/Accepted: 26.01.2012
© Marmara Üniversitesi Tıp Fakültesi Dergisi, Galenos Yayınevi tarafından basılmıştır. / © Marmara Medical Journal, Published by Galenos Publishing.
54
Tanır ve ark.
Wnt/Beta-Katenin Hedef Hücre Zarı Biyomolekülleri
Polarity pathway, (PCP pathway)]” denir2. İkinci yol kalsiyum
(Ca+2) metabolizmasında görev alan biyomolekülleri uyararak
hücre içindeki Ca+2 miktarını arttıran sinyal yoludur. Bu yola da
“Wnt/Ca+2 sinyal yolu” denir3. Bazı araştırıcılar bu iki yolu birlikte
tanımlayarak “standart olmayan (non-canonical pathway)” veya
“β-katenin bağımsız sinyal yolu” olarak da adlandırmaktadırlar1,4.
Üçüncü sinyal yolu ise “Wnt/β-katenin sinyal yoludur”. Bu sinyal
yolu “standart (canonical)” ya da “klasik yol” olarak da literatürde
yer almaktadır1. Wnt/β-katenin sinyal yolu tümör oluşumu ve
birçok ciddi hastalıklarla olan sıkı ilişkisi nedeniyle araştırıcılar
tarafından en çok çalışılan Wnt sinyal yoludur5,6. Wnt/β-katenin
sinyal yolunun tanımlandığı ilk yıllarda hücre siklusunun
düzenlenmesinde, hücre proliferasyonu, farklılaşması ve
adezyonunda önemli görevler üstlendiği ortaya konulmuştur7,8.
Son yıllarda ise bu görevlerinin yanı sıra tümör oluşumunda, sinaps
oluşumu, adipogenez ve anjiogenez gibi önemli biyolojik olaylarda
da rol oynadığı saptanmıştır5,8-11.
Wnt/β-katenin sinyal yolu mekanizması bir hücrenin hücre
zarında, sitoplazmasında ve çekirdeğinde olmak üzere üç ayrı
bölgesinde gerçekleşir. Sinyal mekanizması hücre zarında başlar ve
ekstrasellüler bir uyarı intrasellüler hale gelmiş olur. Wnt/β-katenin
sinyal yolunun hedef hücre zarındaki reaksiyonlarının ayrıntılı
olarak ortaya konulması sinyal mekanizmasının tam olarak
anlaşılmasını sağlayacaktır. Bu nedenle sinyal yolunun başlangıç
basamağında görev alan Wnt, Frizzled (Fz) ve düşük yoğunluklu
lipoprotein ilişkili protein-5/6 (LRP5/6) biyomoleküllerin yapıları
aşağıda ayrıntılı olarak incelenecektir.
Wnt/β-katenin Sinyal Yolunun Hücre Zarındaki Mekanizması
Wnt/β-katenin sinyal yolu adını Wnt proteininden alır12. Bu
protein ergin dönemde hematopoietik hücreler, epitel dokusunun
en alt tabasındaki bazal hücreler, kan damarları, beyin, karaciğer,
akciğer, prostat gibi doku ve organlarda bulunan erişkin kök
hücreler tarafından sentezlenir6,12. Sentezlenen Wnt proteini
çeşitli post-translasyonel modifikasyonlar geçirerek bu hücreler
tarafından ekstraselüler matrikse salınır13. Ekstraselüler matrikste
difüzyon ile hedef hücre zarına gelen Wnt proteini hedef hücre
zarında bulunan Fz ve LRP5/6 isimli reseptörlerine bağlanır14,15.
Wnt proteininin reseptörlerine bağlanması ile oluşan “Wnt-FzLRP5/6” üçlü kompleksi sinyal yolunun başlaması için oluşmuş
olan esas yapıdır14-16 (Şekil). Bu nedenle, Wnt/β-katenin sinyal
mekanizmasının hücre zarındaki aktivasyonunda görev alan
biyomoleküllerden Wnt proteini ile hücre zarı reseptör
proteinlerinden Fz ve LRP5/6 proteinlerinin özelliklerine ve
klinikteki önemine aşağıda detaylı olarak değinilecektir.
çalışmalarda bitkilerde de Wnt sinyal mekanizmasında görev alan
biyomoleküllerin homologları tespit edilmiştir21,22. Bu proteinin
evrimsel geçmişini ortaya koymaya yönelik yapılan bu çalışmalar, bu
gen ailesinin Sölenterlerden (Hydra) insana kadar oldukça
korunarak aktarıldığını göstermiştir. Günümüzde Drosophila’da
tanımlanmış 7 ve C. elegans’da 5 ve insanda 19 adet Wnt geni
bulunmaktadır1,23.
Wnt genlerinin ürünü olan Wnt proteinleri 36-40 kD molekül
ağırlığında ve yaklaşık 350 amino asit uzunluğundadır23. Bu
proteinler 23-25 adet korunmuş sistein rezidülerine sahiptir12,23.
Bu sistein rezidüleri Wnt proteinlerinin hedef hücre zarındaki
reseptörlerine bağlanması için gereklidir. Ayrıca bu rezidüler
arasında oluşan molekül içi disülfit bağları, proteinlerin üç boyutlu
konformasyonunun sağlanmasında ve buna bağlı olarak da
fonksiyonel bir sinyal molekül haline gelmesinde önemli rol
oynar24.
Wnt proteinleri uzun yıllar boyunca hücreden izole
edilememiştir12,13. Yapılan deneylerde Wnt proteinleri hücre zarı
ve ekstraselüler matriks bileşenlerinden heparan sülfat
glikozaminoglikanlarla bağlı olarak izole edilmiş ve in vitro
koşullarda aktivite göstermemiştir13. İlk defa 2003 yılında Willert
ve araştırma grubu kütle spektrometresi kullanarak yaptıkları
çalışmada aktif Wnt3A proteinini izole etmeyi başarmışlardır.
Ayrıca bu çalışmada Wnt’nin sentezlendikten sonra geçirdiği post
translasyonel lipit modifikasyonları da ortaya çıkarılmıştır. Bu bilgi
Wnt proteinlerinin primer amino asit yapısından beklenenden
daha hidrofobik yapıda olduğunu ve bu özelliğin proteinin aktif
halde izole edilmesini zorlaştırdığını da göstermiştir25.
Son yıllarda bir yandan proteinin özelliklerini saptamaya
yönelik çalışmalar yapılırken bir yandan da Wnt geninin anormal
ekspresyonu ve mutant Wnt proteinlerinin olası etkileri ile ilgili
birçok araştırma yapılmaktadır. Bu amaçla yapılan çalışmalarda
WNT-1, WNT-3A ve WNT-16 genlerinin güçlü onkojenik etkiye
sahip olduğu, WNT-5A ve WNT-7A genlerinin ise tümör baskılayıcı
özellikleri gösterilmiştir12,23,26. Elde edilen bu bulgular birçok
hastalığın oluşumunun Wnt proteinleri ve bu proteinlerin görev
aldığı sinyal yolu ile bağlantılı olduğu düşüncesini
desteklemektedir. Örneğin WNT3 geninde meydana gelen
mutasyonların embriyonik dönemde dört uzuv kaybıyla
sonuçlanan tetra-amelia hastalığı ile ilişkisi olduğu
bildirilmektedir26. Ayrıca WNT4 geninin anlatımında meydana
gelen değişikliklerin de over ve meme kanserlerinin yanı sıra
polikistik böbrek hastalıklarında rolü olduğu ifade edilmektedir27.
Wnt
Üçlü kompleks
Wnt
Wnt Proteinleri
Wnt proteinini kodlayan Wnt geni 1982 yılında ilk olarak farenin
meme tümörü ile yapılan viral insersiyon mutasyonu çalışmaları
sırasında protoonkogen olarak bulunmuş ve int-1 adını almıştır17.
Daha sonra bu genin Drosophila’daki segment polaritesinden
sorumlu wingless geni ile homolog olduğu saptanmış ve iki gen
ismi birleştirilerek 1991 yılında Wnt geni literatüre geçmiştir18. Wnt
genleri omurgalı ve omurgasız birçok canlıda saptanmış; ancak tek
hücreli bir ökaryot olan Saccharomyces cerevisiae’de ve
prokaryotlarda bulunamamıştır12,19,20. Son yıllarda yapılan
Sinyal
yolu aktif
Fz
LRP5/6
P
P
P
Fz
LRP5/6
Şekil 1. Wnt/β-katenin sinyal yolunun hedef hücre zarındaki mekanizması
(p=Fosfat) (43. referanstan değiştirilerek çizilmiştir).
Wnt/β-katenin sinyal yolunun bilime olan önemli bir katkısı da
son yıllarda yapılan birçok çalışmada da gösterildiği gibi bu sinyal
yolunda görev alan biyomoleküllerin çeşitli hastalıkların
tedavisinde kullanılmasıdır28-30. Örneğin Wnt1 ve Wnt2
proteinlerini kodlayan genlerdeki herhangi bir mutasyon nedeniyle
Wnt proteini gereğinden fazla sentezlenecek olursa normal
Wnt/β-katenin sinyal yolu aktivasyonu gerçekleşmez. Bu da meme
adenokarsinomu, melanoma, mezotelioma, sarkoma ve küçük
hücreli olmayan akciğer kanseri gibi çeşitli hastalıkların oluşumuna
neden olmaktadır28,29. Araştırıcılar bu hastalıkların oluşumunda rol
oynayan fazla sentezlenmiş olan Wnt1 ve Wnt2 proteinlerine gidip
bağlanarak onların aktivitesini durdurmayı hedeflemişler ve bu
amaçla Wnt-1 ve Wnt-2 proteinlerine özgül olarak bağlanan
monoklonal antikorlar kullanmışlardır. Bu monoklonal antikorlar
Wnt1 ve Wnt2 proteinlerine bağlanarak onların hücre zarında
bulunan reseptörlerine bağlanmasını engellemektedir. Bu şekilde
Wnt/β-katenin sinyal yolunun kontrolsüz aktivasyonu da önlenmiş
olmaktadır. Monoklonal antikorların kullanıldığı bu yöntem ile
farelerde yapılan deneylerde yukarıda sayılan kanser tümörlerinin
büyümesinde azalma olduğu kaydedilmiştir. Bu da Wnt/β-katenin
sinyal yolunun kontrolsüz aktivitesine bağlı olarak oluşmuş
kanserlerin devam etmesini ve yayılmasını önlemede tedavi amaçlı
büyük yararlar sağlamıştır28-30.
Hücre Zarı Reseptör Proteinleri
a. Frizzled (Fz)
Wnt/β-katenin sinyal yolu Wnt proteininin hücre zarındaki
reseptörlerine bağlanmasıyla başlamaktadır16. Sinyal yolunun
başlamasında görev alan bu reseptörlerden ilk olarak “Frizzled
proteini” tanımlanmıştır5. Bu proteini kodlayan FRIZZLED (FZ,
FZD) geni 1996 yılında Drosophila ile yapılan epidermal hücre
polaritesi çalışmaları sırasında saptanmıştır31. Daha sonra yapılan
araştırmalarla insan genomunda da 10 adet FZD geni (FZD1FZD10) bulunmuştur11,31,32.
FZD genlerinin ürünü olan Fz proteinleri yaklaşık 500-700 amino
asit uzunluğunda, 63-80 kDa molekül ağırlığında olan transmembran
proteinlerdir33. Bu proteinlerin hücre dışı kısmında kalan bir amino
terminal (N-terminal) ucu, bir de sitozol içinde kalan karboksi terminal
(C-terminal) ucu vardır. Bu C-terminal ucu hücre zarı içinde 7 kıvrım
oluşturarak bir bütün halinde transmembran proteini olarak görev
yapar. Bu nedenle bu proteine literatürde “7 kıvrımlı reseptör
proteinleri (seven-span membrane receptor)” denir34. Bu proteinlerin
hücre içinde yer alan C-terminal ucu 7 adet hidrofobik domain içerir.
Bu 7 domainin bitiminde bulunan son 2 amino asit oldukça
korunmuştur ve yapılan çalışmalarda bu amino asitlerde meydana
gelen nokta mutasyonların Wnt/β-katenin sinyal yolunu inhibe ettiği
gösterilmiştir34,35. Bu da, bu amino asit dizisinin sinyal yolunun
sitoplazma içindeki işleyişinde önemli rol oynadığını göstermektedir36.
Fz reseptörünün N-terminal ucu ise ekstrasellüler matrikse
uzanır ve 10 adet sistein rezidüsünden oluşan, korunmuş
“sisteince zengin bölge [cystein-rich domain (CRD)]” içerir37. Fz
reseptörünün hücre dışında bulunan bu CRD bölgesinin Wnt
proteinine yüksek affinite ile bağlandığı ortaya konulmuştur. Wnt
sinyali varlığında, Wnt proteini ile ilk ilişki kuran Fz reseptörünün
N-terminalinde bulunan bu CRD bölgesidir. Bu bağlanmanın
Tanır ve ark.
55
ardından reseptörde meydana gelen konformasyonel değişimler
sonucu,
reseptörün
C-terminal
ucu
sitoplazmadaki
biyomoleküllerle ilişki kurar. Bu nedenle bu bölge Wnt/β-katenin
sinyal yolunun başlamasında ve sinyalin hücre zarından
sitoplazmaya aktarılmasında çok önemli bir rol oynamaktadır16,38.
Fz reseptörünün CRD bölgesinde meydana gelen mutasyonlar
Wnt proteininin bu bölgeye bağlanmasını engellemektedir. Buna
bağlı olarak da aktifleşmesi gerektiği durumda Wnt/β-katenin
sinyal yolu inaktif halde kalmaktadır. Böylece bu mutasyon Fz
reseptöründe fonksiyon kaybına neden olmaktadır37,38. Bunun
yanı sıra Fz reseptör geninin aşırı anlatımına neden olan
mutasyonlar da bulunmaktadır. Bu mutasyonlarla ilgili bir hücre
kültürü çalışmasında Fz2, Fz7, Fz8 ve Fz9 reseptörünün
gereğinden fazla sentezlenmesinin, gastrointestinal epitel
hücrelerinin onkojenik transformasyonuna neden olduğu
gösterilmiş ve bu dönüşümde kontrolsüz şekilde aktifleşmiş
Wnt/β-katenin sinyal yolunun rol oynadığı ifade edilmiştir39. Fz
reseptöründe meydana gelen bozukluklar sonucu ortaya çıkan bu
kontrolsüz aktivasyonun özellikle karaciğer kökenli kanser
olgularında, akut ve kronik lenfoblastik lösemilerde ve sinoviyal
sarkomlarda görüldüğü saptanmıştır40,41.
Fz reseptörü de Wnt proteini gibi tedavide kullanılması
düşünülen hedef moleküllerden biridir. Fz reseptörünün tedavide
kullanılabileceğinin gösterilmesi amacıyla sinoviyal sarkoma
hücreleri ile yapılan bir çalışmada özgül poliklonal antikorlar
kullanılarak bu poliklonal antikorların gereğinden fazla
sentezlenmiş olan Fz reseptörüne bağlandığı ve Wnt proteininin
bu reseptörlerle etkileşim kurmasını engellediği gösterilmiştir. Bu
şekilde Fz reseptör geninin aşırı anlatımına bağlı olarak meydana
gelen kontrolsüz Wnt/β-katenin sinyal yolu aktivitesi ortadan
kaldırılmış ve bu kontrolsüz aktivitenin engellenmesi ile tümör
büyümesinde de belirgin bir azalma olduğu gözlenmiştir42.
b. LRP5/6
LRP düşük yoğunluklu lipoprotein reseptör ailesinin bir üyesidir
ve Wnt/β-katenin sinyal yolunun diğer bir reseptörü olan Fz
reseptörü gibi hücre zarına yerleşmiştir. LRP reseptörü hem
metabolizmanın düzenlenmesinde görev alırken hem de Wnt ve
Fz ile birlikte sinyalin başlaması için gerekli olan üçlü kompleksin
içinde yer alır43,44.
Yaklaşık 1615 amino asitten oluşan ve büyük bir ekstraselüler
domain ile kısa bir sitoplazmik kuyruğa sahip olan LRP reseptörleri,
180 kDa molelüler ağırlığa sahiptir ve basit transmembran
proteinleri sınıfına girer43. Memeli hücrelerde bu reseptör sınıfının
LRP5 ve LRP6 olmak üzere iki üyesi vardır. Hem embriyonik hem
de erişkin dokularda sentezlenen bu iki reseptör birbirleri ile
homoloji gösterirler. Bu reseptörlerin hücre dışında kalan kısımları
%73 oranında benzerlik gösterirken hücre içi kısımlarında bu oran
%64’tür. Bu yüksek homoloji nedeniyle Wnt/β-katenin sinyal
mekanizmasından bahsedilirken LRP5/6 şeklinde bir adlandırma
kullanılmaktadır43,44.
LRP5/6 reseptörünün sinyal yolundaki asıl görevi Wnt
proteininin Fz reseptörüne tutunması sonucu oluşan ikili
komplekse gidip bağlanarak üçlü bir kompleks oluşturması ve bu
şekilde “Wnt-Fz” ikilisinin ko-reseptörü olarak davranmasıdır45. Bu
56
Tanır ve ark.
kompleksin yapısında bulunan LRP5/6 reseptörünün sitozol içinde
kalan kısmı 207-218 amino asitten oluşur ve prolin ile serin amino
asitleri bakımından zengindir. Bu kısım 5 adet korunmuş “PPPSPXS
(Prolin-prolin-prolin-serin-prolin)” motifi içerir43,45. Wnt proteini
reseptörlerine bağlanır bağlanmaz, LRP5/6 reseptöründe
konformasyonel bir değişim meydana geldiği ve bu değişimin
etkisi ile reseptörün yapısında bulunan bu motifin çeşitli kinazlar
tarafından fosforillenerek sinyal mekanizmasının sitoplazmaya
aktarılmasında çok önemli bir basamağı oluşturduğu öne
sürülmektedir43-45.
Yapılan biyokimyasal ve genetik çalışmalarda LRP5/6
reseptöründe meydana gelen fonksiyon bozukluklarının diyabet,
kalıtsal göz bozuklukları, meme kanseri ve Alzheimer hastalığı gibi
birçok hastalığın oluşum mekanizmasında görev aldığı
gösterilmiştir. Ayrıca LRP5/6’nın kemik yoğunluğu üzerine olan
etkilerini gösteren birçok çalışma bulunmaktadır. LRP5/6 geninde
fonksiyon kaybıyla sonuçlanan bir mutasyon sonucu osteoblast
proliferasyonunda ve kemik yoğunluğunda azalma meydana
geldiği gösterilmiştir10,46. Gereğinden fazla anlatılan LRP5/6
geninin ise kemik kütlesinin artışına yol açtığı bildirilmiştir. Tüm bu
bulgular, bu reseptörün görev aldığı Wnt/β-katenin sinyal yolunun
osteogenezde önemli rol üstlendiğini göstermektedir47.
Son yıllarda yapılan çalışmalar LRP5/6 antikorlarının tedavide
kullanılabileceğini göstermektedir48. Örneğin, meme tümör
hücreleri ile yapılan bir çalışmada ortama eklenen LRP5/6
antikorlarının ve antagonistlerinin meme tümör hücrelerinde
apoptozisi indüklediği ve hücre proliferasyonunu azalttığı
gözlenmiştir49. Ayrıca, osteosarkoma ve prostat kanser hücrelerinde
LRP5 dominat- negatif plasmid sistemi kullanılmış, bu şekilde bu
kanserlerin oluşumunda etkisi olduğu düşünülen kontrolsüz Wnt/βkatenin sinyal yolu aktivitesi ortadan kaldırılmıştır50.
Sonuç olarak, Fz, LRP5/6 ve Wnt proteinlerinin Wnt/β-katenin
sinyal yolundaki rolleri birçok çalışmayla aydınlatılmaya
çalışılmasına rağmen, sinyal mekanizmasının başlangıç
reaksiyonları tam olarak ortaya konulamamıştır. Sinyal yolunun
hedef hücre zarındaki reaksiyonları ile ilgili olarak yanıt aranan en
önemli sorular; Wnt proteinlerinin reseptörleri ile nasıl ilişki
kurduğu, reseptörlerini nasıl seçtiği, Wnt-Fz-LRP5/6 üçlü
kompleksinin nasıl bir araya geldiği ve sinyalin sitoplazmaya nasıl
aktarıldığıdır. Dolayısıyla, Wnt/β-katenin sinyal mekanizmasını
aydınlatmak amacıyla yapılan tüm katkılar, mekanizmanın
bütününün anlaşılmasında oldukça önemlidir. Ayrıca, kontrolsüz
şekilde aktifleşmiş olan Wnt/β-katenin sinyal yolunun inhibitörler,
antikorlar ve antagonistler gibi çeşitli biyomoleküllerle bloke
edilmesi, bu sinyal yolunun oluşumunda rol oynadığı hastalıkların
tedavisinde yeni seçenekler sağlayacaktır.
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58
Review / Derleme
DOI: 10.5472/MMJ.2012.02383.1
Liver Diseases Associated with Pregnancy
Gebeliğe Özgü Karaciğer Hastalıkları
Emel AHISHALI
Department of Gastroenterology, Dr. Lutfi Kırdar Kartal Education and Research Hospital, Istanbul, Turkey
Abstract
Özet
Pregnancy is a time of great maternal physiological and metabolic changes.
Pregnancy-related liver disease is the most frequent cause of liver dysfunction
in pregnancy and provides a real threat to fetal and maternal survival. Liver
diseases associated with pregnancy include hyperemesis gravidarum,
intrahepatic cholestasis of pregnancy, preeclampsia and eclampsia, hemolysis
(H), elevated liver enzymes (EL) and a low platelet count (LP) (HELLP)
syndrome and acute fatty liver of pregnancy. A rapid diagnosis differentiating
between liver disease related and unrelated to pregnancy is required in
women who present with liver dysfunction during pregnancy. This review
summarizes the incidence, risk factors, pathogenesis, clinical presentation,
diagnosis, treatment and outcome of liver diseases unique to pregnancy.
Key Words: Pregnancy, Hyperemesis gravidarum, Intrahepatic cholestasis of
pregnancy, Preeclampsia and eclampsia, HELLP syndrome, Acute fatty liver of
pregnancy.
Gebelik anne adayında önemli fizyolojik ve metabolik değişikliklerin olduğu bir
dönemdir. Gebelerdeki karaciğer disfonksiyonunun en sık nedeni gebelikle ilişkili
karaciğer hastalıklarıdır. Gebelikle ilişkili karaciğer hastalıkları fetal ve maternal
sağ kalımı açık bir şekilde tehdit eder. Gebeliğe bağlı karaciğer hastalıkları
hiperemezis gravidarum, gebeliğin intrahepatik kolestazı, preeklampsi ve
eklampsi, hemoliz (H), karaciğer enzimlerinde yükselme (EL) ve düşük
trombosit sayısı (LP) (HELLP) sendromu ve gebeliğin akut yağlı karaciğerini
kapsamaktadır. Gebelikte karaciğer disfonksiyonu gelişen kadınlarda gebelikle
ilişkili ve ilişkisiz karaciğer hastalıkları arasında hızlı bir ayırıcı tanı gereklidir. Bu
derlemede gebeliğe özgü karaciğer hastalıklarının insidansı, risk faktörleri,
patogenezi, klinik bulguları, tanısı, tedavisi ve sonuçları özetlenmiştir. (Marmara
Üniversitesi Tıp Fakültesi Dergisi 2012;25:58-63)
Anahtar Kelimeler: Gebelik, Hiperemezis gravidarum, Gebeliğin intrahepatik
kolestazı, Preeklampsi and eklampsi, HELLP sendromu, Gebeliğin akut yağlı
karaciğeri.
Introduction
Various changes in the gastrointestinal system and liver occur
during gestation as in other organs and systems. Normal
physiological changes during gestation may mimic signs of
chronic liver disease. Spider angiomas and palmar erythema may
develop due to gestational hyperestrogenemia, and they
disappear after the birth. Plasma volume starts to increase at the
6th week of gestation, and it is raised by approximately 50% at
the 36th week of gestation. Although the erythrocyte volume is
elevated slightly, the hematocrit is decreased due to hemodilution
which occurs secondary to the increased total blood volume.
Cardiac output increases until the second trimester and then
gradually returns to normal limits towards term. Total hepatic
blood flow is not changed, but the fraction of cardiac output
passing to the liver is decreased. Blood pressure is lower during
gestation and if it is increased, preeclampsia or eclampsia should
be considered1.
The serum albumin level is decreased owing to hemodilution
and diminished synthesis. Coagulation factors like factor VII, VIII,
X and fibrinogen are increased because of enhanced hepatic
synthesis. Hypercholesterolemia and hypertriglyceridemia are
Correspondence to/İletişim: Dr. Emel Ahishali, M.D., Department of Gastroenterology, Dr. Lutfi Kırdar Kartal Education and Research Hospital, Cevizli, Istanbul, Turkey
Submitted/Başvuru Tarihi:02.03.2012 Accepted/Kabul Tarihi: 05.04.2012
Emel Ahıshalı
considered as normal findings of gestation, since serum
cholesterol and triglyceride levels may increase by 50% and 30%,
respectively. Prothrombin time (PT) and activated partial
thromboplastin time (APTT) are not changed2-4. Normal values of
liver function tests during gestation are shown in Table I.
Among the liver diseases associated with pregnancy are
hyperemesis gravidarum, intrahepatic cholestasis of pregnancy,
preeclampsia and eclampsia, acute fatty liver of pregnancy and
hemolysis (H), elevated liver enzymes (EL) and low platelets (LP)
(HELLP) syndrome. This review outlines the incidence, risk factors,
pathogenesis, clinical presentation, diagnosis, treatment and
outcome of liver diseases associated with pregnancy.
Hyperemesis Gravidarum
Hyperemesis gravidarum (HG) is generally encountered in
0.3-2% of all pregnancies in the first trimester before the 10th
week of gestation, and nearly half of the patients require
hospitalization. It is characterized by intractable nausea and
vomiting leading to dehydration, fluid-electrolyte imbalance,
body weight loss of more than 5% and ketonuria. Generally it
starts at the 4th-10th week, and alleviates by 16th-18th week.
However, it may persist until the third trimester in 15-20% of
patients, and until parturition in 5-10% of patients1,5.
The pathogenesis is not clearly known, but it is believed to be
multifactorial with possibly endocrine, immunological and
psychological factors playing roles in the etiology1,5. Human
chorionic gonadotropin (hCG) is a strong stimulator of the
secretions of the gastrointestinal system and it resembles thyroid
stimulating hormone. Its increase leads to hyperthyroidism, so
that severe and elongated vomiting is observed. hCG production
reaches its peak at the 12th-14th week of gestation, which
coincides with the initiation of nausea and vomiting6-8.
Progesterone can lead to decrease in the motility of the
gastrointestinal system during gestation. It is known that
elevations in estrogen and estradiol cause nausea and vomiting in
pregnant women6. T cell mediated immune reactivation,
immunoglobulins and the complement system are also
considered to play an important role in HG etiology5. Among the
risk factors that have been reported to be associated with HG
development are a young maternal age, a multiple pregnancy,
59
molar pregnancy, nulliparity, a female fetus, hyperthyroidism,
psychiatric illness, presence of family history, specific nutrient
deficiencies and chronic infection of helicobacter pylori1,9-11.
Liver function tests are lowered in 50-67% of cases.
Transaminases, especially aspartate aminotransferase (AST), are
increased 2-4 fold, but they may also be increased up to 10-20
fold. Jaundice is not common and serum bilirubin levels are
generally below 4 mg/dl. Among the other biochemical disorders
are increased serum urea and creatinine, hypophosphatemia,
hypomagnesemia and hypokalemia10-12. Complications are rare
in HG, but retinal hemorrhage, Wernicke’s encephalopathy,
esophageal tear or rupture, pneumothorax and splenic avulsion
may be encountered1,10.
Diagnosis is mainly based on clinical findings; it is diagnosed by
the typical initiation of the symptoms at 4th-10th weeks of gestation
and by ruling out other diseases like gastroenteritis, viral hepatitis,
pancreatitis, cholelithiasis, peptic ulcer, genitourinary system
diseases, metabolic disorders, diabetes, porphyria, neurological
diseases, drug toxicity and psychological problems. Liver biopsy,
though unnecessary may reveal nonspecific changes including mild
steatosis and cholestasis1,4,13.
Treatment is symptomatic with intravenous fluids and measures
to prevent vomiting. Antiemetics like ondansetron, metoclopramid,
phenothiazines and droperidol are known to be safe to use.
Ondansetron is the most widely used and effective antiemetic.
Metoclopromid, pyridoxine, antihistaminics and anticholinergics
may also be used in the treatment. Daily ginger supplementation
(1 g/day) has been shown to be useful in HG without causing
teratogenic effects. Severe dehydration or ketonuria requires
hospitalization with intravenous fluid and electrolyte replacement
therapy. Thiamin should be given in order to prevent Wernicke’s
encephalopathy. Occasionally oral or enteral nutrition is not
tolerated, and total parenteral nutrition may be indicated.
Corticosteroids are used in treatment of refractory HG cases. The
guidelines of the “The Royal College of Obstetricians and
Gynecologists” recommend prophylaxis with low molecular weight
heparin in cases of immobility and dehydration6,7,9,14. It has also
been reported that non-pharmacological treatments like hypnosis
and acupuncture are also effective7,9,15,16.
HG generally self-recovers near the 20th week of gestation
independently of treatment. HG may cause fetal growth
Table I. Liver function tests in normal pregnancy3
Non-pregnant
1st trimester
2nd trimester
3rd trimester
AST (IU/L)
7-40
10-28
10-29
11-30
ALT (IU/L)
0-40
6-32
6-32
6-32
Bilirubin (mg/dl)
0-0.99
0.2-0.93
0.17-0.76
0.17-0.81
GGT (IU/L)
11-50
5-37
5-43
3-41
ALP(IU/L)
30-130
32-100
43-135
133-418
5.3-5.7
5.6-6.5
Bile acids (μmol/L)
5-10
AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyl transferase; ALP, alkaline phosphatase.
60
Emel Ahıshalı
retardation and death in developing countries or in those with
limited public health preventive services. Fetal complications arise
mainly due to the low body weight of the pregnant woman. In
developed countries, fetal or maternal complications are very rare.
Abnormalities in liver function tests are improved by rehydration
treatment1,4,10.
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic liver
disease, that recovers after the birth. Its incidence is between
1/1000 and 1/10000 pregnancies. Its prevalence varies according
to ethnic background and geographic region with the highest
rates found in South America (4-6.5%) and the lowest in
Scandinavia (1-2%). Once ICP develops in a patient, the
probability of recurrence in subsequent pregnancies is as high as
40-70%. The ICP development rate is higher in cases of multiple
pregnancies after in vitro fertilization treatment and cholestasis
due to oral contraceptives. Moreover, a maternal age above 35
years, a history of cholelithiasis in the mother or in her family, and
the presence of hepatitis C have been reported as risk factors in
the development of ICP17,18.
The reasons for the development of ICP are not well-known.
It is believed to be multifactorial with possible genetic, endocrine
and environmental factors playing roles in the pathogenesis. ICP
is related to a biliary transport defect in canalicular membrane and
mutations of genes coding for biliary transport proteins play an
important role in the pathogenesis. Elevation of circulating sex
hormones are also reported to cause cholestasis by lowering the
expression and/or function of canalicular transport proteins19,20.
Regional differences in the prevalence of the disease also suggest
a possible relationship with nutritional habits. On the other hand,
owing to the increased intestinal permeability in the pregnant the
absorption of bacterial endotoxins is increased which in turn
stimulates Kupffer cells to secrete proinflammatory cytokines
leading to liver damage17-21.
ICP develops in the second half of gestation and increased
serum bile acids and itching are among its typical features.
Although it is considered that itching results from accumulation of
bile acids in the skin, no correlation has been detected between
the degree of itching and serum bile acid levels. Itching develops
in 80% of pregnant women after the 30th week of gestation. It
worsens at night and causes insomnia leading to fatigue and
tiredness during the day. Jaundice develops in 10-20% of patients
1-4 weeks after itching, and mild nausea may also accompany
this. General signs of cholestasis like loss of appetite and
steatorrhea may develop and weight loss and deficiencies of fat
soluble vitamins may be encountered17-19.
In a normal pregnancy, there is a minimal increase in serum total
bile acids. However, in ICP, cholic acid (CA) and chenodeoxycholic
acid (CDCA) levels increase up to 10-100 fold. Serum alanine
aminotransferase (ALT) and aspartate aminotransferase level are
increased by 2-10 folds in 80% of ICP cases. Bilirubin is normal or
slightly increased, and does not generally exceed 5 mg/dl. γglutamyl transferase (GGT) is normal or increased 2-4 fold, and the
ABCB4 gene mutation is considered to be responsible in cases with
high GGT. Five to 10 fold increases in alkaline phosphatase (ALP) are
observed probably by contribution of placental ALP. Serum 5'nucleotidase is also increased17-19.
A diagnosis is made by excluding other liver diseases related to
gestation, chronic liver diseases and certain disorders resulting in
intra- and extrahepatic cholestasis in a pregnant woman with itching,
increased bile acids and abnormal liver function tests. A liver biopsy
is not indicated for diagnosis. Follow-up of the patient twice a week
and, if required, hospitalization is recommended. The aim is to
induce labor once the 37th week of gestation is completed.
Ursodeoxycholic acid (UDCA), rifampicin (600mg/day) and
dexamethasone (12mg/day) are used in the medical treatment.
UDCA (1g/day-15mg/kg/day) decreases itching. The CA/CDCA
ratio can be normalized by altering the composition of the bile acid
pool and this improves biochemical findings of cholestasis17-19.
The outcome of a pregnancy with ICP is benign. Itching is
usually relieved within hours after the delivery but may persist for
two days. Abnormal biochemical tests generally are normal within
2-4 weeks, but occasionally may last for 8 weeks. Among the fetal
complications are preterm delivery, intrapartum fetal distress,
meconium stained amniotic fluid and intrauterine death. Perinatal
mortality rate ranges between 3.5-11%17-19.
Preeclampsia and Eclampsia
Preeclampsia is a multi-system disease involving mainly the
urinary system, central nervous system and liver. Preeclampsia is
defined as hypertension (HT; systolic blood pressure ≥140 mm Hg or
diastolic blood pressure ≥90 mm Hg) and proteinuria (300 mg or
greater in a 24-h urine specimen) which develops at the 20th week of
gestation and/or within 48 hours postpartum and progresses to
eclampsia by the onset of epileptic seizures. Although eclampsia
typically occurs after the onset of hypertension and proteinuria, 20%
of women who develop eclampsia do not have proteinuria22,23.
Eclampsia is encountered in 5-10% of all pregnancies. Among the risk
factors for preeclampsia are maternal age (<16 years and > 45 years),
primigravidity, presence of hypertension before gestation, a multiple
pregnancy, molar pregnancy, obesity, a history of preeclampsia in
previous pregnancies and a positive family history4,10.
The placenta rather than the fetus is central to the pathogenesis
of preeclampsia owing to the observations of an increased
prevalence of preeclampsia in the setting of molar pregnancies and
the resolution of the symptoms upon placental removal at
delivery22. The pathophysiological mechanisms leading to
preeclampsia remain to be elucidated, although defective
placentation, with abnormal development of placental vasculature
and hypoxic insult are reported to be important in the early
development of the disease. Endothelial dysfunction due to
vasoconstriction, activation of the coagulation cascade, metabolic
changes and increased inflammatory response with a shift in the
balance of vasoactive mediators favoring vasoconstriction are
thought to play important roles in the pathogenesis4,10,22,23.
Histological findings of severe preeclampsia include acute atherosis
with multiple infarcts, sclerotic, narrowed arteries and arterioles,
deposition of fibrin and thrombosis. In addition, hepatic arterial
vasospasm and fibrin accumulation in portal and periportal areas
account for the development of liver damage leading to lobular
ischemia and hepatitis necrosis10.
A wide spectrum of clinical manifestations are observed during
the course of preeclampsia including hypertension and
proteinuria, persistent severe headache, visual disturbances,
hyperreflexia with brisk tendon reflexes, vomiting, epigastric pain
or tenderness, sudden onset of severe edema in the hands, face,
or feet, pulmonary edema, oliguria from acute renal failure and
grand mal seizures. The diagnosis is easy when hypertension and
proteinuria typically starts after 20 weeks of gestation. However,
the diagnosis may be difficult in atypical cases without typical
signs and up to 20% of women with atypical preeclampsia have
slight or no proteinuria. The degree of proteinuria in preeclampsia
may vary from minimal to nephrotic; however, the amount of
proteinuria does not seem to affect maternal or fetal outcomes22.
Laboratory tests reveal proteinuria, signs of microangiopathic
anemia, and hyperuricemia. Transaminases are increased by 2-5 fold
in 20-30% of patients sometimes reaching levels up to 10-20 folds.
The increase in ALP occurs due to the pregnancy. Direct bilirubin, PT
and albumin levels are generally normal, whereas indirect bilirubin is
slightly increased and does not exceed 5mg/dl4,10.
The only efficient treatment of preeclampsia is the delivery of
the child. Dietary supplementation with at least 1 g of calcium a day
reduces the relative risk of preeclampsia, with the effect observed
predominantly in high risk women and those with low dietary
calcium. Antiplatelet drugs, primarily low dose aspirin, reduce the
relative risk of preeclampsia and of stillbirth or neonatal death8,10,24.
Antihypertensive drugs such as hydralazine, labetalol and
nifedipine are used in the treatment of severe hypertension in
preeclampsia while methyldopa is recommended for mild to
moderate hypertension24,25. Prophylaxis against convulsions with
intravenous magnesium sulfate administrations should be
considered in patients with severe preeclampsia26,27.
In general, mild preeclampsia which develops after the 34th
week of gestation has better maternal and fetal outcomes, but if
the onset of the disease is before the 33rd week the outcomes are
poor. Maternal mortality is rare in developed countries, however,
mortality rates reaching up to 15-20% are recorded in developing
countries. Fetal mortality has a lower rate and occurs in 1-2% of
deliveries5,8. Among the neonatal morbidities are abruptio
placenta, preterm birth and intrauterine growth retardation, while
hypertensive crisis, renal failure, pulmonary edema and
cerebrovascular events account for maternal morbidities. Women
with preeclampsia are subject to increased risk of future
development of cardiovascular disease including hypertension,
which stresses the need for aggressive screening and
treatment5,8,10,24.
Emel Ahıshalı
61
HELLP Syndrome
This syndrome is a serious complication in pregnancy
characterized by hemolysis, elevated liver enzymes and a low
platelet count and hence the term HELLP was coined as the
acronym for these features. It has lonh been known that
preeclampsia may be associated with hemolysis, elevated liver
enzymes and thrombocytopenia. Although HELLP was first
regarded as an entity separated from severe preeclampsia, the
syndrome is currently regarded as a variant of severe preeclampsia
or a complication25-27. The HELLP syndrome is encountered in
about 0.1 to 0.9% of all pregnancies and in 10 to 20% of cases
with severe preeclampsia3,15,28. The HELLP syndrome develops
generally in the second and third trimesters. In approximately
30% of cases, the onset is in the postpartum period mostly in the
first 48 hours after delivery and sometimes this process may
extend up to the 7th day after delivery1,10. Risk factors for the
HELLP syndrome are advanced maternal age (>40), white race,
multiparity, previous histories of preeclampsia4,10.
Abnormal placental development, complement and
coagulation cascade activation, vasoconstriction, thrombocyte
aggregation, abnormal concentration of vascular growth factors
and changes in thromboxane-prostacyclin ratio have been
suggested as playing a role in the pathogenesis10.
Patients with the HELLP syndrome typically present with
right upper abdominal quadrant or epigastric pain, nausea and
vomiting. The upper abdominal pain may be fluctuating and
colic-like. A history of malaise some days before the onset of the
disease are reported by many patients. Non-specific viral
syndrome-like symptoms, headache, visual disturbances and
subtle signs of preeclampsia are also among the less common
symptoms of the syndrome25,26.
The presence of three laboratory findings, signs of hemolysis,
increased levels of serum transaminases and thrombocytopenia are
diagnostic for the complete form of the HELLP syndrome, while a
partial or incomplete syndrome presents only one or two elements
of the triad. There are two major classifications systems in the
diagnosis of the HELLP syndrome, as shown in Table II4,10,26. The
PT is normal unless albumin and direct bilirubin levels change and
disseminated intravascular coagulation (DIC) develops5,10.
During the clinical course of the HELLP syndrome, maternal
and fetal conditions deteriorate progressively and sometimes
suddenly. Therefore, prompt hospitalization and observation in a
labor and delivery unit is mandatory in patients with the
suspected diagnosis. Assessment and stabilization of the maternal
condition, particularly coagulation abnormalities are of utmost
importance and referral to a tertiary care center should be
considered in patients remote from term27.
Blood pressure control and seizure prophylaxis are important
in the treatment, but the definitive treatment is delivery.
Intravenous magnesium sulfate treatment as a prophylaxis against
convulsions should also be performed along with antihypertensive
medications as in patients with severe preeclampsia25,27. Delivery
62
Emel Ahıshalı
Table II. Classification systems in the HELLP syndrome26.
HELLP class
Tennessee Classification
Mississippi Classification
1
Platelets ≤ 100x109/L
AST ≥ 70 IU/L
LDH ≥ 600 IU/L
Platelets ≤ 50x109/L
AST or ALT ≥ 70 IU/L
LDH ≥ 600 IU/L
2
Platelets ≤ 100x109/L- ≥ 50x109/L
LDH ≥ 600 IU/L
3
Platelets ≤ 150x109/L-≥ 100x109/L
LDH ≥ 600 IU/L
AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase
Tablo III. Swansea criteria3
Six or more of the following features in the absence of another explanation:
Vomiting
Abdominal pain
Polydipsia/polyuria
Encephalopathy
Elevated bilirubin (>0.81 mg/dL)
Hypoglycaemia (<72 mg/dL)
Elevated uric acid (>5.71 mg/dL)
Leukocytosis (>11×106/L)
Ascites or bright liver on ultrasound scan
Elevated transaminases (>42 IU/L)
Elevated ammonia (>47 µmol/L)
Renal impairment (creatinine>1.69 mg/dL)
Coagulopathy (prothrombin time>14 s or activated partial
thromboplastin time>34 s)
Microvesicular steatosis on liver biopsy
should be performed if gestation is >34 week in the presence of
severe complications or if these are any signs of multiorgan
dysfunction. If gestation is between 27-34th weeks, delivery may
be postponed for 24-48 hours by administering corticosteroids for
pulmonary maturation5,10,25,27. Postpartum management
including anti-seizure prophylaxis is almost identical to that
performed before the delivery. In this period a more aggressive
antihypertensive approach may be appropriate in the absence of
the risk of the compromising the uteroplacental circulation25.
Maternal and perinatal mortality rates are reported to be
1-3.5% and 7-22%, respectively, although markedly higher
maternal mortality rates (24%) and perinatal mortality rates (34%)
are also recorded3. Among the maternal complications are DIC
(21%), abruptio placenta (16%), acute renal failure (7.7%),
pulmonary edema (6%), subcapsular hematoma in the liver (0.9%)
and retinal detachment (0.9%). Prematurity or intrauterine growth
retardation is observed in 33% of pregnancies3,10,11.
Acute Fatty Liver of Pregnancy
Acute fatty liver of pregnancy (AFLP) rarely occurs in the third
trimester of gestation with an incidence of 1/10000-1/15000, but
causes high maternal and fetal mortality rates. AFLP is seen in pregnant
women of all ages and ethnic backgrounds and geographical area does
not seem to affect the prevalence of the disease. It can be encountered
in primiparous and multiparous pregnant women, particularly those
with a preeclampsia history8,10,11.
Mitochondrial dysfunction, particularly deficiencies of fatty
acid beta oxidation enzymes in fetal liver are suspected to play a
role in the pathogenesis. The most frequently deficient enzyme in
this disorder is the long-chain 3-hydroxyacyl-CoA dehydrogenase
(LCHAD)1,5,10. LCHAD is a component of the enzyme complex
known as mitochondrial trifunctional protein (MTP). G1528C and
E474Q mutations of MTP are known to cause LCHAD
deficiencies28. In the fetuses that are homozygous for these
mutations, fetal fatty acids accumulate and eventually pass into
the maternal circulation of the heterozygous mother. Long chain
fatty acids from the fetus and the subsequently produced
triglycerides can cause overloading of the fat stores and functional
deterioration in the maternal liver5,8,10,28. The onset of AFLP is
generally between 30th and 38th weeks of gestation. The most
commonly encountered symptoms are loss of appetite, nausea,
vomiting and right upper quadrant pain, and in advanced phases
acute liver insufficiency signs may develop. Approximately 50% of
patients present clinical signs of preeclampsia10.
Laboratory findings include a moderate increase in serum
transaminases, particularly ALT, however, severely elevated serum
transaminases may also be encountered. Total bilirubin is generally
mildly increased (<5 mg/dl), and hypoglycemia develops
approximately in 40% of the patients5. Plasma ammonium levels
may also increase. Laboratory findings of normocytic anemia,
coagulopathy in the presence or absence of DIC and acute renal
failure along with mild leukocytosis, normal platelet counts or
thrombocytopenia, hypoalbuminemia and increased amylase and
lipase levels may also be seen10,29-31.
Ultrasound and computerized tomography are the most
common non-invasive methods used in the early diagnosis of AFLP.
Emel Ahıshalı
Ultrasound is the diagnostic tool of choice in liver screening owing
to its convenience and safety. Although liver biopsy is considered as
the gold standard for confirming a diagnosis of fatty liver, its clinical
use should be avoided in cases complicated by DIC30. The presence
of more than 5 Swansea criteria represents a validated method for
supporting the clinical diagnosis of AFLP (Table III)3.
Diagnosis and treatment of AFLP is a medical and
gynecological emergency. Terminating the pregnancy with
appropriate timing is the main target of the treatment30. Early
diagnosis and treatment of AFLP decrease maternal and fetal
mortality and morbidities. Pregnancy should be monitored under
intensive care conditions from the time of diagnosis. Increased
transaminases and encephalopathy recover generally in 72 hours
after the delivery; this interval may be elongated up to 1-4 weeks.
Rarely liver transplantation is required as a result of acute liver
failure1,5,10. Artificial liver support systems, such as the molecular
absorbents recirculating system and plasma exchange may also
be used in cases of acute liver failure30.
Maternal and fetal mortality ranges between 3-12% and 1566%, respectively. Cardiomyopathy, hypoglycemia, sudden death
and rarely liver failure may develop in the newborn with LCHAD
deficiency. Myopathy, neuropathy, retinopathy and cardiac
arrhythmias can also be seen as late complications. If the mother
carries the LCHAD mutation, the probability of AFLP recurrence is
20-70%. Therefore, the subsequent pregnancies are recommended
to be followed up at a tertiary healthcare service unit5,10,29.
Clinical findings of AFLP are generally alleviated after delivery
and the pathological alterations recover within months. Close
monitoring and supportive treatment are also essential after
delivery. Potentially hepatotoxic drugs such as contraceptives
should be avoided. The prognosis is mostly good following active
treatment30.
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64
Özgün Araştırma / Original Article
DOI: 10.5472/MMJ.2012.02176.1
Şizofreni Hastalarında Oksidatif Stres ve Serbest Radikal
Hasarının Göstergesi Olarak İdrarda Malondialdehit Ölçümü
Measurement of Urinary Malondialdehyde Levels as an Indicator of Oxidative Stress
and Free Radical Injury in Schizophrenic Patients
Bahadır EKER1, Memduha AYDIN2, M. Kemal KUŞCU2, Mehmet Z. SUNGUR2, A. Suha YALÇIN1
1Tıbbi Biyokimya Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, İstanbul, Türkiye
2Psikiyatri Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, İstanbul, Türkiye
Özet
Abstract
Amaç: Oksidatif stres ile antioksidan savunma mekanizmaları arasındaki
denge ve bu dengenin bozulmasının birçok hastalığın gelişimi ve
prognozunda önemli bir rolü olduğu düşüncesi gün geçtikçe daha fazla
kabul görmektedir. Bu çalışmada, yaşadıkları yüksek stresin getirdiği
oksidatif hasar baz alınarak şizofreni hastaları üzerinden bu hasara bağlı
olarak açığa çıkan diğer oksidatif stres belirteçleri ile idrar malondialdehit
ölçümlerinin karşılaştırılması ve korelasyonunun araştırılması amaçlanmıştır.
Hastalar ve Yöntem: Çalışmaya Marmara Üniversitesi Hastanesi Psikiyatri
polikliniğine başvuran 20 şizofreni hastası ve 21 sağlıklı kontrol alınmış,
hastalardan ve kontrol grubundan alınan kan ve idrar örneklerinde oksidatif
stres parametreleri incelenmiştir.
Bulgular: Bulgularımız, oksidatif stres ile ilgili parametrelerden yükseltgenmiş
glutatyon, plazma lipid peroksidasyonu ve idrar malondialdehit düzeylerinin
şizofreni hastalarında kontrollere göre daha yüksek olduğunu, ayrıca özellikle
hasta grubunda idrar ve plazma malondialdehit düzeylerinin belirgin
derecede uyumlu olduğunu göstermiştir.
Sonuç: Çalışmamız daha fazla sayıda katılımcı ile yapılacak araştırmalar ile
desteklendiği takdirde, idrar malondialdehit ölçümünün kolay uygulanabilir ve
ucuz bir oksidatif hasar tarama belirteci olarak kullanılabileceğini ve yapılacak
taramalar sayesinde bazı hastalıkların önlemesine ve/veya yeni farmakolojik
ajanların geliştirilebilmesine katkı sağlayabileceğini düşündürmektedir.
Anahtar Kelimeler: Şizofreni, Malondialdehit, Oksidatif stres, İdrar
Objective: The idea that oxidative stress has a significant role in
development and prognosis of many diseases is being more widely
accepted by the authorities. This study aims to examine urinary
malondialdehyde assays and their concordance with other oxidative stress
biomarkers in schizophrenic patients who have a highly stressful life due to
their illness.
Patients and Methods: Participants were 20 schizophrenic patients who
were being followed by Marmara University Medical School Hospital
outpatient clinic and 21 healthy controls. Blood and urine samples were
examined for oxidative stress parameters.
Results: Our results indicate that oxidized glutathione and plasma and urine
malondialdehyde levels of patients were higher than those of control group.
Urinary and plasma malondialdehyde levels showed a significant correlation
especially in the patient group.
Conclusions: If the study is supported by additional studies and repeated
with higher sample sizes the urinary malondialdehyde assay which is an
easy and cheap method, may be used as an oxidative screening test and
thus may prove to be useful for preventing oxidative stress dependent
diseases and developing new pharmacological agents. (Marmara Medical
Journal 2012;25:64-8)
Key Words: Schizophrenia, Malondialdehyde, Oxidative stress, Urine
Giriş
Oksidatif stres, oksidasyon ile antioksidan savunma sistemi
arasındaki dengenin oksidasyon lehine bozulmasıdır. Çoğunlukla
artmış serbest radikal üretiminin sonucu olarak gelişir. Bunun
yanında antioksidan savunma sisteminin zayıflaması veya her iki
durumun ortaklaşa etkisiyle de oluşabilir1. Oksidatif stres, hücresel
toksisiteye yol açan bir dizi patofizyolojik sürecin tetiklenmesine
İletişim/Correspondence to: Prof. Dr. A Suha Yalçın, Tıbbi Biyokimya Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, Haydarpaşa, İstanbul, Türkiye.
Eker ve ark.
Şizofrenide Oksidatif Stres
sebep olur. Serbest radikaller kısa ömürlü, reaktif moleküller olup,
normal metabolik süreçler ve/veya çeşitli dış faktörlerin etkisiyle
oluşurlar. Serbest radikaller organizma için fagositozda rol almak
gibi faydalı işlevleri yanında, aşırı miktarda bulunduklarında lipitler
ve glikoproteinler gibi hücresel yapılar üzerine toksik etkiler
oluştururlar2,3. Lipitler bu hasara en duyarlı olan ve üzerinde şu
ana dek en çok çalışılan bileşiklerdir4-6. Poliansature yağ asitlerinin
çift bağları ile reaksiyona giren bu zararlı reaktifler lipit
hidroperoksitlerinin oluşmasına yol açarlar7. Poliansature yağ
asitlerinin temel sekonder oksidasyon ürünü olması ve serbest
radikal hasarıyla ilişkisi olduğu düşünülen pek çok hastalıkta
seviyelerinin yükseldiği bilindiğinden, malondialdehit en sık
kullanılan oksidatif hasar belirtecidir8,9.
Beyin dokusu, çeşitli nedenlerle (yüksek oksijen tüketimi, hızla
peroksitlenebilen fosfolipitlerin fazla miktarda bulunması ve
nöronların yenilenememesi gibi) serbest radikal hasarına özellikle
duyarlıdır. Ayrıca, katekolamin metabolizması vücutta serbest
radikal üreten başlıca kaynaklardandır. Artmış katekolamin
metabolizması ile birlikte olan durumlarda serbest radikal hasarının
fazla olduğu bilinmektedir. Bu durum, şizofreni etyolojisinde en
önemli hipotezlerden biri olan dopamin hipotezi ile beraber
değerlendirildiğinde çok anlam kazanan bir patofizyolojidir10-12.
Çalışmamızın amacı, oksidatif stresin bir göstergesi olarak
idrarda malondialdehit ölçümünü gerçekleştirmek ve bu yöntemin
diğer oksidan parametrelerle ve özellikle en sık kullanılan plazma
malondialdehit ölçümü ile korelasyonunu şizofreni hastaları
üzerinden değerlendirmektir.
Hastalar ve Yöntem
65
Eritrosit Glutatyon (GSH) ve Yükseltgenmiş
Glutatyon (GSSG) Düzeyleri
Ölçümler glutatyonun sülfhidril grubu ile 5,5’-ditiyobis (2nitrobenzoik asit) reaksiyonu sonrasında oluşan ürünün
konsantrasyonunun spektrofotometrik olarak tayini şeklinde
gerçekleştirildi. Oluşan sarı renkteki ürünün 412 nm’deki
ekstinksiyon katsayısı (13,600 M-1cm-1) kullanılarak hesaplandı ve
sonuçlar μmol glutatyon / g Hb olarak ifade edildi. Eritrosit
yükseltgenmiş glutatyon (GSSG) düzeyleri serbest tiol gruplarının
floresans veren o-phtaldialdehyde ile oluşturduğu kompleksin
yaydığı floresansın 350 nm dalga boyunda eksitasyon ve 420 nm
dalga boyunda emisyon olarak ölçülmesi prensibi ile tayin edildi ve
sonuçlar µmol GSSG / g Hb olarak ifade edildi13.
Plazma Glutatyon Transferaz Aktivitesi
Glutatyon transferaz 1-kloro-2,4-dinitrobenzen (CDNB) ile
glutatyon arasındaki konjugasyonu katalizler. Enzim aktivitesi her iki
substratın son konsantrasyonları 1 mM olacak şekilde hazırlanan
inkübasyon karışımına eklenen plazma örneklerinde ölçüldü14.
Hesaplamada glutatyon ve CDNB konjugasyonu sonucu oluşan
ürün için saptanmış olan ekstinksiyon katsayısı (ε=9,6 mM-1.cm-1)
kullanıldı. Enzimsel konjugasyondan kör değeri çıkarıldı ve sonuçlar
nmol ürün/dakika/ml plazma olarak ifade edildi.
Eritrosit Katalaz Aktivitesi
Katalaz hidrojen peroksitin su ve moleküler oksijene yıkımını
katalizler. Enzim aktivitesi hidrojen peroksitin ışığı absorbe
etmesinden yararlanılarak 230 nm’deki yıkım hızının
spektrofotometrik olarak takibi yoluyla ölçüldü15. Hesap için
hidrojen peroksitin ekstinksiyon katsayısı (e=0,071 mM-1cm-1)
kullanıldı, sonuçlar U/g Hb olarak belirtildi.
Plazma Eritrosit ve İdrar Malondialdehit (MDA) Düzeyleri
Marmara Üniversitesi Hastanesi Psikiyatri polikliniğine
başvuran ve Amerikan Psikiyatri Derneği'nin Mental Bozuklukların
Tanısal ve Sayımsal (DSM-IV) Tanı Ölçütleri Elkitabı'na göre
şizofreni tanısı konulan 20 hasta çalışmaya alınmıştır. Kontrol
grubu, yaş ve cinsiyet yönlerinden araştırma grubuyla eşleşen,
hiçbir psikiyatrik bozukluk tanısı almamış ve birinci derece
akrabaları arasında şizofreni tanısı almış kimse olmayan 21 sağlıklı
kişidir. Araştırma grubu ile kontrol grubuna ait sosyodemografik
bilgiler Tablo I’de verilmiştir.
Çalışmaya Alınma Kriterleri: Amerikan Psikiyatri Derneği’nin
Derneği'nin DSM-IV Tanı Ölçütleri Elkitabı'na göre “Şizofreni”
tanısı alınması, 18-45 yaş arasında olmak, kendisi ve en az bir
yakınından bilgilendirilmiş onam alınması.
Çalışmadan Dışlama Kriterleri: Ciddi bir dahili ya da nörolojik
hastalığa (kanser, hipertansiyon, hiper-hipolipidemi, kronik böbrek
yetmezliği, diabet, epilepsi, serebro-vasküler olay, kafa travması
öyküsü) sahip olmak, gebe ya da post-partum dönemde olmak.
Çalışmamız Marmara Üniversitesi Tıp Fakültesi Araştırma Etik
Kurulu tarafından onaylanmış olup çalışmaya katılan kişilerden
aydınlatılmış onam formu alınmıştır. Hem araştırma grubu
hastalarından hem de kontrol grubundaki sağlıklı bireylerden
sabah 07.00-10.00 arasında kan ve idrar örnekleri alınmış, alınan
örneklerde aşağıdaki incelemeler yapılmıştır.
Plazmada lipit peroksidasyonu ürünleri ile tiyobarbitürik asit
(TBA) arasındaki reaksiyon sonucu oluşan kırmızı renk
spektrofotometrik olarak ölçüldü16. TBA ile reaksiyona girerek aynı
rengi veren suda çözünür maddelerin ortamdan uzaklaştırılması
için, serum lipitleri proteinlerle birlikte fosfotungstik asit/sülfürik asit
ile çöktürüldü. Sonuçlar nmol MDA/mL plazma olarak ifade edildi.
Eritrosit lipit peroksidasyonu için, hidrojen peroksit ile eksojen
oksidatif baskı altında tutulan eritrositlerde zar lipitlerinin yıkım
ürünü olan MDA ve TBA ile inkübasyonu sonucu oluşan pembe
Tablo I. Hasta grubuna ve sağlıklı kontrol grubuna ait demografik bilgiler
Yaş (Ortalama ± Standart sapma)
Kadın
Erkek
Bekar
Evli
İlkokul ve ortaokul
Lise ve üzeri
Çalışan
Çalışmayan
Hasta Grubu
Sağlıklı Kontrol
31,15±0,03
11
9
20
5
15
4
16
31,26±6,05
12
9
11
10
1
20
15
6
66
Eker ve ark.
renkli kompleksin 532 nm’de verdiği absorbans ölçüldü. Sonuçlar
nmol MDA/g Hb olarak ifade edildi17. İdrarda da TBA reaksiyonu
sonucu oluşan renkli ürünün absorbans ölçümü yapıldı. Sonuçlar
MDA için çizilen standart grafiğinden yararlanılarak hesaplandı18.
Verilerin Değerlendirilmesi ve İstatistiksel Analiz
Elde edilen veriler SPSS (Statistical Program for Social Sciences) for
Windows 15,0 istatistik paket programıyla analiz edilmiştir. Tek
değişkenli analizlerde, kategorik değişkenlerin (örnek, demografiklerin)
karşılaştırılmasında Ki-Kare, sürekli değişkenlerin (örnek, ölçek
puanların) incelenmesinde ise t-test ve Pearson Korelasyon testi
kullanılmıştır. Sürekli değişkenlerin karşılaştırılmasında dağılımına
Kolmogorov- Smirnov Testi ile bakılmıştır. Normal dağılım
göstermeyen değişkenlerin gruplar arası karşılaştırılmasında MannWhitney U testi kullanılmıştır. Çok değişkenli analizde lojistik regresyon
kullanılmıştır. Anlamlılık düzeyi 0,05 olarak alınmıştır. Tüm analizler ikikuyrukludur.
Bulgular
Şizofreni hastalarının klinik bilgileri aşağıda verilmiştir. Hastalar
ortalama 11,70±5,34 yıl önce şizofreni teşhisi almış ve ortalama
7,62±3,55 yıldır ilaç kullanmaktadır. On iki hastada (%60) ailede
şizofreni hikayesi vardır. On hastada (%50) ciddi yaşam olayı
(sevilen bir kişinin hastalığı, sevilen bir kişinin ölümü, ilişkisel
sorunlar ve ayrılıklar) tespit edilmiştir. Cinsiyet, eğitim düzeyi ve
yaş açısından araştırma grubu ve kontrol grubu arasında istatistiksel
olarak anlamlı fark yoktur. Medeni hal açısından iki grup arasında
(Ki-kare=14,16, p<0,05) istatistiksel olarak anlamlı fark vardır.
Araştırma grubunda daha önce evlenmiş veya evli olan yoktur ve
bekâr sayısı (n=20) kontrol grubundan (n=11) daha fazladır.
Çalışma durumu açısından, gruplar arasında istatistiksel olarak
anlamlı fark vardır (Ki-kare=17,79, p<0,01). Kontrol grubuna göre
(n=18) daha az sayıda hasta (n=4) halen çalışmaktadır.
anlamlılık düzeyinde gruplar arası fark olmadığından VKİ’e bağlı
oksidatif stres farklılıkları elimine edilmiştir. Şizofreni hastaları ve
kontrol grubu arasında GSSG (µmol/g Hb) açısından istatistiksel
anlamlılık düzeyinde farklılık vardır (t=2,46, p<0,05). Şizofreni
grubunun GSSG düzeyi (0,23±0,15 µmol/g Hb), kontrol grubuna
(0,13±0,10 mmol/g Hb) göre daha yüksektir. Benzer şekilde idrar
MDA (mM) düzeyleri açısından da istatistiksel anlamlılık düzeyinde
gruplar arası farklılık vardır (t=2,66, p<0,05). Hasta grubu
(1,52±1,48 mM), kontrol grubuna göre (0,63 ± 0,35 mM), daha
yüksek düzeyde idrar MDA düzeyine sahiptir. Plazma açısından da
şizofreni grubu istatistiksel anlamlılık düzeyinde daha yüksek
ortalama sırasına sahiptir (U=102,00, p<0,01). İdrar ve eritrosit
MDA değerleri hasta, kontrol ve tüm veriler için korelasyon
açısından karşılaştırıldığında, kontrol grubu dışında korelasyon
belirlenmedi (r=0,512 p<0,05). Hasta grubu plazma lipit
peroksidasyonu MDA değerleri ile idrar lipit peroksidasyonu MDA
değerleri arasında istatistiksel olarak anlamlı kuvvetli bir korelasyon
(r=0,844 p<0,001) olduğu belirlendi (Şekil 1). İdrar ve plazma
MDA değerleri kontrol ve tüm veriler açısından da korele bulundu
(sırasıyla r=0,657 p<0,001, r=0,795 p<0,01).
Tartışma
Serbest radikaller son derece reaktif ve kısa ömürlü bileşiklerdir.
Bu yüzden doğrudan ölçümleri zordur ve genellikle lipitler,
proteinler ve DNA ile reaksiyonları sonucu oluşan çeşitli son
ürünlerin ölçümü gibi dolaylı metotlar kullanılır. Bunlardan en
yaygın olarak kullanılan, lipit peroksidasyonunun son ürünlerinden
malondialdehitin ölçümüdür. Protein hasarı, DNA hasarı ve
antioksidan seviyelerinin tayini (örn. glutatyon peroksidaz, katalaz
ve süperoksit dismütaz düzeylerinin ölçülmesi) de en çok
kullanılan yöntemlerdendir9. Çalışmamızda, serbest radikal
hasarının göstergesi olarak idrarda malondialdehit ölçümünün
Oksidatif Stres Göstergeleri ile Hasta Demografik
Bilgileri ve Hastalık Gösterge İlişkileri
Araştırma Grubu ile Kontrol Grubunun Oksidatif
Stres Göstergelerinin Karşılaştırılması
Şizofreni hastaları, oksidatif stres göstergeleri ve vücut kitle
indeksi (VKİ) açısından kontrol grubu ile karşılaştırıldığında
Kolmogorov-Smirnov Testi’ne göre RBC-LP ve plazma-LP dışındaki
değişkenler normal dağılım göstermektedir. VKİ’e göre istatistiksel
6,00
Hasta Grubu
5,00
4,00
İdrar MDA
Hasta grubunun oksidatif stres göstergeleri ile hastalık
değişkenleri arasındaki ilişkiye bakıldığında, cinsiyet açısından
oksidatif stres parametreleri yönünden istatistiksel anlamlılık
düzeyinde fark bulunmamıştır. Önemli yaşam olayları bildiren
hastaların diğer hastalara göre daha yüksek GSSG ve plazma lipid
peroksidasyon (LP) düzeyleri vardır, sırasıyla U=19,50, z=2,28,
p<0,05, ve U=18,00, z =2,15, p<0,05. Aile öyküsünde psikoz
bulunan hastaların da GSH düzeyleri, 13,00 (126,00), istatistiksel
anlamlılık düzeyinde aile öyküsü olmayan hastalara, 6,75 (54,00),
göre daha yüksektir, sırasıyla U=18,00, z=2,32, p<0,05. İlaç
kullanım süresi ile GSH ve plazma LP arasında istatistiksel anlamlılık
düzeyinde pozitif korelasyon vardır, sırasıyla r=0,60, p<0,01 ve
r=0,55, p<0,05.
3,00
2,00
1,00
0,00
R Sq Linear = 0,712
0,00
2,00
4,00
6,00
Plazma-LP
8,00
10,00
12,00
Şekil 1. Hasta grubu idrar MDA değerleri ile plazma lipid peroksidasyon
(LP) MDA değerlerinin karşılaştırılması (Pearson Correlation, 2-tailed:
r=0,844 r2=0,712 p<0,001)
Eker ve ark.
diğer parametrelerle korelasyonunu ve şizofreni hastalığı ile
oksidatif stres ilişkisini araştırdık.
Şizofreninin de dahil olduğu birçok hastalıkta oksidatif stres
konusu bilimsel çalışmalar arasındaki güncelliğini korumaya
devam etmektedir. Şizofreni hastalarında yapılan oksidatif stres
çalışmaları oksidan ve antioksidan sistemler arasında bir
dengesizlik olduğunu ortaya koymuştur19,20. Çalışmamızda,
araştırma grubu ile kontrol grubu demografik özellikleri ve oksidatif
stres göstergeleri açısından karşılaştırıldığında, iki grup arasında
demografik değişkenler açısından anlamlı farklılık bulunmamıştır.
Hastaların oksidatif stres değişkenleri ile klinik göstergelerinin
ilişkisi incelendiğinde, çok önemli yaşam olayı bildiren hastaların
GSSG ve plazma MDA düzeylerinin çok önemli yaşam olayı
olmayan hastalara göre daha yüksek olduğu bulunmuştur. Bu
bulgular, stresli yaşam olaylarının fiziksel ve ruhsal sağlığı etkilediği
yönündeki bulgularla, özellikle de biyolojik stres göstergelerini
olumsuz etkilediğini gösteren çalışmalarla örtüşmektedir20,21.
Uzun süreli stresin biyolojik sistemlerde kalıcı hasarlara yol
açabildiği, özellikle de bağışıklığı düşürebildiği birçok araştırıcı
tarafından ileri sürülmektedir22-24. Bu çalışmada GSSG, idrar MDA
ve plazma MDA değerlerinin şizofreni hastaları ve sağlıklı kontroller
arasında farklılık gösterdiği belirlenmiştir. Hasta grubunda kontrol
grubuna göre daha yüksek tespit edilen bu parametreler
literatürdeki bulgularla uyumludur ve hasta grubunun oksidatif
stres altında olduğunu göstermektedir. Eritrosit MDA düzeyleri,
şizofreni grubunda kontrol grubuna göre daha yüksek
bulunmuştur, ancak farkın istatistiksel olarak anlamlı olmadığı
görülmüştür. Bu örneklem sayısının sınırlı olmasına bağlı olabilir.
Çalışmamızda idrar MDA düzeyine de bakılmıştır. İdrar MDA
düzeyi, plazma MDA düzeyinin bir izdüşümü olarak
görülmektedir25-28. Oksidatif stres üzerine etkili olabilecek,
hastalığa ait olan ve olmayan diğer faktörler (örn. ilaç kullanımı,
yaş, cinsiyet, sigara, beslenme alışkanlıkları gibi) de göz önünde
bulundurulmalıdır29. Bu faktörler arasında ilaç kullanımı önemli bir
yer tutar. Bu konuda yapılmış olan çalışmaların sonuçları ilaç
kullanımının, ilacın türünden bağımsız olarak oksidatif stresi
arttıran bir faktör olduğunu, ilacın tipik ya da atipik olmasının
anlamlı bir farklılık yaratmadığını, antipsikotik ilaç dozunun
artmasıyla antioksidan potansiyelin düştüğünü ve oksidatif stresin
arttığını göstermektedir30. Antipsikotik ilaçlar genel olarak oksidan
özellikleri antioksidan özelliklerinden daha fazla olan
moleküllerdir31,32. Çalışmamızda, diğer bazı çalışmalarla paralel
şekilde, ilaç kullanım süresi ile hem GSH hem de plazma MDA
düzeyleri arasında anlamlı pozitif korelasyon saptanmıştır33,34.
Oksidatif stres düzeyine etkili olabilecek bir diğer faktör de
cinsiyet farklılıklarıdır. Birçok çalışma erkeklerin daha yüksek
antioksidan savunma sistemine sahip olduğunu göstermektedir.
Erkekler lehine olan bu fark, araştırmaların genelinde hastalık
durumunda da kendini göstermektedir. Bu çalışmada, önceki birkaç
araştırmaya benzer şekilde, hasta grubunda antioksidan düzeyleri
bakımından cinsiyetler arası fark gözlenmemiştir. Bu sonuç,
hastalığın cinsiyetleri antioksidan açısından birbirine yaklaştırdığı,
kadınların hastalığa karşı antioksidan sistem cevabının daha yüksek
olduğu şeklinde yorumlanabilir25,35,36. Ancak oksidatif stres
düzeyine bireysel ve çevresel birçok faktörün birlikte etki ettiği ve bu
67
yüzden herhangi birinin etkisinin çok net olmadığı akılda
tutulmalıdır9. Bu konuda daha net bilgiler edinilebilmesi için, mesela
ilaç faktörü ile ilgili olarak, hiç tedavisiz hastaların atipik ve tipik
antipsikotiklerle uzun dönemli tedavilerini içeren, prospektif ve
örneklem sayısının fazla olduğu çalışmalara ihtiyaç vardır.
Çalışmamızın kısıtlılığı örneklem sayısının düşük olmasıdır.
Düşük örneklem sayısı istatistiksel sonuçların gücünü ve
güvenirliğini düşürmektedir. Serbest radikal hasarı, birçok hastalığın
etiyolojisi ve prognozu açısından üzerinde önemle durulan bir
kavramdır. Lipitler bu hasara en duyarlı olan ve üzerinde şu ana dek
en çok çalışma yapılan bileşiklerdir. Poliansature yağ asitlerinin çift
bağları ile reaksiyona giren bu zararlı reaktifler lipit
hidroperoksitlerinin oluşmasına yol açarlar. Malondialdehit,
poliansatüre yağ asitlerinin temel sekonder oksidasyon ürünü
olması ve serbest radikal hasarıyla ilişkisi olduğu düşünülen pek çok
hastalıkta seviyelerinin yükselmesi nedeniyle yaygın olarak kullanılan
bir oksidatif hasar belirtecidir8. Çalışmamızda, idrar MDA düzeyleri
ile plazma MDA düzeyleri arasında önceki çalışmalarda37,38 da ileri
sürüldüğü gibi anlamlı bir korelasyon olduğu gözlenmiştir.
Kolay, etkin ve ucuz oksidatif hasar belirteçleri bulunması hem
bu hastalıkların kötüleşme yatkınlığını belirleyen faktörlerin
aydınlatılması, hem de bu yatkınlığa yönelik koruyucu
müdahalelerin oluşturulabilmesi açısından çok önemlidir. Şizofreni
hastalarında antioksidan desteğinin pozitif ve negatif semptomları
gerilettiğini bildiren çalışmalar vardır39. Bu yönde elde edilecek
bulgular koruyucu hekimlik uygulamalarının da gelişmesine katkı
sağlayacaktır. Erken ve uygun müdahalelerle şizofreni gibi birçok
hastalığın önlenmesi ve daha iyi prognoz ile seyretmesinin önemi
tartışılmazdır40. Elde edilen bulgular, ileri ve daha geniş katılımlı
çalışmalar ile desteklendiği takdirde, idrarda MDA ölçümü rutin
klinik laboratuvar uygulamalarında ucuz, kolay uygulanabilir ve
güvenilir bir tarama yöntemi olarak kullanım alanı bulabilir.
Teşekkür
Bu araştırma Marmara Üniversitesi Bilimsel Araştırma Projeleri
Birimi tarafından desteklenmiş (SAG-C-TUP-040609-0162 ve SAGC-TUP-090909-0284) ve Marmara Üniversitesi Tıp Fakültesi
Araştırma Etik Kurulu tarafından onaylanmıştır (Karar tarihi ve
sayısı: 10.10.2008-716).
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69
Original Article / Özgün Araştırma
DOI: 10.5472/MMJ.2012.02201.1
Does the FSH/LH Ratio in the Serum on the Third Day of the
Cycle Predict ICSI Success?
Siklusun 3.Günü Normal FSH Değeri Olan Kadınlarda FSH/LH Oranı ICSI Başarısını
Öngörebilir mi?
Tevfik YOLDEMİR, Mithat ERENUS
Department of Obstetrics and Gynecology, School of Medicine, Marmara University, İstanbul, Turkey
Abstract
Özet
Objective: To determine whether the follicule stimulating hormone (FSH)/
luteinizing hormone (LH) ratios on the third day of the cycle predict intracytoplasmic sperm injection (ICSI) outcomes in women with normal day 3 FSH
levels.
Patients and Methods: A retrospective cohort analysis of one hundred and
ninety-nine consecutive women undergoing ICSI treatment with long-down
regulation and recombinant follicular stimulating hormone injections was
carried out in a University hospital. Four groups were compared in terms of in
vitro fertilization (IVF) outcomes. Groups A, B, C and D consisted of women with
FSH/LH ratios of <1; ≥1 and <1.5; ≥1.5 and ≤2 and >2, respectively. The clinical
pregnancy and implantation rates per transfer were compared.
Results: There was no significant difference between the groups regarding the
clinical pregnancy or implantation rates per transfer.
Conclusion: It appears that the basal FSH/LH ratio does not predict the cycle
outcome in ICSI cycles in women with normal day 3 FSH levels. (Marmara
Medical Journal 2012;25:69-73)
Key Words: FSH/LH ratio, Pregnancy, ICSI, Cancellation
Amaç: Siklusun 3.günü normal FSH değeri olan kadınlarda follikül stimule
edici hormon (FSH)/luteinize edici hormon (LH) oranının sitoplazma içi
sperm enjeksiyonu (ICSI) başarısının öngörülebilirliğini araştırmak.
Hastalar ve Yöntem: Uzun protokol ve rekombinant folikül stimüle edici
hormon kullanılarak ICSI tedavisi alan ardışık yüz doksan dokuz infertil kadın
retrospektif olarak analiz edildi. Grup A, B, C ve D sırasıyla FSH/LH oranları
<1; ≥1 ile <1.5 arası; ≥1.5 ile ≤2 arası ve >2 olan kadınlardan oluşturuldu.
Transfer başına klinik gebelik ve implantasyon oranları karşılaştırıldı.
Bulgular: Transfer başına klinik gebelik ve implantasyon oranları gruplar arasında
benzer idi.
Sonuç: Siklusun 3.günü FSH/LH oranı ICSI sikluslarında tedavi sonuçlarını
normal 3. gün FSH seviyesi olan kadınlarda öngöremez. (Marmara
Üniversitesi Tıp Fakültesi Dergisi 2012;25:69-73)
Anahtar Kelimeler: FSH/LH oranı, Gebelik, ICSI, İptal
Introduction
In vitro fertilization (IVF) is a stressful and expensive procedure
for patients who are hoping to get pregnant. Markers of ovarian
reserve were investigated in order to help predict a patient’s
prognosis, including the likelihood of cycle cancellation, the
required dose of medication, number of oocytes and embryos
generated, as well as the prognosis for pregnancy. Ovarian reserve
has been used to predict prognosis in IVF treatments1. Clinical
markers of ovarian reserve include basal (day 3) levels of FSH,
inhibin, and anti-mullerian hormone; antral follicle counts (AFC) and
ovarian volumes2. The day 3 FSH level which is the most widely
used clinical parameter has a limited3 or lower predictive value4.
Women with normal FSH levels on cycle day 3 can require higher
Correspondence to/İletişim: Tevfik Yoldemir, M.D., Department of Obstetrics and Gynecology, School of Medicine, Marmara University, İstanbul, Turkey.
70
Yoldemir et al.
The Predictivity of FSH/LH Ratio on ICSI Success
than average doses of medication where disappointing cycle
outcomes can be expected . Better markers of poor prognosis are
needed to identify these patients, to aid in planning their IVF cycles,
and to counsel them as to the likelihood of success.
Poor ovarian responsiveness and low pregnancy rates (i.e.
diminished ovarian reserve) can be predicted in patients
undergoing one of the assisted reproduction treatments1 on the
basis of several parameters, including: elevated day 3 FSH values5,
abnormal clomiphene citrate challenge tests6, abnormal GnRHagonist stimulation tests7, abnormal exogenous FSH ovarian
reserve tests8 or elevated day 3 oestradiol concentrations9 A
number of hormonal parameters are currently thought to be
predictive of poor ovarian responsiveness to stimulation and low
pregnancy rates in patients undergoing one of the assisted
reproduction treatments1. None of these tests, however, was
found to be sufficiently accurate for predicting the ovarian
response3,4.
The objective of our study was to evaluate whether the
FSH/LH ratio on cycle day 3 can be used to predict the ICSI-cycle
outcome in women with normal day 3 FSH values.
Patients and Methods
One hundred and ninety-nine women undergoing
consecutive IVF treatments at the Assisted Reproductive
Techniques (ART) Unit at Marmara University Hospital in Istanbul,
Turkey, were recruited in a retrospective cohort study. Exclusion
criteria were: age over 39 years, cycle day 3 FSH level >12 IU/L,
endometriosis (other than minimal); the presence of only one
ovary or previous ovarian surgery; polycystic ovary syndrome or
other endocrine disorders. In our ART unit, a detailed explanation,
both verbal and written, is given to each infertile couple prior to
ART treatments. Patients gave written consent to publication of
any study derived from aggregate data. Ethical approval for this
study was not required and has not been included as there were
no interventions that are not a part of standard care. All practices
and protocols conformed to the ethical requirements for assisted
reproductive technology programs of the Ethics Commitee of
Marmara Medical School and it conforms to the provisions of the
Declaration of Helsinki.
All patients undergoing ART treatment in our institution do
receive intracytoplasmic sperm injection (ICSI) no matter what the
cause of infertility is. Patients were seen on day 3 of the cycle
before their stimulation. On that day, serum samples were
collected in the morning after a 12 h fasting. 5 ml of venous blood
was collected. All patients underwent a transvaginal ultrasound
documenting antral follicule count (AFC) by one examiner. All
measurements were performed on one ultrasound machine
(General Electric Loqic 200, 8-4 MHz, Istanbul, Turkey). AFCs
measured all follicles between 2 and 8 mm on each ovary12.
Subjects commenced down-regulation with a daily subcutenous
injection of leuprolide acetate (1 mg/mL; Lucrin flacon , Abbott,
Turkey) in the mid-luteal phase of the previous cycle. When adequate
down regulation had been achieved (endometrial thickness <4 mm
or serum estradiol <50 pg/ml), usually after at least 10 days of
leuprolide acetate , controlled ovarian stimulation (COS) was started
with recombinant FSH preparations, either Gonal F (MerckSerono,Turkey) or Puregon (Schering-Plough,Turkey) at starting
doses between 150 and 300 IU per day. Dose adjustments were
individualized after 5 days of ovarian stimulation. Final oocyte
maturation was induced by human chorionic gonadotrophin (hCG),
10,000 IU (Pregnyl, Schering-Plough, Turkey) when the two leading
follicles were 18 mm in mean diameter. The analogue was continued
till the day of the hCG injection.
Oocytes were retrieved 34 h after hCG administration under
guided vaginal sonography, with the patient in a sedated but
conversant state. An ICSI procedure was performed 3-5 h after
retrieval of every oocyte. Approximately 16-19 h after the
injection, normal fertilisation was checked. Selection for embryo
replacement was made according to top quality embryo selection
criteria. Embryos were transferred in a blastocyte medium (G2,
Vitrolife, SISMED, Istanbul, Turkey). All embryos were transferred
with the Wallace catheter (Smiths Medical International, UK) on
the third day after ICSI. Abdominal ultrasonographic guidance
was used. Luteal phase support was provided by vaginal
progesterone gel 8% (Crinone, Serono, Turkey) starting on the
day of ovum pick-up.
Clinical pregnancy was determined by the presence of a
gestational sac during an ultrasound exam. The implantation rate
was calculated as the ratio between the number of embryonal sacs
diagnosed by sonography and the total number of embryos
transferred into the uterus. Clinical pregnancy rates and
implantation rates were calculated per embryo transfer.
All demographic information, IVF cycle information, and cycle
outcomes were obtained from the patients’ charts. The charts
were reviewed by one investigator. Patients were placed into four
groups for analysis: FSH/LH ratio <1(group A); FSH/LH ratio
between ≥1 and <1.5 (group B); FSH/LH ratio between ≥1.5 and
≤2 (group C) ,and FSH/LH ratio >2 (group D) .
Stata/SE 9.2 (Statacorp, Texas) was used for all analyses. For
the whole group statistical evaluation, the Kruskal-Wallis test was
used; p<0.05 was considered significant. The groups were
compared with eachother by the Mann-Whitney U test. The
Bonferroni adjusted level of significance was needed to obtain
statistical significance, calculated as p<0.0083 (0.05/6 = 0.0083).
Multivariable logistic regression modeling was used to
compute the odds ratios (ORs) of variables predictive of clinical
and ongoing pregnancies after fresh ETs , and of the cycle
cancellation rate. The independent variables were age, duration of
stimulation, total dose of FSH administrated, AFC, day 3 FSH
levels, day 3 LH levels and day 3 FSH/LH ratios.
Results
A total of 199 cycles were retropectively analysed. All women
had a basal FSH value of less than 12 IU/L. Of the four groups with
FSH/LH ratios of <1; ≥1 and <1.5; ≥1.5 and ≤2; and >2, group A
included 65, group B 70, group C 43 and group D 21 cycles.
Indications for ICSI in group A were male factor (45.3%), tubal
(7.8%), or unexplained infertility (39.1%). The percentages of
Yoldemir et al.
distribution in group B were 58.6%, 12.9% and 14.3%,
respectively. Indications for ICSI in group C were male factor
(59.5%), tubal (14.3%), or unexplained infertility (14.3%). 71.4%,
5% and 9.5% of women in group D had male factor, tubal, or
unexplained infertility, respectively.
The treatment cycle characteristics between the groups are
given in Table I. ICSI cycle outcomes were comparable between the
groups. The clinical and ongoing pregnancy rates per transfer were
similar. Implantation rates per transfer did not show a significant
difference between the groups (Table II).
The multivariate analysis showed that there was no association
between the rate of clinical pregnancy and age, duration of
stimulation, total dose of FSH administered , AFC, day 3 FSH levels,
day 3 LH, or day 3 FSH/LH ratios (Table III). There was no
association between the rate of ongoing pregnancy and age,
duration of stimulation, total dose of FSH administered, AFC, day 3
FSH levels, day 3 LH, day 3 FSH/LH ratio (Table III). The rate of
cycle cancellation was not associated with age, duration of
stimulation, total dose of FSH administrated or AFC, day 3 FSH/LH
ratios (Table III).
71
Discussion
As the age of the women increases during the reproductive
years, the oocyte population declines together with endocrine
changes that have an impact on reproductive outcomes.10 A
transient FSH increase in the early follicular phase is the initial
response to ageing , with a normal secretion of estradiol. Cycles
shorten in response to the rise in FSH concentrations and the
consequent stimulation of accelarated follicular development.
Later, increases of LH levels occur. Higher levels of serum FSH,
increased FSH/LH ratios11 and elevated concentrations of serum
estradiol12 have been suggested as associated with poor ovarian
responses during assisted conception cycles. However, no perfect
test or combination of tests has been found to predict the ovarian
response to gonadotropin stimulation during ART cycles. Hence,
studies are being conducted regarding this dilemma13.
It is crucial for the infertile couples going through ART to
predict their chances of conception. Thus, an acceptable predictive
parameter is needed for counselling before treatment. Cycle day 3
Table I. Treatment cycle characteristics between groups
FSH / LH ratio
Number of cycles
Mean FSH (mIU/ml)
Mean LH (mIU/ml)
Age (years)
Antral Follicule Count (#)
Total gonadotropin dose (IU)
Mean duration of COH (days)
Mean number of oocytes collected (#)
Metaphase II oocytes (#)
Number of fertilized oocytes (#)
Percentage of embryos with >6 cells on day 3 (#)
Number of embyos transferred on day 3 (#)
<1
65
≥1 and <1.5
70
≥1.5 and ≤2
43
>2
21
5.66±1.66a,b
7.80±2.85e
29.12 ±3.83
9.23 ± 3.61
2249± 864.2
8.44±1.67
13.45±6,62f
10.60±5.20g
7.33±3.74i
75.42±0,36
2.86±0.43
6.17±1.34c
4.98±1.26e
29.17±3,63
8.45 ± 3.55
2580.8±672.3
8.47±1.1.32
11.93±6.08
9.4±4.55h
7.02±3.35j
61.94±0.4
2.95±0.34k
7.24±2.67a,d
4 .35±1.70e
29.65±2.99
6.68 ± 2.65
2332.9±842.4
8.33±1.31
11.43±6.5
9.34 ±5.39
6.33±4.08
59,26±0.39
2.78±0.53
9.39±3.84b,c,d
3.56±1.72e
29.48±4.08
8.07 ± 2.02
2503±965.6
7.89±1.49
7.2±3.71f
5.26±2.81g,h
3.58±2.19i,j
56.86±0.47
2.53±0.84k
Values shown are mean ± standard deviation (mean ± SD), COH=controlled ovarian hyperstimulation
p value <0.0083 is statistically significant.
a,j p=0.002; b,c,e,g p=0.0001; d,f,i p=0.001; h
p=0.008; k p=0.006
Table II. ICSI cycle outcomes of patients
FSH / LH ratio
Number of cycles
<1
65
≥1 and <1.5
70
≥1.5 and ≤2
43
>2
21
Cancellation rate (%)
9.23±0.29
11.43±0.32
11.63±0.32
13.63±0.35
Transfer rate (%)
90.77±0.29
88.57±0.32
88.37±0.32
86.36±0.35
Clinical pregnancy rate per transfer (%)
42.37±0.5
37.1±0.49
28.95±0.46
52.63±0.51
Ongoing pregnancy rate per embryo transfer (%)
30.51±0.46
27.42±0.45
21.05±0.41
31.58±0.48
Implantation rate per embryo transfer (%)
18.96±0.29
13.98±0.25
10.53±0.22
14.91±0.27
Values shown are mean ± standard deviation (mean ± SD)
For all comparisons p value >0.0083
72
Yoldemir et al.
Table III . Multivariate analysis
Odds
Ratio
P
value
95% confidence
interval
Age
0.88
0.07
0.77-1.01
AFC
1.09
0.29
0.93-1.27
Duration of stimulation
1.30
0.19
0.88-1.95
Clinical pregnancy rate
Total dose of FSH used
0.99
0.58
0.99-1.00
Number of oocytes collected
0.93
0.48
0.76-1.14
Day 3 FSH
0.70
0.06
0.49-1.02
Day 3 LH
1.14
0.22
0.92-1.42
Day 3 FSH/ LH ratio
1.81
0.066
0.96-3.41
Odds
Ratio
P
value
95% confidence
interval
Age
0.97
0.68
0.86-1.11
AFC
1.08
0.34
0.92-1.27
1.51
0.06
0.98-2.35
Ongoing pregnancy rate
0.99
0.37
0.99-1.00
0.98
0.83
0.81-1.18
Day 3 FSH
0.81
0.23
0.57-1.14
Day 3 LH
1.08
0.44
0.88-1.32
Day 3 FSH/ LH ratio
0.93
0.84
0.44-1.94
Odds
Ratio
P
value
95% confidence
interval
Cycle cancellation rate
Age
1.03
0.75
0.86-1.24
AFC
0.79
0.055
0.62-1.01
1.17
0.74
0.45-3.03
1.00
0.71
0.99-1.00
1.45
0.27
0.76-2.76
Day 3 FSH/ LH ratio
0.75
0.59
0.27-2.11
AFC: antral follicule count
FSH levels have been proposed for this purpose14,15. FSH
concentration is the result of the feedback effects at the pituitary in
response to the concentrations of inhibin B and estradiol produced
by the follicular cohort16. Since basal FSH concentration is an
indirect marker of ovarian reserve, it has been used to predict the
cancellation rate in ART17.
The basal FSH concentration has been used as a prognostic
criterion before an ovarian stimulation is started. Dose adjustments of
gonadotropins and preferences for certain protocols have been
planned under the influence of basal FSH concentrations from a
pretreatment cycle. Variations of FSH values between cycles have
been reported18 especially in women with low ovarian reserve due to
their age or to low ovarian responses to ovulation induction.
However, Penarrubia et al19 have reported no significant inter-cycle
variations in three consecutive cycles. The extent to which inter-cycle
variability might affect patients’ prognosis during ART cycles has
been questioned. Scott et al.20 and Martin et al.21 advised that such
variability had minimal relevance for the clinical decision.
Several earlier studies have investigated ovarian response to
ovulation induction in patients with elevated FSH/LH ratios.
Mukherjee et al.22 reported decreased ovarian responses and lower
pregnancy rates in 14 patients with a FSH/LH ratio >3.6. Barroso et
al.23 reported similar results in 28 patients with a FSH/LH ratio >3.
Shrim et al.24 chose the cut-off ratio as 3 and found lower
pregnancy rates in 41 patients with an elevated FSH/LH ratio. In
contrast to these previous studies our study included only 6 women
out of 199 with a FSH/LH ratio >3. The reason for the differences of
the outcomes between our study and previous studies is probably
that women with basal FSH values lower than 12 IU/dl were
included. This value has been set as our clinic’s upper FSH level for
expecting good ovarian response to controlled ovarian stimulation.
Comparable pregnancy rates were found for all the groups with 0.5
ratio increments starting from 1.
Mukherjee et al.22 suggested that the poor response to ovarian
stimulation could be due to low day 3 LH concentrations since
there were no differences in day 3 FSH values between the two
groups. Nocci et al.25 and Mukherjee et al.26 argued that a
decreased day 3 LH concentration (which could be reflected as an
elevated FSH/LH ratio) is predictive of a reduced ovarian response.
They speculated that there might be reduced activity of one or
more of the known ovarian regulators when the early follicular LH
concentration was low, and that this could influence follicular
growth. Alternatively, a low LH concentration could simply be a
marker of impaired balance between the gonad and the pituitary
gland. Similarly, the mean day 3 LH concentrations decreased in
our study as the FSH/LH ratio increased. The mean day 3 LH
concentration in the highest ratio group was significantly lower
than in the other groups. However, the mean LH concentrations in
all of our groups were higher than 3 mIU/ml; thus our patients had
higher basal LH values in contrast to those reported by Mukherjee.
Our study group D had the lowest mean day 3 LH concentration
and the lowest number of total oocytes and metaphase II oocytes
were collected, which supports Noci’s speculation25 that there
could be reduced activity of one or more of the known ovarian
regulators when the early follicular LH concentration is low. The
difference in mean LH levels between our study groups did not
reflect on pregnancy rates between the groups. In group D of our
study, 8 women out of 21 had LH concentration lower than 3
IU/ml, the percentage being higher than for the previous three
groups (2/65; 4/70 and 5/43 in groups A, B and C; respectively).
Our study population had cycle day 3 serum FSH levels within
normal limits. The increase in FSH/LH ratio is the result of both the
decrease in LH and the elevated FSH values. Although lower LH
values had been previously23,24 reported as the cause of the high
FSH/LH ratio, no association between follicular phase serum LH levels
and IVF pregnancy outcomes were confirmed27,28. We could not
obtain the results suggested by Liu and Greenblatt29. Our group with
the lowest mean serum LH value had the least number of fertilized
oocytes. Since a comparable number of embryos were transferred,
similar pregnancy outcomes with the other groups with higher
serum LH levels but lower FSH/LH ratios could be achieved.
Conclusion
Elevated FSH/LH ratio22,23 or low day 3 LH levels in the
presence of normal baseline FSH24-26 were associated with an
inferior IVF outcome. On the basis of our findings, it seems that the
FSH/LH ratio cannot be used to predict the ICSI success in women
with normal baseline FSH levels as long as a comparable number of
good quality embryos are transferred on day 3.
Acknowledgement
The authors declare that they have no conflict of interest.
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74
Özgün Araştırma / Original Article
DOI: 10.5472/MMJ.2011.02200.1
Lokal İleri Evre Özefagus Kanserinde
Kemoradyoterapi Deneyimimiz
Chemoradiotherapy Experience in Locally Advanced Esophageal Cancer
İlknur ALSAN ÇETİN1, P. Fulden ÖNCÜ YUMUK2, Beste M. ATASOY1, Faysal DANE2, Hale Başak ÇAĞLAR1, Roman İBRAHİMOV1,
Hasan Fevzi BATIREL3, Ufuk ABACIOĞLU1
1Radyasyon Onkolojisi Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, İstanbul,Türkiye
2Tıbbi Onkoloji Bilim Dalı, İç Hastalıkları Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, İstanbul, Türkiye
3Göğüs Cerrahisi Anabilim Dalı, Tıp Fakültesi, Marmara Üniversitesi, İstanbul, Türkiye
Özet
Abstract
Amaç: Bu çalışmada lokal ileri evre özefagus kanseri tanısıyla neoadjuvan/
definitif kemoradyoterapi (KRT) uygulanan hastaların sonuçlarının bildirilmesi
amaçlanmıştır.
Objective: In this study, we report our neoadjuvant/definitive
chemoradiotherapy (CRT) experience in locally advanced esophageal cancer
patients.
Patients and Methods: A total of 15 patients were retrospectively evaluated.
Histological diagnosis were as follows: squamous cell 10, adenocarcinoma 4,
adenosquamous carcinoma1. Initial stage was T3N0M0 5 or
T3N1M0/T4N0M0 10. Radiotherapy was administered at median of 50 Gy
(1.8-2 Gy/day, 5 fractions/week) and cisplatin and 5-fluorouracil were given
concurrently on the first and the last week of radiotherapy.
Results: Continuous applicability of concurrent chemoradiotherapy was 80%.
Median follow-up was 15 months (range, 3-70 months). One of the five
patients who were treated with neoadjuvant approach had local
progression,and three had distant metastasis. Three patients (30%) who were
planned to be treated with definitive CRT had downstaging and surgery was
recommended. Two-year local control rate was 22%, distant metastasis-free
survival rate was 45% and overall survival rate was 31%. Grade III dysphagia
was observed in 6% of patients.
Conclusion: Treatment of locally advanced esophageal cancer remains
controversial. Although patients who had surgery were reported to have longer
survival and better local control rates, the feasibility of triple-modality treatment
is limited to the center's experience. For this reason, all patients should be
evaluated individually with a multidisciplinary approach. (Marmara Medical
Journal 2012;25:74-7)
Key Words: Chemoradiotherapy, Esophageal cancer, Locally advanced stage,
Surgery
Hastalar ve Yöntem: Histolojik tanısı skuamöz hücreli 10, adenokarsinom 4,
adenoskuamöz karsinom 1 olan, T3N0M0 5 veya T3N1M0/T4N0M0 10,
toplam 15 hasta geriye dönük olarak incelendi. Ortanca radyoterapi dozu 50
Gy (1,8-2 Gy/gün, 5 fraksiyon/hafta) olup eş zamanlı kemoterapi
radyoterapinin ilk ve son hafta sisplatin ve 5-florourasil olarak uygulandı.
Bulgular: Eş zamanlı kemoterapinin kesintisiz uygulanabilirlik oranı %80 idi.
Medyan takip 15 ay (aralık, 3-70 ay) idi. Neoadjuvan olarak tedavi edilen beş
hastadan birinde lokal progresyon, üçünde uzak metastaz izlendi. Baştan
definitif KRT planlanan hastalardan üçüne (%30) evrede küçülme izlenerek
cerrahi önerildi. İki yıllık lokal kontrol (LK) %22, uzak metastazsız sağkalım
(UMSK) %45 ve genel sağkalım (GSK) %31 olarak saptandı. Derece III disfaji
oranı %6 idi.
Sonuç: Lokal ileri evre özefagus kanserinde tedavi tartışmalıdır. Cerrahi şansını
elde eden hastalarda daha uzun sağkalım ve lokal kontrol bildirilirken üçlü
modalite tedavilerin yapılabilirliği merkezin deneyimi ile sınırlıdır. Bu nedenle
tüm hastalar bireysel olarak ve multidisipliner yaklaşım ile değerlendirilmelidir.
Anahtar Kelimeler: Cerrahi, Lokal ileri evre, Kemoradyoterapi, Özefagus
kanseri
İletişim/Correspondence to: Doç. Dr. Beste Atasoy, Radyasyon Onkolojisi Kliniği, Sağlık Bakanlığı Marmara Üniversitesi Pendik Eğitim ve Araştırma Hastanesi, Mimar Sinan Cad. No:41, Fevzi Cakmak Mah.,
Pendik, İstanbul, Türkiye E-posta: [email protected]
Çetin ve ark.
Lokal İleri Evre Özefagus Kanserinde Kemoradyoterapi
Giriş
Amerika Birleşik Devletleri’nde 2010 istatistiklerine göre yıllık
beklenen yeni özefagus kanseri hastası 16.640 ve beklenen ölüm
14.500’dür1. Yüksek oranda letal seyreden hastalıkta tanı anında
hastaların üçte ikisi inoperabl olarak değerlendirilmektedir2,3.
Erken evre dışında opere edilebilir hastalarda tek başına cerrahi ile
3 yıllık sağkalım %20 civarındadır4. Benzer şekilde tek başına
radyoterapiyle alınan sonuçlar da yüz güldürücü değildir5. Buna
karşılık, cerrahiye eş zamanlı kemoradyoterapinin neoadjuvan
olarak eklenmesiyle sağkalım sonuçları, patolojik tam cevap ve R0
rezeksiyon oranları artmaktadır6. Multimodalite tedavilerin
incelendiği meta-analizler de bu sonucu desteklemektedir7-11.
Eş zamanlı definitif kemoradyoterapi (KRT) yapılan hastalarda
sonuçlar iyileşmesine rağmen lokal yineleme oranları hâlâ %50
civarındadır. Beş yıllık sağkalım oranlarıysa %10-%20’yi
geçememektedir5,12-15. Bununla birlikte KRT sonrası cerrahinin
yapılabildiği hastalarda artan lokal kontrol ve sağkalım sonuçları
umut vericidir16-20. Ancak üç tedavi modalitesinin birlikte
kullanılması toksisiteyi arttırdığından, bu multidisipliner yaklaşımın
olduğu deneyimli merkezlerde yapılması önerilmektedir16-21.
Bu çalışmada, lokal ileri evre özefagus kanseri tanısı alarak
merkezimizde eş zamanlı definitif KRT uygulanmış hastaların
geriye dönük incelemesi yapılarak sağkalım ve toksisite analizleri
üzerinden tedavi seçenekleri tartışılmıştır.
Hastalar ve Yöntem
Bu çalışma Marmara Üniversitesi Tıp Fakültesi Girişimsel Olmayan
Çalışmalar için kurulmuş Etik Kurul’un onayı ile gerçekleştirilmiştir.
Tablo I. Hasta ve hastalık özellikleri
n (%)
Hasta sayısı
Cinsiyet
Kadın
Erkek
15
4 (18)
11(72)
Ekim 1997 ile Mart 2009 tarihleri arasında Radyasyon Onkolojisi
Kliniğine özefagus kanseri tanısıyla başvurmuş 32 hasta geriye dönük
olarak incelendi. Bu hastalardan genel durum bozukluğu ya da
metastatik hastalık nedeniyle palyatif ve/veya tek başına radyoterapi
(RT) almış hastalar dışında eş zamanlı KRT almış 15 hasta analizlere
dahil edildi. Tüm hastaların Karnofsky Performans Skoru ≥70 olup
hasta ve hastalığa ait özellikler Tablo I’de gösterilmiştir. Tüm
hastalarda tanı, endoskopik inceleme ile tümör dokusundan alınan
örneğin patolojik değerlendirilmesi sonucu konmuştu. Evreleme
amaçlı kontrastlı toraks bilgisayarlı tomografi (BT), abdominal BT veya
manyetik rezonans görüntüleme (MRG) istendi. Görüntüleme ile
şüpheli lenf nodu pozitifliği düşünülen hastalarda mediastinal lenf
nodu değerlendirmesi mediastinoskopiyle yapıldı.
Tüm hastaların tedavisinde bilgisayarlı tedavi planlama sistemi
kullanıldı. 2000 yılından sonra tüm hastalarda planlama sistemine
aktarılan BT görüntüleri üzerinden hedef hacim çizilerek konformal
planlama yapıldı. Klinik hedef hacim için %95 ile %107’lik izodoz
aralığı seçildi. Eksternal RT 1,8-2 Gy/gün konvansiyonel şemaya göre
uygulandı. Tedavinin I. fazında ön-arka iki alandan tümör bölgesine
süperior-inferior doğrultuda 5 cm ekleyerek 45-50,4 Gy; tedavinin II.
fazında (boost) ön-arka/oblik iki ya da üç-dört alandan tümör
bölgesine süperior-inferior doğrultuda 2 cm eklenerek 5.4-14.4 Gy
verilmiş olup ortanca toplam doz 50 Gy (45-59.4 Gy) idi. Servikal
özefagus yerleşimli bir hastanın tedavisi 50 Gy’de medulla spinalis
alan dışında bırakılarak ±2 cm’lik tedavi alanına 2 Gy/gün’den
toplam 66 Gy uygulandı. RT medyan 5 haftada tamamlandı.
Eş zamanlı kemoterapi (KT) böbrek fonksiyonları normal olan
hastalarda RT’nin ilk ve son haftası sisplatin 75 mg/m2 (1.gün) ve
5-florourasil 1g/m2 (1-4. gün) IV olarak verildi.
İstatistiksel Analiz
Sağkalım analizlerinde tanı tarihi başlangıç olarak kabul edildi.
Sağkalım tanımlamalarında lokal kontrol (LK), uzak metastazsız
sağkalım (UMSK) ve genel sağkalım (SK) kullanıldı. Buna göre tanı
anından klinik, endoskopik ya da radyolojik olarak lokal hastalık
progresyonun saptandığı zamana kadar geçen süre LK; uzak
metastazın saptandığı zamana kadar geçen süre UMSK ve
herhangi bir nedene bağlı olarak tanıdan ölüme kadar geçen süre
SK tanımlamasında kullanıldı (Şekil 1). Sağkalım analizi için Kaplan
Meier metodu uygulandı.
Yaş
Medyan
Aralık
Tümör yerleşimi
Servikal
Üst
Orta
Alt
1 (6,6)
2 (13,3)
4 (26,6)
8 (53,3)
Histoloji
Skuamöz hücreli
Adenokarsinom
Adenoskuamöz
10 (66,6)
4 (26,6)
1 (6,6)
Evre
IIA (T3N0M0)
III (T3N1M0 veya T4N0M0)
100
52
17- 82
LK
UMSK
GSK
Sağ kalım (%)
80
60
40
20
0
5 (33)
10 (66,6)
75
1
21
41
61
81
101
121
Zaman (ay)
Şekil 1. İki yıllık lokal kontrol (LK), uzak metastazsız sağkalım (UMSK),
genel sağkalım (GSK) sonuçları
76
Çetin ve ark.
Bulgular
Sağkalım Değerlendirmesi
Tüm hastalarda radyoterapi planlanan şekilde tamamladı.
Analiz sırasında yaşayan ve hastalıksız olarak takip edilen bir hasta
vardı. Tüm hastalar değerlendirildiğinde 5 hastada (%33) uzak
metastaz (3 akciğer, 2 kemik, 1 karaciğer) ve 11 hastada (%73)
lokal progresyon saptandı.
Tanı anında T3N0M0 olarak değerlendirilen beş hastadan biri
tedavi sonu sisplatine bağlı böbrek toksisitesi nedeniyle takibin
3. ayında kaybedildi. Bir hastada lokal progresyon izlenirken üç
hastada uzak organ metastazına bağlı ölüm oldu. Baştan lokal ileri
evre olduğu düşünülen hastalardan üçünde KRT sonrası takipte klinik
ve radyolojik olarak evrede küçülme (downstaging) saptanarak
cerrahi önerildi. Bu hastalardan biri operasyonu kabul etmedi. Opere
olan diğer iki hastadan birinde postoperatif patoloji piyesinde %80
regresyon saptandı. Bu hasta analiz sırasında relapssız olarak 70 aydır
takipteydi. Dış merkezde opere olan diğer hasta postoperatif
dönemde kaybedildi. Bir hasta 66. ay takibinde lokal ve sistemik
hastalık progresyonu olmaksızın kalp yetmezliği tanısıyla kaybedildi.
Tüm grupta ortanca takip 15 ay (aralık, 3-70 ay), ortanca
sağkalım 13 ay (aralık, 3-70 ay), LK 9 ay (aralık, 4-70 ay) ve UMSK
16 ay (aralık, 7-70 ay) idi. Skuamöz hücreli kanser alt tipinde ise
medyan sağkalım 15 ay idi. Tüm grupta iki yıllık LK oranı %22,
UMSK %45 ve GSK %31 olarak saptandı.
Eş zamanlı KRT’nin Uygulanabilirliği ve
Yan Etki Değerlendirmesi
Eş zamanlı KT 12 (%80) hastada planlandığı şekilde ve
kesintisiz olarak uygulandı. Kemoterapisi kesilen bir hastada
derece III disfaji izlenmişken, diğer bir hastada pansitopeni
görüldü. Başka bir hastada serum kreatinin değerinin 1,5 g/dL’nin
üzerine çıkması sonucu kemoterapisi sonlandırıldı.
Yan etkilerin değerlendirilmesinde Genel Toksisite Kriterleri
(CTC) v3.0 kullanıldı22. Bu kriterlere göre derece II iştahsızlık %34,
derece II bulantı %27, derece II kilo kaybı %34, derece II halsizlik
%20 oranında izlenirken disfaji hem derece II (%54) hem de
derece III (%6) olarak görüldü.
Tartışma
Amerikan Radyoterapi Onkoloji Cemiyetinin (RTOG) 85-01
numaralı çalışmasında lokal ileri özefagus kanserinde definitif
kemoradyoterapi (fluorourasil ve sisplatinle eş zamanlı 50 Gy RT)
tek başına 64 Gy RT ile karşılaştırılmış ve 5 yıllık sağkalım oranları
%32’ye karşılık %12 ile kombine kolda avantajlı bulunmuştur5,14.
Cerrahi düşünülmeyerek tüm hastalarda baştan definitif
kemoradyoterapi planlanmış olan çalışmamızda ise iki yıllık lokal
kontrol ve genel sağkalım oranları sırasıyla %22 ve %31’dir.
Özefagus kanserinin submukozal yayılım gösterme özelliğinden
dolayı Herskovic ve ark.5,14 çalışmalarında başlangıç tedavi alanı (I.
faz) olarak supraklavikuler alandan özefago-gastrik bileşkeye kadar
tüm özefagusu seçmiş ve bu hacime 30 Gy uygulamış, ardından
alan küçültmesiyle (II. faz) tümör bölgesine süperior-inferior yönde
5 cm ekleyerek 20 Gy vermişlerdir. Çalışmamızda bundan farklı
olarak RT alanı baştan tümör bölgesine 5 cm eklenmesiyle
oluşturulmuş, alan küçültmesi sırasında da tümöre 2 cm eklenmiştir.
Bu tedavinin korkulan bir yan etkisi olan derece III disfaji %6 olarak
izlenmiş ve eş zamanlı KRT‘nin uygulanabilirliği de %80 olarak
gerçekleşmiştir. Toksisite açısından günlük pratik ve literatür dikkate
alındığında eş zamanlı KT’nin verilebilirlik oranı yüksektir.
Eş zamanlı KRT çalışmalarında patolojik tam cevap oranı %25
ile %40 arasında bildirilmektedir5,12-15. KRT ile sağkalım
sonuçlarının iyileştirilmesine rağmen lokal başarısızlık hâlâ %50’ler
düzeyindedir18-21. Çalışmamızda da lokal progresyon %73
oranında izlenmiştir. Minsky ve ark.21 tarafından lokal kontrolü
arttırmak amacıyla yapılan ve KT ile eş zamanlı RT dozunun
arttırıldığı (50 Gy karşılık 65 Gy) çalışmada ise genel sağkalımda
artış (2 yıl için %31’e karşılık %40) izlenmiş ancak bu sonuç lokal
kontrole yansımamıştır. Üstelik yüksek doz kolunda kabul edilemez
toksisite (ölüm oranı %1’e karşılık %11) görülmüştür. Özefagus
kanserinde tek başına RT dozunu arttırmanın yararının olmadığı,
lokal kontrolde daha etkin tedavilere gerek olduğu açıktır.
Cerrahi öncesi tek başına indüksiyon KT’nin yerini araştıran
çalışmalarda tam cevap elde edilemezken KT sonrası yapılan
cerrahide mortalite oranı %4 ile %10 arasında değişmektedir6,16-18.
Neoadjuvan KRT’nin ardından cerrahinin tek başına cerrahi ile
karşılaştırıldığı meta-analizlerde ise sağkalım oranları neoadjuvan
tedavi lehine gözükmektedir8-10.
Çalışmamızda KRT sonrası evre küçülmesi izlenen üç hastadan
ikisinde cerrahi seçeneği tartışılmış, kabul eden iki hastada
uygulanmıştır. Üçlü modalite tedavinin uygulandığı bu iki
hastadan biri 70 aydır relapssız takiptedir. Aynı hastanın patoloji
piyesinde KRT sonrası primer tümörde %70 regresyon izlenmiştir.
Kemoradyoterapiyi takiben cerrahinin uygulandığı üçlü modalite
tedavilerinde tam cevabı oranı %20-30 düzeyindedir10. Ancak
üçlü tedavinin henüz uzun dönem sonuçları yoktur. Çalışmamızda
opere olan diğer hasta postop dönemde kaybedilmiştir. Gebski ve
ark.7 10 çalışmayı değerlendirdikleri meta-analizlerinde üçlü
tedaviyle mortalite hazard oranını 0,81 olarak bulunmuşlardır. İki
yıllık mutlak sağkalım artışı ise %13’dür. Histolojik alt gruplar
dikkate alındığında skuamöz ve adenokanser arasında cevap
oranlarının farklı olduğu bildirilmektedir19. Burmeister ve ark.19
üçlü modalite uygulanan hastaların incelendiği çalışmalarında
skuamöz hücreli kanser alt tipinin sağkalım avantajı gösterdiğini
bildirmişlerdir. Çalışmamızda incelenen hastalardan 10’u skuamöz
hücreli kanser alt tipine sahiptir.Tüm grupta GSK süresi ortanca 13
ay iken bu hastalarda 15 aydır.
Lokal agresif özelliği bilinen bu kanser türünde çalışmamızda
takipler sırasında %33 hastada sistemik progresyon izlenmiştir. Eş
zamanlı tedavi sırasında verilen KT subklinik metastazları
engellemeye yetmemektedir. Üçlü tedavi sonrası adjuvan KT’nin
sağkalıma katkısı açık olmamakla beraber adjuvan sistemik tedavi
gerekli görülebilmektedir.
Sonuç
Lokal ileri evre özefagus kanserinde cerrahi şansını elde eden
hastalarda daha uzun sağkalım ve daha iyi lokal kontrol
bildirilirken üçlü modalite tedavilerin yapılabilirliği merkezin
deneyimi ile sınırlı olduğunda bu hastalar multidisipliner
yaklaşımın yapıldığı merkezlerde tedavi edilmelidir.
Kaynaklar
1.
Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin
2010; 60: 277–300. doi: 10.3322/caac.20073
2. Sagar PM, Gauperaa T, Suc-Ling H, et al. An audit of the treatment of the
cancer of the oesophagus. Gut 1994; 35: 941-5.
3. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on
esophageal carcinoma. Cancer 1996; 78: 1820-8. doi: 10.1002/
(SICI)1097-0142(19961015)78:8<1820
4. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery
compared with surgery alone for localized esophageal cancer. N Eng J
Med 1998; 339:1979-84.
5. Herskovic A, Martz K, Al-Sarraf MV, et al. Combined chemotherapy and
radiotherapy compared with radiotherapy alone in patients with cancer
of the esophagus. N Eng J Med 1992; 326: 1593-8.
6. Boset JF, Gignoux M, Triboulet JP, et al. Chemoradiatherapy followed by
surgery compared with surgery alone in squamous cell cancer of the
esophagus. N Eng J Med 1997; 337: 161-7.
7. Gebski V, Burmeister B, Smithers BM, et al. Survival benefits from
neoadjuvant chemoradiotherapy or chemotherapy in esophageal
carcinoma: a meta-analysis. Lancet Oncol 2007;8:226–34. doi:10.1016/
S1470-2045(07)70039-6
8. Greer SE, Goodney PP, Sutton JE, et al. Neoadjuvant chemoradiotherapy
for esophageal carcinoma: A meta-analysis. Surgery 2005; 137:172-7.
doi:10.1016/j.surg.2004.06.033
9. Fiorica F, Di Bona D, Schepis F, et al. Preoperative chemoradiotherapy for
oesophageal cancer: A systematic review and meta-analysis. Gut 2004;
53:925-30. doi:10.1136/gut.2003.025080
10. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that
compared neoadjuvant chemoradiation and surgery to surgery alone for
resectable esophageal cancer. Am J Surg 2003;185:538-43.
doi:10.1016/S0002-9610(03)00066-7
11. Graham AJ, Shrive FM, Ghali WA, et al. Defining the optimal
treatment of locally advanced esophageal cancer: A systematic review
and decision analysis. Ann Thorac Surg 2007; 83:1257-64.
doi:10.1016/ j.athoracsur.2006.11.061
12. Coia LR, Engstrom PF, Paul AR, et al. Long-term results of infusional 5-FU,
mitomycin-C, and radiation as primary management of esophageal
carcinoma. Int J Radiat Oncol Biol Phys 1991;20:29-36.
doi:10.1016/0360-3016(91)90134-P
Çetin ve ark.
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13. Wong RK, Malthaner RA, Zuraw L, et al. Cancer Care Ontario Practice
Guidelines Initiative Gastrointestinal Cancer Disease Site Group.
Combined modality radiotherapy and chemotherapy in nonsurgical
management of localized carcinoma of the esophagus: a practice
guideline. Int J Radiat Oncol Biol Phys 2003; 55:930-42. .
doi:10.1016/S0360-3016(02)04278-5
14. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally
advanced esophageal cancer: long-term follow-up of a prospective
randomized trial (RTOG 85-01). Radiation Therapy Oncology Group
JAMA. 1999; 281:1623-7.
15. al-Sarraf M, Martz K, Herskovic A, et al. Progress report of combined
chemoradiotherapy versus radiotherapy alone in patients with
esophageal cancer: an intergroup study. J Clin Oncol 1997;15:277-84.
16. Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery
compared with chemoradiation alone in squamous cancer of the
esophagus: FFCD 9102. J Clin Oncol 2007; 25:1160-8. doi:
10.1200/JCO.2005.04.7118
17. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal
therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;
335:462-7. doi: 10.1056/NEJM199608153350702
18. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative
chemoradiation versus surgery alone in patients with locoregional
esophageal carcinoma. J Clin Oncol 2001;19:305-13.
19. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus
chemoradiotherapy followed by surgery for resectable cancer of the
oesophagus: A randomised controlled phase III trial. Lancet Oncol
2005;6:659-68. doi:10.1016/S1470-2045(05)70288-6
20. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality
therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared
with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol
2008;26:1086-92. Doi: 10.1200/JCO.2007.12.9593
21. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy
Oncology Group 94-05) phase III trial of combined-modality therapy for
esophageal cancer: high-dose versus standard-dose radiation therapy. J
Clin Oncol 2002;20:1167-74.
22. Common Toxicity Criteria v.3.0. http://www.eortc.be/services/
doc/ctc/default.htm. Erişim tarihi 16.09.2011
78
DOI: 10.5472/MMJ.2012.02304.1
Reasons for Non-Participation of Turkish Patients in
International Clinical Trials
Türk Hastaların Uluslararası Klinik Araştırmalara Katılmayı Kabul Etmeme Nedenleri
Semra YÖRÜK1, Emel TETİK1, Atila KARAALP2
1Clinical Research Unit, Sanofi-aventis Turkey, Istanbul, Turkey
2Department of Clinical Pharmacology, School of Medicine, Marmara University, Istanbul, Turkey
Abstract
Özet
Objective: Turkey is an emerging country in terms of clinical research with a
large population of patients not previously exposed to clinical trials. Despite
its increasing importance in the clinical research field, the recruitment process
is very difficult for various reasons and may become a serious research
limitation. A project was designed and implemented with a view to
understanding the perceptions of Turkish participants to clinical trials.
Methods: Investigators were given a questionnaire booklet to complete with
information about all patients that were potentially eligible for active
involvement in international clinical trials. A total of 39 investigators from
eight cities participated in the survey and they provided information on 410
patients who were candidates for ongoing international trials.
Results: A total of 306 out of 410 patients were eligible for the trials; the
remaining 104 patients were ineligible based on inclusion and exclusion
criteria, and physician estimation on patient’s compliance. Of the 306
eligible patients, 80 refused to sign an informed consent form. The two
most common reasons for refusing to participate in a clinical trial were
the influence of patients’ relatives (36.7%) and the risk of adverse events
(27.8%). These were followed by the need for additional visits/tests
(18.9%), the risk of being treated with inactive agents - i.e. placebo(15.2%), and the probability of being randomized to unknown products
(12.7%).
Conclusion: Patient barriers for enrollment include the ‘guinea pig’ perception
held by patients and/or relatives, anxiety caused by uncertainty, additional
demands of the trial, and concerns about information and consent. (Marmara
Key Words: Clinical research, Informed consent, Patient’s perception,
Recruitment and retention
Amaç: Türkiye, daha önce bir klinik çalışmaya katılmamış hasta sayısının yüksek
oluşundan dolayı, klinik araştırma alanında dikkati üzerine çeken bir ülkedir. Klinik
araştırma alanındaki artan önemine rağmen hasta alım süreci çeşitli sebeplerden
ötürü çok güç olmakta ve bu durum araştırmaların ciddi ölçüde zorlanmasına
neden olabilmektedir. Klinik çalışmalarda Türk katılımcıların algılarının anlaşılması
açısından, bir proje tasarlanmış ve uygulamaya konulmuştur.
Yöntem: Araştırıcılara, aktif uluslararası klinik çalışmalara katılmaya potansiyel
hastaların çalışmaya uygunluğu ve var ise reddetme nedenlerini prospektif
olarak girecekleri bir anket kitapçığı verilmiştir. Sekiz şehirden toplam 39
araştırıcı bu ankete katılmıştır. Araştırıcılar sürmekte olan uluslararası çalışmalar
için aday olan 410 hastanın bilgilerini vermişlerdir.
Bulgular: Toplam 410 hastadan 306’sı çalışmalar için uygun bulunmuştur;
geriye kalan 104 hasta dahil etme ve dışlama kriterlerine veya çalışmaya olası
uyum problemine dayalı olarak uygun bulunmamıştır. Uygun bulunan 306
hastanın 80’i bilgilendirilmiş gönüllü olur formu imzalamayı reddetmiştir. Bir
klinik araştırmaya katılmayı reddetmenin en çok rastlanan iki nedeni hastanın
yakınlarının etkisi (%36) ve advers olay riskidir (%27,8). Diğer nedenler ise
ek vizitlere/testlere gerek duyulması (%18,9), aktif olmayan ajanlarla yani
plasebo ile tedavi edilme riski (%15,2) ve bilinmeyen ürünlere randomize
edilme riskidir (%12,7).
Sonuç: Hasta ve yakınlarındaki “kobay algısı”, belirsizliğin verdiği sıkıntılar,
çalışmanın ek külfetleri ve bilgilenme ve onam ile ilgili endişeler klinik
araştırmalara hasta alımının önündeki engellerdir. (Marmara Üniversitesi Tıp
Fakültesi Dergisi 2012;25:78-82)
Anahtar Kelimeler: Klinik araştırma, Bilgilendirilmiş onam, Hastaların görüşü,
Hasta alımı ve tutumu
Correspondence to/İletişim: Semra Yörük MD, Clinical Research Team Manager, Sanofi-aventis TURKEY Büyükdere Cad. No 193, 34394 Levent, İstanbul, Turkey
Phone: +90 212 339 1037 Fax: +90 212 339 1049 E-mail: [email protected]
Yörük et al.
Reasons for Non-Participation in Clinical Trials
Introduction
Clinical research is defined as any research involving human
subjects which explores novel pharmaceutical approaches to the
conditions of individuals suffering from debilitating and lifethreatening diseases. However, most people are unaware of clinical
trial processes and the role of research in the development of future
drugs, devices and biologics for treatment.
Obtaining freely given informed consent for participation in
research, involves important substantive ethical principles, including
respect for persons, human dignity, and autonomy. Good Clinical
Research Practice Guidelines1 requires that all patients participating in
clinical trials give written informed consent prior to participation in a
clinical trial. To ensure that patients fully understand factors related to
their care, researchers must explain to volunteers the details of the
trial. The research team then provides an informed consent
document, which includes key details about the study, such as its
purpose, duration, required procedures, risks and potential benefits
of investigational drugs (or treatments) and key contacts to get
further information in case of need. The participant then decides
whether or not to sign the document. Informed consent is not a
contract; participants therefore have a legal right to refuse any clinical
trial proposed and may withdraw from the trial at any time1-3.
Informed refusal is a medico-legal concept whereby a person
refuses an intervention based upon an understanding of the
relevant facts and of the implications of not following a
recommended diagnostic or therapeutic action. Informed refusal is
linked to the informed consent process, as a patient has the right to
consent, but also may choose to refuse4.
Despite its increasing importance in the clinical research field,
the recruitment process is very difficult for various reasons, and may
become a serious research limitation. One of the main barriers for
recruitment to a trial is patient refusal during the informed consent
process. If the reasons for refusal are known, researchers can focus
on improving research participants’ understanding of the disclosed
information. From a review of the literature, we found that this
79
information related to reason of refusal was unavailable for the
Turkish population even though there are large
numbers of
publications per therapeutic area (e.g anesthesiology, oncology,
psychiatry, etc). The present survey was planned to overcome the
current lack of information about Turkish patient attitudes towards
clinical trial participation in order to improve patient recruitment
strategies for future trials.
Methods
A project entitled Clinical Research Patient Recruitment and
Retention Project (ClinRec) was launched by the Sanofi-aventis
Turkey Clinical Research Unit in 2006. The project was created with
a view to understanding the perceptions of Turkish participants in
international clinical trials and to overcome recruitment and
retention barriers in international interventional clinical trials.
As the first step of the project, a survey of investigators, who
were actively participating to an international Sanofi-aventis trial, was
conducted between June and December 2007 to evaluate the
reasons for patient non-participation in clinical trials. Investigators
were given a questionnaire booklet prepared by Sanofi-aventis Turkey
clinical research team and asked to complete it with information on
all patients who were potentially eligible for participation in active
multinational, multi-centric, interventional, phase II and III clinical
trials, regardless of sponsor. Due to the confidentiality of the trails, the
questionnaire did not solicit information regarding therapeutic area
(e.g cancer type for oncology trials), phases, investigational drugs or
biologics, registered or unregistered investigational products, long or
short-term trials, objectives, duration of enrollment, or a targeted
population.
This survey collected the reasons for refusing to sign an informed
consent from investigators in two steps: whether or not the patient
was eligible for the trial and if patient was eligible, whether or not the
patient had signed the informed consent. If the answer to signing
informed consent was “No”, then the reason(s) for refusing consent
was/were asked to be ticked by investigators (Table I).
Table I. Questionnaire content
No. Gender* Date of Birth
Eligibility for Trial
(If patient not eligible, please tick reason)
Has patient signed Informed Consent?
(If not, please tick reason)
Yes
If "Yes", go straight to next column →
Yes
No
If “No”, tick at least one reason below:
No
Inclusion criteria
Exclusion criteria
Treatment/follow-up compliance issues
Other
*Gender: “E” for Males and “K” for Females
If "No", tick at least one reason below:
Informed Consent Form too long
Factors concerning patient’s family
Risk of taking inactive agents
Risk of being randomized on investigational arm
Additional tests and visits required by clinical trials
Trial specific additional visits
Possible side effects
Already covered by social security
No specific reason (before ticking here, underlying
reason should be questioned in detail)
Other
Yörük et al.
80
Tablo II. Location of sites
Location
No. of sites
Istanbul
Ankara
Izmir
Edirne
Kocaeli
Adana
Erzurum
Gaziantep
14
11
6
3
1
1
1
1
10
Number of investigators
8
6
4
2
0
y
ry
s
y
y
*
s
gy
og
ic
rge
se
og
gy
og
lo
ol
Su
ol
ed
lo
r
o
ol
ea
i
r
r
n
s
p
o
U
i
u
c
ri
rd
ula
to
tD
Ne
oc
sc
On
Ca
Or
va
es
nd
o
i
h
E
C
rd
Ca
*Oncology: Medical Oncologist: 4; Uro-oncologist : 3; Pediatric Oncologist: 2
Figure 1. Number of Investigators per Therapeutic Area
40
Number of patients
30
20
10
to
Re
la
te
d
Ri
sk
pa
tie
nt
s
of
re
la
ad
Ad
tiv
ve
es
di
rs
tio
e
na
ev
lv
en
is
ts
Ra
its
Ri
nd
sk
an
om
d
o
ft
iz
te
at
ak
st
io
s
in
n
g
to
p
la
in
ce
ve
st
bo
ig
at
io
na
ld
ru
Al
g
re
ad
N
o
y
O
co
sp
th
ve
ec
er
re
ifi
ed
d
by
re
he
as
on
al
th
in
su
ra
nc
IC
e
F
to
o
lo
ng
IC
F
no
tc
le
ar
0
ICP:Informed Consent Form
Figure 2: Distribution of reasons for not signing Informed Consent Form
(more than one reason could be selected)
Investigators filled in the questionnaire prospectively based
upon their active trials. Local studies were not included in this study
as informed consent details/criteria for national clinical trials are
generally not similar to the international clinical trials in terms of
content, complexity and length.
Results
A total of 39 investigators from university or state hospitals
located in eight different Turkish cities responded to the survey.
Sixty-four per cent of the sites were located in two big mega cities;
Istanbul and Ankara (Table II). The distribution of therapeutic areas
among respondents is shown in Figure 1. Based on their reports, the
total number of trials was 87.
Collectively, investigators entered information on 410 patients in
the questionnaire. Of these patients, 244 (59.5%) were male and
144 (35.1%) were female, while gender was unspecified for a
further 22 (5.4%) (missing data).
The median age of 388 patients whose information could be
gathered from questionnaire was 62 (age range 12-89), although
information regarding age was missing for remaining 22 patients.
Six patients were in the pediatric age group (<18 years), 17 patients
in the young adult category (18-25 years), and 156 patients
(40.2%) were identified as over 65 years of age.
Based on the criteria in the questionnaire in Table I, 306 out of
410 patients were considered eligible for the trials.
Based on information gathered from the investigators, 80 out of
306 eligible patients (26.14%) refused to sign the informed consent
form. Only one reason was mentioned by 68 patients, while for 11
patients investigators selected more than one reason; one patient
did not indicate any reason.
The influence of patient relatives (36.7%) and the risk of adverse
events (27.8%) were the two most common reasons for refusing
participation in a clinical trial (Figure 2). The need for additional
visits and/or tests (18.9%) was seen as the third most common
reason, followed by the risk of being treated with inactive agents
(15.2%) and the possibility of being treated with unknown
(i.e. products under investigation) products (12.7%). For one
patient no reason for refusal was specified. Reasons concerning the
length and complexity of informed consent and health insurance
coverage were not ticked by investigators for any patients.
Discussion
The present study is the first survey that explores the decisions
of Turkish patients offered a chance to participate in an international
randomized clinical trial. The study was planned to gather data
prospectively through investigators, from their potential patients who
were candidates for any on-going trials regardless of sponsor.
However, during the creation of this questionnaire, information about
the details of clinical trials (e.g. phases, investigational drugs or
biologics, registered or unregistered investigational products, long or
short-term trials and objectives of the trials) was deliberately omitted,
due to the confidentiality of the trials. Also, we did not increase the
number of questions since this might have had a negative impact on
responses from researchers but even with these lower numbers of
question, we still have missing information on the age and the
gender of some patients . The design of the trial may be considered
as a limiting factor of this survey. However, the gathered data is
almost similar with the literature which is discussed below to give
some perspective for further investigations in this area. A second step
could therefore be implemented to evaluate the impact of trial
details, as well as general patient perceptions of trial participation.
In a recent study, of the attitudes toward clinical trials of patients
who had been admitted to outpatient clinics of research hospitals in
Istanbul, it was shown that 33.7 per cent of the survey group
indicated that they may agree with participating in a clinical tria5.
Although that study gave valuable information about the Turkish
population, the data of the present study adds important information
to it with the patients who had been invited to participate in a real
international randomized clinical trial.
Informed consent is a legal doctrine that has been developed by
the courts over a number of years. The doctrine of informed consent
was derived from the Nuremberg Code in 1947, which required that
doctors obtain the voluntarily informed consent of the subject prior
to conducting medical experimentation6. The principles established
by this code for medical practice have now been extended into
general codes of medical ethics.
It is widely recognized on a global basis that many patients prefer
to play an active part in the decision-making process in daily practice.
This paradigmatic shift can be attributed to several developments,
such as the availability of more alternative treatments and recognition
of the patient as an active health consumer and autonomous
decision-maker. Weinfurt explored this shift in oncology research and
concluded that new outcome measures might be needed to assess
the effects of cancer comprehensively7.
In the present survey, patients’ relatives were the main cause of
non-participation in clinical trials. This may be related to community
perceptions of clinical research. The Nuremberg case (the practices
of Nazi doctors) and the thalidomide case served to create negative
perceptions of clinical research many years ago. This perception by
patients or relatives is one of the main barriers to enrollment. Not
only in Turkey but worldwide the media also feeds the perception of
patients as ‘guinea pigs’ in clinical trials8.
Diane Simmons, president and chief executive of the Center for
Information and Study on Clinical Research Participation (CISCRP), is
fully aware that it does not help to refer to clinical trial volunteers as
‘guinea pigs’ and has urged newspaper staff to consider using more
respectful terms in future9. The term she had in mind was ‘medical
hero’ based on evidence from a CISCRP campaign showing that
public perceptions of clinical trial participants have a significant
impact on recruitment. The CISCRP campaign resulted in a 38%
increase in patient recruitment over the control group10.
Informed consent protects the patients by providing them with
complete information on which to make an informed decision.
Investigators or research staff should explain the purpose and expected
duration of the subject’s participation, describe the procedures that
subjects will undergo during the study, and identify any procedures
which are experimental. Informed consent should also feature a
description of foreseeable risks or discomforts to the subject, as well as
any benefits to patients or others. Similarly, a disclosure of appropriate
alternative procedures or courses of treatment if there are any that
might be advantageous to the subjects should be included in the
informed consent form2. In this survey, adverse events and risks related
to new investigational treatments were found to be one of the most
frequent reasons for refusing participation.
Yörük et al.
81
The primary authority who can convince a patient to take part in
a clinical trial is the physician. Tanai et al, reviewed the characteristics
of and the outcomes for patients with advanced non-small-cell lung
cancer who declined to participate in randomized clinical
chemotherapy trials11. They retrospectively evaluated patients’
characteristics and outcomes from two randomized clinical trials for
patients who had not received chemotherapy for advanced nonsmall cell lung cancer. Among the background patient characteristics,
the only variable associated with trial participation or refusal was the
frequency of physician visits for patients (p<0.001). There was no
evidence to suggest any difference in the characteristics and clinical
outcomes between the two groups. It was concluded that trial
designs and the doctor-patient relationship may have an impact on
patient participation in randomized trials.
Informed consent is a legal condition whereby a person gives
consent based upon a clear appreciation and understanding of the
facts, implications and future consequences of an action. This is a
particularly complex decision in clinical trials, because there are often
unproven benefits and increased risks associated with the
experimental treatments being offered. Complications and drug side
effects are commonly referred to in research studies as adverse
events. Adverse events that are already known to occur from past
experience with the treatment or drug under study (e.g. from trials
at an earlier phase) are called suspected (anticipated) adverse events.
On the other hand, unexpected complications may still arise and
they are called unsuspected (unanticipated) adverse events (e.g.
any new complications that appear during Phase III trials). In this
survey, the risk of being faced with an adverse event is the second
most frequent reason for declining participation. Weckstem et al,
also suggested that possible side effects are the most frequent
reason for declining a trial by cancer patients12.
Coverage of all treatment and trial specific evaluation costs is an
ethically important point in clinical trials. Economically
disadvantaged patients may be considered vulnerable subjects13. In
Turkey, total social security coverage is as high as 94%14, and some
investigators have frequently mentioned that some of their patients
had refused to participate as they were covered by social security.
However, health insurance coverage was not cited as a reason for
declining participation in a trial in this survey.
Informed consent can be complex to evaluate, in this case
because it was unclear whether either the expression of consent or
an acknowledged understanding of its implications was genuinely
comprehended by the patients. Contrary to expectations, the
terminology and length of the informed consent form appeared to
have no impact on the survey results. As information about the
patients’ understanding of the informed consent process is lacking in
the present study, the issue could be addressed in a second wave of
ClinRec projects. Although not conclusive, available data suggest that
research participants may frequently not understand the disclosed
information. Failure to understand the details and risks of the trial
may not only compromise participation, but also the process of
informed consent. It is important to understand the psychosocial
outcomes related to the decision-making processes in individuals
who are eligible for, and are considering participation in clinical trials,
and specifically to consider factors such as : knowledge about
treatment options, expectations of treatment outcomes, satisfaction
with decision-making, and regret over treatment decisions15. It has
been suggested that making a truly informed decision requires that
82
Yörük et al.
participants receive and weigh information from a variety of different
sources, which may not be possible if consent is given quickly. Stryker
et al, conducted a survey to understand the psychosocial outcomes
related to decision-making processes in individuals eligible for
participation in clinical trials15. The survey, which covered 50
individuals eligible to participate in selected clinical trials, measured
satisfaction with decision-making, decisional regret, and timing of
consent (early versus late signers). The authors concluded that
participants who enroll in clinical trials quickly may believe they do
not fully understand the implications of trial participation, and
emphasized that more effort is needed to ensure that clinical trial
participants fully understand the risks and benefits of participation
and are satisfied with their decision to enroll in a trial prior to signing
consent forms. Efforts to improve understanding through the use of
multimedia and enhanced consent forms have had limited success.
Flory and Emanuel concluded that having a study team member or
a neutral educator spend more time talking one-on-one to study
participants appears to be the most effective available way of
improving research participant’s understanding16. Nowadays,
decision-aids are being explored for use in clinical trials; and it has
been cited that more than 90% of patients found this helpful in terms
of trial participation and understanding of the information sheet17.
Decision-aids typically contain evidence-based information presented
in a simple, graphical form and lead patients through a process of
clarifying their values and weighing the pros and cons of the options
before decision making18.
New technologies (internet communications tools –e.g.
Facebook, Twitter- and mobile tools such as Short Message Service)
are under evaluation as a means of reaching patients and building
patient trust of clinical research. Utilization of these tools by patients
for communicating with other patients, and by advocacy and
support groups is growing exponentially. Many such groups have
made it known that they would positively welcome news about
trials that might affect the health of their members. These web
based tools are also used frequently to share experience. Using
these new technologies and communication tools in a preplanned,
prospective way may help recruitment to clinical trials.
Conclusion
Patient barriers for enrollment include the ‘guinea pig’
perception held by patients and /or relatives, anxiety caused by
uncertainty, additional demands of the trial, and concerns about
information and consent. Having dedicated research staff on hand
to support clinical staff and patients during the informed consent
process may help to overcome these barriers, as time constraints
faced by the investigator are one of the main barriers in enrollment.
Additional work is needed on simplifying the informed consent
form and properly evaluating strategies to further overcome
enrollment barriers. A short and a long term communication
campaign to present scientific information about clinical trials from
academicians/professionals to the public will also help to improve
recruitment in clinical trials in Turkey.
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commission on the medical war crimes, and the Nuremberg code. Bull
Hist Med 2001;75: 37–71.
Weinfurt K P. Outcomes research related to patient decision making in
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doi: 10.1016/S0149-2918(03)80104-2
Lemonick MD, Goldstein A. At your own risk. Time (US Edition). April 22,
2002; 159: 46-56.
Hare J. Battling for patients. Scrip Clinical Research 24 August 2009
http://www. scripclinicalresearch.com Accessed July 20th, 2010.
Simmons D. Restoring public trust in clinical research through outreach
and education Monitor 2008 September; 23-6.
Tanai C, Nokihara H, Yamanoto S, et al. Characteristics and outcomes of
patients with advanced non-small-cell lung cancer who declined to
participate in randomised clinical chemotherapy trials. Br J Cancer 2009;
100: 1037-42. doi:10.1038/sj.bjc.6604982
Weckstem D, Thomas C, Emery IF, et al. The assessment of cost and other
barriers to patient clinical trial participation in the community setting.
2010 ASCO Annual Meeting. Citation: J Clin Oncol 2010;28:7s (suppl;
abstr 6030)
Smith-Tyler J. Informed consent, confidentiality, and subject rights in
clinical trials. Proc Am Thorac Soc 2007;4: 189-93.
Republic of Turkey, Ministry of Health Statistical Data, December 2008,
www.sgk.gov.tr (legal web site of Turkish Ministry of Health) Accessed on
July 20th,2010.
Stryker JE, Wray RJ, Emnos KM, et al. Understanding the decisions of
cancer clinical trial participants to enter research studies: Factors
associated with informed consent, patient satisfaction, and decisional
regret. Patient Educ Couns 2006; 63: 104-9.
doi:10.1016/j.pec.2005.09.006
Flory J, Emanuel E. Interventions to improve research participants’
understanding in informed consent for research: A systematic review.
JAMA 2004; 292:1593-601. doi:10.1001/Jama.292.13.159
Juraskova I, Butow P, Lopez A L, et al. Improving informed consent in
clinical trials: Successful piloting of a decision aid. J Clin Oncol 2007;
25:1443-56. doi:10.1200/JCO.2006.09.5471
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health treatment or screening decisions: Systematic review. Br Medical J
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83
DOI: 10.5472/MMJ.2012.01947.3
Infants with Cholestasis: Diagnosis, Management and Outcome
İnfantlarda Kolestaz: Tanı,Tedavi ve Prognoz
Nafiye URGANCI1, Feyzullah ÇETİNKAYA1, Derya KALYONCU1, Esra PAPATYA ÇAKIR1, Banu YILMAZ2
1Child
Health and Pediatrics Clinic, Şişli Etfal Training and Research Hospital, İstanbul, Turkey
Clinic, Şişli Etfal Training and Research Hospital, İstanbul, Turkey
2Patology
Abstract
Özet
Objective: : Infants with cholestatic jaundice were evaluated retrospectively
in terms of etiologies, diagnostic methods, laboratory findings, treatment
procedures and long- term prognosis.
Patients and Methods: The study consisted of 70 children (52.8% male,
47.1% female) with cholestasis ranging in age from 15 days to 8 months
(mean age, 60±26 days). Patients were divided into three groups
according to the diagnosis: (i) patients with extrahepatic biliary atresia, (ii)
patients with intrahepatic biliary hypoplasia, and (iii) patients with
hepatocellular disease. Their clinical parameters were evaluated.
Results: In the group with extrahepatic biliary atresia the onset of jaundice
was significantly earlier and the presence of acholic stool and total bilirubin
levels were remarkably higher than in the groups with intrahepatic
biliary hypoplasia or hepatocellular disease. Serum gamma-glutamyl
transpeptidase (GGT) and alkaline phosphotase (ALP) levels were found to
be significantly higher in the groups with extrahepatic biliary atresia and
intrahepatic biliary hypoplasia than the group with hepatocellular disease
(p<0.001 and p<0.01, respectively). The contribution of technetium-99m
(99mTc) scintigraphy to the diagnosis was significantly higher in the group
with extrahepatic biliary atresia than the groups with intrahepatic biliary
hypoplasia and hepatocellular disease (p<0.002).
Conclusion: It was found that cholestasis, acholic stool and elevated GGT
are better markers for extrahepatic biliary atresia than for intrahepatic biliary
hypoplasia or hepatocellular disease in infants. The contribution of
scintigraphy to the diagnosis was found to be higher in the group with
extrahepatic biliary atresia than in the other groups. (Marmara Medical
Journal 2012;25:83-6)
Key Words: Biliary atresia, Hepatocellular disease, Neonatal cholestasis,
Biliary hypoplasia, Jaundice
Amaç: Kolestaz nedeniyle takip edilen çocuk hastalarda etyoloji, tanı
yöntemleri,laboratuvar bulguları,tedavi şekilleri ve uzun dönem prognozları
açısından geriye dönük olarak incelenmesidir.
Hastalar ve Yöntem: Çalışmaya 15 gün-8 ay (ortalama yaş, 60±26 gün,
%52,8 erkek, %47,1 kız) kolestaz tanısı ile izlenmiş olan 70 vaka dahil edildi.
Hastalar, (i) ekstrahepatik, (ii) intrahepatik biliyer atrezili hastalar, intrahepatik
biliyer hipoplazi (iii) hepatoselüler hastalığı olanlar olmak üzere 3 gruba
ayrıldı. Klinik parametreleri değerlendirildi.
Bulgular: Ekstrahepatik biliyer atrezili hasta grubunda diğer gruplara kıyasla
sarılığın başlangıç zamanı belirgin olarak daha erken, total bilirubin düzeyi
daha yüksek ve akolik dışkı görülme sıklığı daha fazla saptandı. Serum
gama-glutamil transpeptidaz (GGT) ve alkalin fosfotaz (ALP) düzeyleri
ekstrahepatik biliyer atrezi ve intrahepatik biliyer hipoplazi gruplarında
hepatoselüler hastalığı olan gruba göre daha yüksek saptandı ( p<0.001 ve
p<0.01). Sintigrafinin tanıya katkısı ekstrahepatik biliyer atrezi grubunda
intrahepatik biliyer hipoplazi ve hepatoselüler hastalığı olan gruplara göre
daha anlamlı saptandı (p<0.002).
Sonuç: Kolestaz, akolik dışkı ve yüksek GGT düzeyleri ekstrahepatik biliyer
atrezili vakalarda, intrahepatik biliyer hipoplazi ve hepatoselüler hastalığı
olan vakalara göre daha iyi belirteçlerdir. Technetium-99m (99mTc) ile
yapılan sintigrafinin tanıya katkısının ekstrahepatik biliyer atrezi grubunda
diğer gruplara göre daha belirgin olduğu görüldü. (Marmara Üniversitesi
Tıp Fakültesi Dergisi 2012;25:83-6)
Anahtar Kelimeler: Biliyer atrezi , Hepatoselüler hastalık, Neonatal kolestaz,
Biliyer hipoplazi, Sarılık
Correspondence to/İletişim: Derya Kalyoncu, M.D., Child Health and Pediatrics Clinic, Şişli Etfal Training and Research Hospital, İstanbul, Turkey
84
Urgancı et al.
Infants with Cholestasis
Introduction
Cholestasis is defined as reduced bile flow and abnormal
accumulation of conjugated bilirubin, indicating impaired
hepatobiliary function. Obstructive (extrahepatic, intrahepatic) or
hepatocellular (infectious, metabolic, toxic, genetic or idiopathic)
diseases may cause cholestasis in newborns and infants1-5.
Although extrahepatic biliary atresia (EHBA) and neonatal
hepatitis constitute a major part of the cholestatic diseases, it is
difficult to make a differential diagnosis in cases with severe
neonatal hepatitis mimicking EHBA3,6,7.
Therefore, further studies are being conducted to use more
effective methods in the differential diagnosis of neonatal
cholestasis6-9.
Early detection is essential to facilitate timely intervention and
minimize adverse outcomes in several conditions, including biliary
atresia, hypothyroidism, and galactosemia. Thus, a systematic
approach is helpful to establish the diagnosis quickly. Even when
treatment is not available and effective, infants who have progressive
liver disease benefit from optimal nutritional support and medical
management of the complications of cholestasis and possibly
cirrhosis.
The aim of this retrospective study is to evaluate 70 cases with
cholestasis in the neonatal period and in infancy in terms of
etiologies, diagnostic methods, treatment modalities and the
relationship of these with prognosis.
Patients and Methods
Seventy infants with neonatal cholestasis diagnosed between
1998 and 2004 at the Department of Pediatric Gastroenterology
of Sisli Etfal Training and Research Hospital Istanbul, Turkey were
evaluated retrospectively. Neonatal cholestasis was defined as
prolonged conjugated hyperbilirubinemia concentration in a
neonate at a level above 1.0 mg/dl where the total serum
bilirubin is <5.0 mg/dl, or greater than 20 percent of the total
serum bilirubin where the total serum bilirubin is >5.0 mg/dl.
Patients were divided into three groups according to the
diagnosis: (i) patients with EHBA, (ii) patients with intrahepatic
biliary hypoplasia (IHBH) and (iii) patients with hepatocellular
disease (HCD). Significantly low birth weight for gestational age,
the onset time of jaundice, and the presence of acholic or
hypocholic stools were recorded. Hemoglobin levels, white
blood cell counts, levels of alanine transaminase, gammaglutamyl transpeptidase (GGT), alkaline phosphatase (ALP), acid
phosphatase, total bilirubin and direct bilirubin, total protein,
albumin, globulin, alpha 1-antitrypsin were examined in all cases.
Also serological tests for hepatitis B, hepatitis A, toxoplasma,
rubella, cytomegalovirus (CMV), herpes simplex (TORCH) and
Epstein Barr virus infections, Venereal Disease Research Laboratory
(VDRL), blood and urine tests for amino acids, sweat chloride test,
thyroid function tests and abdominal ultrasonography were done.
Bone marrow aspirates were examined to rule out storage
diseases. A closed needle liver biopsy using a Menghini needle
was performed in sixty-six cases under intravenous sedation
with midazolam (0.1 mg/kg). Informed consents were taken
from all of the parents before the biopsy. If histopathological
examination of the liver revealed the presence of bile duct
proliferation, periportal fibrosis and bile duct obstruction, the
condition was described as EHBA. If the ratio of the number of
bile ducts to the number of portal fields was < 0.5, then it was
described as IHBH, and HCD was diagnosed by the presence
of a lobular disorder, giant cell formation, portal inflammation
and minimal fibrosis. Thirty-one cases underwent biliary tract
scintigraphy with 99mTc, and excretion into the intestine
observed during hepatobiliary scintigraphy was used to rule out
EHBA.
All the cases received a formula rich in medium-chain fatty acids
in addition to the maternal milk, but those diagnosed as metabolic
diseases received a specific formula and vitamins A, D,E and K.
Patients with cholestasis were started on ursodeoxycholic acid (10
mg/kg/day). Perioperative cholangiography was done to confirm
the diagnosis of EHBA and a Kasai operation was performed to
establish bile drainage in these patients. If bile flow is not restored
by the Kasai procedure or if life- threatening complications of
cirrhosis ensued then a liver transplantation was considered.
Statistical Analysis
The statistical analysis was performed by the program SPSS
11.0 (Chicago, IL, USA). The chi-square test, Fisher’s exact test,
ANOVA (Tukey-Kramer Test) were used. A value of p<0.05 was
considered statistically significant.
Results
The age of patients ranged from 15 days to 8 months (mean,
60±26 days), and the male: female ratio (37 male, 33 female) was
1.12. The history of 30 patients (42.8%) revealed parental
consanguinity and four (5.7%) were sibling deaths. All of the
patients were born at term, and 12 had low birth weights.
Fourteen of the patients (20%) had EHBA, six (9.2%) had
IHBH and 50 (71.42%) had HCD. In the EHBA group, two had a
CMV infection and one had a hepatitis B infection. In the HCD
group, 11 (22%) patients had idiopathic neonatal hepatitis (INH),
22 (44%) had CMV hepatitis, four had tyrosinemia, four had
septicemia, two had Niemann-Pick disease, one had hepatitis A,
one had hepatitis B, one had a congenital rubella infection, one
had alpha 1-antitrypsin deficiency, two had galactosemia and one
had hemochromatosis. No case of syndromic variety was
diagnosed. No relationship was established between the age of
patients at admission to hospital and the rate of splenomegaly.
Portal hypertension was not detected in any patient. The clinical
and laboratory findings are shown in Tables I and II.
The onset time of jaundice was significantly earlier for EHBA
than for HCD (p<0.05). The presence of acholic stool was
remarkably higher in the EHBA group. Serum GGT and ALP levels
were significantly elevated for EHBA and IHBH (p<0.001 and
p<0.01, respectively). Although CMV IgM was positive in all
patients diagnosed as CMV hepatitis, CMV DNA was detected in
only 12 patients. Increased serum phenylalanine and tyrosine
levels were documented in four patients, and succinylacetone was
Urgancı et al.
85
Table I. Clinical Findings in Patients with Neonatal Cholestasis
HCD (n=50)
EHBA (n=14)
IHBH (n=6)
44 (88%)
14 (100%)
4 (66.6%)
62 (88.5%)
15.9*
4.5*
11*
17.6 (1-99) jaundice(days)
·Acholic stools
16 (32%)**
13 (92.8%)**
3 (50%)**
32 (45.7%)
·Hepatomegaly
38 (76%)
14 (100%)
6 (100%)
58 (82.8%)
·Splenomegaly
33 (66%)
11 (78.5%)
2 (33.3%)
46 (65.7%)
· Jaundice
·Onset time
Total (n=70)
HCD: hepatocellular disease, EHBA: extrahepatic biliary atresia, IHBH: intrahepatic biliary hypoplasia
* p< 0.05 ** p<0.001
Table II. Laboratory Findings in Patients with Neonatal Cholestasis
HCD (n=50)
EHBA (n=14)
IHBH (n=6)
188±243
228±275
167±133
·GGT (IU/L)
116±94*
480±234*
321±235*
·ALP (IU/L)
143±211
870±654
679±546
· T. bilirubin (mg/dl)
7.8±4.9
14.4±5.9**
9.4±4.5
· D.bilirubin (mg/dl)
5.8±3.8
8.7±6.3
7.8±6.4
·ALT (IU/L)
HCD: hepatocellular disease, EHBA: extrahepatic biliary atresia, IHBH: intrahepatic biliary hypoplasia
* p<0.01
found in the urine of all four patients. None of the patients were
diagnosed as neonatal intrahepatic cholestasis caused by citrin
deficiency (NICCD).Only one had high serum ferritin levels and
high transferrin saturation. Bone marrow examinations showed
storage cells in only two patients.
Abdominal ultrasonography (US) was normal in 12 cases. Thirtythree cases had hepatosplenomegaly and 25 had isolated
hepatomegaly. No anatomical abnormalities were observed in the
bile ducts by US. The children were also evaluated for triangular cord
(TC) sign, presence and morphology of gall bladder and contraction
after oral feed. The ultrasonographic findings were not significantly
different between the groups (p>0.05). In twelve patients with EHBA
(85.7%), three cases with IHBH (50%) and eighteen cases with HCD
(36%), hepatobiliary scintigraphy (99m Tc) showed no excretion into
the intestinum. Scintigraphy contributed to the diagnosis of the EHBA
group in particular, more than in the other two groups (95%
CI:0.35-0.58; p<0.002). Liver tissue specimens were taken from 65
patients (92.85%). Five patients with EHBA, four with CMV hepatitis,
two with tyrosinemia, and two with idiopathic neonatal hepatitis had
severe portal fibrosis and progression to cirrhosis. Liver tissue
specimens revealed increased iron deposition in hemochromatosis
and the presence of diastase-resistant hepatocyte inclusions that stain
positively for periodic acid-Schiff in alpha 1-antitrypsin deficiency.
No improvement was observed in 3 of 10 patients with CMV
infection who received antiviral treatment (gancyclovir). A Kasai
operation was performed in 6 patients with EHBA. One of those
patients who is still being followed up received a liver transplant. In
addition, two patients with galactosemia, one with a hepatitis A
infection, one with neonatal hepatitis associated with a congenital
rubella infection, one with alpha1- antitrypsin deficiency and one
with a chronic active hepatitis B infection are still outpatients being
followed up by our department of pediatric gastroenterology.
Discussion
Since an early diagnosis is very important for the prognosis, the
direct bilirubin level should be measured in all infants admitted
with jaundice10,11. Mowat et al.12, Alagille et al.13, and Lai et al.6
have reported that the reliability of the onset time of the jaundice
was 83.3% and 57.1% in EHBA and HCD, respectively. It has been
determined that herpes viruses, particulary CMV, rubella virus and
probably enteroviruses may play a role in the development of
intrahepatic neonatal cholestatis. Recently, it has been suggested
that the reovirus type 3 and the rotavirus type 2 may be associated
with EHBA14-16. Fischler et al.17 showed by polymerase chain
reaction (PCR) that CMV infection had a role in EHBA as well and
also in intrahepatic neonatal cholestasis. CMV IgM and CMV DNA
were positive in two of our twelve patients with biliary atresia. It has
been reported that intrauterine CMV infection may lead to
intrahepatic biliary tract hypoplasia18 . In our study CMV Ig M and
CMV DNA were found positive in one of six patients with IHBH.
Based on the period during which atresia occurs, EHBA is divided
in embryonic or fetal form and a more common, perinatal form. In
our study, the cases with EHBA were classified as embryonic because
the jaundice started shortly after birth. Although there is frequently
an association with a variety of congenital anomalies in this form of
EHBA, we did not detect any anomalies in our cases.
Chang et al.19 reported that most of their patients with
neonatal hepatitis were due to a CMV infection. Fifty-six of our
cases (80%) had intrahepatic cholestasis. Twenty-nine of those
86
Urgancı et al.
(51.7%) were due to infections, ten (17.8%) to metabolic
diseases, and six (10.7%) IHBH. Almost 34% of our cases with
neonatal hepatitis had CMV hepatitis. CMV IgM was positive in all
cases whereas CMV DNA was positive in only 12 cases. None of
five infants whose mothers had positive serology for CMV IgM,
had clinical or laboratory findings compatible with CMV hepatitis.
Idiopathic neonatal hepatitis has an incidence of 1:5000 births
and constitutes approximately 50% of prolonged neonatal
jaundice2. In our study, 11 (15.7%) of our cases were diagnosed
as isonicotinylhydrazine (INH). This higher rate can be explained
by difficulties in determining the viral factors. Jacquemin et al.20
reported that in patients with temporary neonatal cholestasis, the
jaundice resolved in 3.5 months and liver enyzmes normalized in
10 months. It has been shown that in cases with neonatal
cholestasis who had a history of neonatal asphyxia, the bilirubin
levels improved in 6 months and liver function tests within 1
year21. Similarly, we observed that in cases with intrahepatic
cholestasis, the direct bilirubin levels normalized in 5.5 months,
and liver enzymes within 11 months.
There are many inherited metabolic disorders which may
present with hepatitis-like manifestations22. 14.2% of our cases were
diagnosed as tyrosinemia, galactosemia, Niemann- Pick disease or
alpha1-antitrypsin deficiency. Although, citrin deficiency has been
reported to manifest as neonatal intrahepatic cholestasis23, none of
our patients had an abnormal amino acid analysis that demonstrated
citrin deficiency. Also, none of our patients was diagnosed as having
cystic fibrosis which is very common in our country due to high
prevalence of parental consanguinity.
In conclusion, infectious diseases and metabolic disorders are
the most common causes of neonatal cholestasis in our country
because of the high rate of parental consanguinity and
inadequate prenatal follow-up programs. The early identification
and treatment of children with cholestasis is essential, especially of
those who need corrective surgery for extrahepatic biliary atresia
in order to improve long-term outcomes. It is important to keep
in mind that jaundice, acholic stools and elevated GGT are better
markers for patients with EHBA compared to patients with
intrahepatic biliary hypoplasia and hepatocellular disease .
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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doi:10.1007/s00431-002-1045-2.
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DOI: 10.5472/MMJ.2012.02272.1
A Turkish Adaptation of the Student Version of the Jefferson
Scale of Physician Empathy
Jefferson Doktor Empati Ölçeği Öğrenci Versiyonunun Türkçe Adaptasyonu
İpek GÖNÜLLÜ1, Derya ÖZTUNA2
1Department
of Medical Education and Informatics, School of Medicine, Ankara University, Ankara, Turkey
2 Department
of Bioistatistics, School of Medicine, Ankara University, Ankara, Turkey
Abstract
Özet
Objective: The aim of this study was to adapt the student version of the
Jefferson Scale of Physician Empathy (JSPE) to Turkish medical students in
order to assess its reliability and validity, and to analyze the gender and year
differences.
Materials and Methods: The student version of the JSPE was translated
into Turkish using back-translation procedures, and was administered
to 752 medical school students from the first to fifth years of study. To
assess the dimensionality of the scale, confirmatory factor analysis
(CFA) for categorical data was carried out. Internal consistency was
assessed by Cronbach’s alpha. Subscale scores were compared in terms
of gender and year.
Results: The three-dimensional structure of the JSPE was confirmed by CFA
except item 18. The internal consistencies of the subscales were 0.83, 0.70
and 0.60, respectively. There were statistically significant gender and
medical school year differences in terms of “perspective taking” and
“compassionate care” scores.
Conclusion: The student version of JSPE was successfully adapted, and the
adapted scale can be used in Turkey. (Marmara Medical Journal 2012;25:87-92)
Key Words: Undergraduate medical education, Empathy, Jefferson Empathy
Scale, Reliability, Validity, Confirmatory factor analysis
Amaç: Çalışmanın amacı Jefferson Doktor Empati Ölçeği öğrenci
versiyonunun güvenirlik ve geçerliliğinin değerlendirilmesi, cinsiyet ve eğitim
yıllarına göre farklılıklarının analiz edilmesi için tıp fakültesi öğrencilerine
adaptasyonunun yapılmasıdır.
Gereç ve Yöntem: Jefferson Doktor Empati Ölçeği öğrenci versiyonu iki yönlü
çeviri yapılarak Türkçe'ye çevrilmiş ve 1.-5. sınıf düzeylerindeki 752 tıp
fakültesi öğrencisine uygulanmıştır. Ölçeğin boyutluluk yapısının
değerlendirilmesinde kategorik verilerde doğrulayıcı faktör analizi (DFA)
kullanılmıştır. İç tutarlılık Cronbach alfa katsayısı ile değerlendirilmiştir. Alt
ölçek puanları eğitim yıllarına göre farklılıkları karşılaştırılmıştır.
Bulgular: DFA, bir madde hariç ölçeğin mevcut üç boyutlu yapısını doğrulamıştır.
Alt ölçekler için iç tutarlılık katsayıları sırasıyla 0,83, 0,70, ve 0,60 olarak
bulunmuştur. "Perspektif alma" ve "şevkatli bakım" puanları açısından cinsiyet ve
eğitim yılları arasında istatistiksel olarak anlamlı farklılık bulunmuştur.
Sonuç: Türkçe'ye adaptasyonu başarılı biçimde yapılan Jefferson Doktor Empati
Ölçeği öğrenci versiyonu, Türkiye'de tıp fakültelerinde öğrenciler üzerinde
kullanılabilir. (Marmara Üniversitesi Tıp Fakültesi Dergisi 2012;25:87-92)
Anahtar Kelimeler: Mezuniyet öncesi tıp eğitimi, Empati, Jefferson Empati
Ölçeği, Güvenirlik, Geçerlilik, Doğrulayıcı faktör analizi
Introduction
Empathy which means understanding another person’s feelings
is a crucial aspect of professionalism in the practice of medicine.
Currently, medical educators emphasise professionalism, particularly
in terms of empathy. Hojat et al.1,2 define empathy in patient-care
situations as “a cognitive attitude that involves an ability to
understand the patient’s inner experiences and perspective and a
Correspondence to/İletişim: İpek Gönüllü MD, PhD, Department of Medical Education and Informatics, School of Medicine, Ankara University, Ankara, Turkey
88
Gönüllü et al.
A Turkish Adaptation of Jefferson Empathy Scale
capability to communicate this understanding”. In this definition
there are three key terms; cognition, understanding and
communication. These three key terms are very important in the
construct of empathy in the context of patient care3.
Lillo et al. consider that empathy involves cognition and is thus
distinguished from sympathy4 which is a predominantly affective or
emotional attribute opposed to empathy5. Both concepts involve
sharing, but empathetic physicians share their understanding,
whereas sympathetic physicians share their emotions with their
patients2,6. In this case empathy, almost always leads to positive
clinical outcomes, whereas sympathy in excess will be detrimental to
objectivity in clinical decision making3. Understanding can be
represented by the physician’s ability “to stand in a patient’s shoes
without leaving his or her own personal space and” to view the world
from the patient’s perspective without losing sight of his or her
professional responsibilities1. Further, a physician’s capability to
communicate this understanding, the patient’s inner experiences and
perspective is also required for empathy2. To understand a patient's
inner experiences and feelings and to view the outside world from
the patient’s perspective will help the physician to foster the patient’s
satisfaction, improve compliance with the health condition and
increase physician’s ability to properly diagnose and treat.
Evolving changes in the health care system such as increasing
technology-based diagnosis and waning bedside interactions,
strains the physician-patient relationship, and empathy becomes
important and timely in medical education. Many changes within
the health-care system that undermine empathy in therapeutic
relationships have stimulated medical educators to begin studying
the development and correlates of physician empathy and its
contribution to clinical outcomes. Enhancing empathic
engagement in patient care is one of the important tasks of
medical education7. A meaningful interpersonal relationship is
assumed to be important for better clinical outcomes, so
physicians should be educated not only in the biomedical aspect
of disease but also in the psychosocial factors of illness. Thus, it has
become increasingly important for medical educators to evaluate
the level of empathy in medical students in order to provide an
appropriate education.
The Jefferson Scale of Physician Empathy (JSPE) was developed as
a self-report scale by researches at Jefferson Medical College in the
United States to measure empathy specifically in medical students,
physicians or health professionals within the context of the physicianpatient relationship1,2,5,8,9. The JSPE has two versions, one for
students (S-Version) and one for physicians and other health
professionals (HP-Version), and includes 20 items to measure the
three underlying constructs of empathy (perspective taking,
compassionate care, and standing in patient’s shoes). It has been
proved that the JSPE has satisfactory psychometric properties2,9,10.
Empathy like other personal qualities varies among individuals,
because it depends upon developmental, experimental, social,
educational and other endogenous and exogenous factors. It also
varies in different cultures because of cultural norms, social
learning and also different medical curriculums. It has been
reported that there were changes in empathy among medical
students as they progress through medical school11. It is
important to record these differences and their effects in different
cultures while developing educational programs.
JSPE has been translated into 38 languages and has been used in
many countries to date5. The results of previous validation studies
(e.g. Mexican, Polish, Japanese, Italian and Korean) have shown
satisfactory psychometrics of the scale and a number of similarities
and differences have been illustrated4,12-16. The differences among
the countries suggest that different cultures or medical curriculums
may influence empathy measures and outcomes1.
The importance of determining the factors that affect empathy in
medical students has long been recognized by Turkish researchers17.
However, there is no adapted or original measurement tool that can
be used to determine empathy in medical students in Turkey.
Consequently, it is necessary to adapt and use the JSPE in medical
schools. The primary purpose of this study was to adapt the student
version of JSPE to the Turkish population and examine the reliability
and validity of it for use in Turkish medical schools. In addition to the
psychometric properties of the JSPE, empathy score differences were
tested in terms of gender and year.
Method
Participants
This study has been applied on students between the 1st and
years of study during 2008 and 2009 at Ankara University
School of Medicine (AUSM) in Turkey. Volunteers, who completed
the JSPE, were not compensated for their participation.
The medical curriculum in AUSM which runs a 6-year
programme comprises 3 years of preclinical work followed by 3
years of clinical work (2 years of clerkships and one year’s
internship). Turkish medical schools are undergraduate schools
which start after high school. Thus, Turkish medical students are
likely to be younger than U.S. medical students. Classes in
communication skills are arranged during the 1st, 2nd, and 3rd
years, and these include 6 hours of class and 1 hour of
standardized patient interview in each year.
5th
Instrument
In this study, the student version (S-Version) of the JSPE,
translated into Turkish was used. The S-version was developed to
measure medical students’ attitudes toward empathic physicianpatient engagement in the context of patient care. Psychometric
properties of this scale have been previously reported1,2,5,9-11.
The scale includes 20 items (10 items positively worded and
10 items negatively worded) answered on a 7-point Likert scale
from 1 (strongly disagree) to 7 (strongly agree). The score interval
is 20-140, higher scores show higher empathic consistency.
Procedures
The JSPE was translated into Turkish by three bilingual medical
doctors. By using the back-translation procedure, the original
translated version was sent to another three bilingual medical
doctors to ensure the accuracy of the translation and they were
asked to translate the Turkish version back into English. Backtranslators were not aware of the intent and concepts underlying
the scale16. Then a committee (one of the authors, one
psychiatrist, one professor of ethics and a bilingual translator) was
constituted in order to produce a final version based on the
reviewed, three back-translated versions. In 2008-2009, we
distributed the final translated version of the JSPE to the 1st, 2nd,
3rd, 4th and 5th year students during their regular classes, they
took the test individually, and were told that the instrument was
about empathy, the results would be used for research purposes.
The study was approved by the University’s Research Ethics
Committee.
The psychometric properties of a scale are determined
through a range of analyses. This includes tests for reliability and
validity. Reliability is concerned with the consistency of the scale.
Validity is concerned with whether the scale measures the
characteristic it purports to measure.
The most common form of reliability test for a self-completed
scale in a Likert format, such as the present scale, is internal
consistency and this was tested by Cronbach’s alpha coefficient18.
Usually a reliability of 0.70 is required for analysis at the group
level, and values of 0.85 and higher for individual use19.
The validity of the student version of JSPE was examined by
confirmatory factor analysis (CFA). In order to assess whether the
data would fit the proposed model for “Perspective taking”,
“Compassionate care” and “Standing in the Patient’s Shoes”
components, a three-factor CFA for categorical data was applied
with a weighted least (WLSM)X2 estimation with robust standard
errors and mean- and variance-adjusted statistics. Items with path
weights below 0.40 or those with the proportion of explained
variance (R2) below 0.30 were eliminated. The following goodnessof-fit indices were used to assess the degree of fit between the
model and the sample: Comparative Fit Index (CFI; >0.90:
acceptable, >0.95: excellent), Tucker-Lewis Index (TLI; >0.90:
acceptable, >0.95: excellent) and root-mean-square error of
approximation (RMSEA; <0.08: acceptable, <0.05: excellent)20.
After the CFA, a Mann-Whitney U test and a Kruskal-Wallis
variance analysis were used to compare the (sub)scale scores in
terms of gender and year, respectively. The post-hoc test for
Kruskal-Wallis variance analysis was used to perform pairwise
comparisons. Mean±standard deviation (SD) [median (minimummaximum)] was used as descriptive statistics. p<0.05 was
considered as statistically significant. Data were analyzed using
the Statistical Package for the Social Sciences (SPSS 11.5), and
MPlus21.
Results
The study sample consisted of 752 participants from first to
fifth years with varying numbers of students at AUSM in Turkey. In
terms of year levels, the distribution of the total sample was as
follows: first year 256 (34.0%), second year 169 (22.5%), third
Gönüllü et al.
89
year 160 (21.3%), fourth year 80 (10.6%) and fifth year 87
(11.6%). Among the students indicating their genders (n=725),
374 (51.6%) of them were male.
Confirmatory Factor Analysis
In our study, the 20 items were subjected to three-factor CFA
to confirm the structure of empathy. According to factor loadings,
R2 and goodness-of-fit statistics, a three-factor structure was
confirmed for the student version of the Jefferson Scale of
Physician Empathy. Items and factor loadings are given in Table I.
Except for Item 18, all 19 items loaded 0.40 or higher. The data
showed a reasonable fit to the model, in which CFI=0.915,
TLI=0.967 and RMSEA=0.065.
Item 18, “Physicians should not allow themselves to be
influenced by strong personal bonds between their patients and their
family members” loaded on the “compassionate care” component
with a factor loading of below 0.40 (-0.010). The underlying reason
for this could be that this item may have lost its accuracy after it had
been translated into Turkish. It may need more careful adaptation in
wording, without the losing intended key concept. Cultural factors
could be another reason because strong personal bonds between the
Turkish family members are very common and are very important
elements of our family life. Also the personal bonds between the
Turkish family members are stronger than Western cultures, but more
studies should be done to justify the underlying reason.
Reliability
The internal consistencies of the components were adequate
at the factor level with Cronbach's alphas of 0.83, 0.70 and 0.60
for the “perspective taking”, “compassionate care” and “standing
in the patient’s shoes” components respectively.
Group Differences
We assessed the gender and year differences for the factor
scores, and found that there were statistically significant gender
and year differences in terms of “perspective taking” and
“compassionate care” scores (Table II). While the empathy scores
for “perspective taking” were higher for females (p=0.001), those
for “compassionate care” and “standing in the patient’s shoes”
were higher for males (p<0.001 and p=0.286, respectively). For the
examination of the year differences, only “compassionate care”
factor scores were found to be statistically significantly different
(p<0.001). Post-hoc tests showed that there were differences
between 1st - 2nd, 1st - 3rd, 1st - 5th, 2nd-3rd and 2nd-4th years.
Discussion
As empathy is essential for the patient-physician relationship,
improving medical students’ empathy is one of the important
tasks of medical education. Development and manifestation of
empathy in the patient care context is a function of experimental
and psychosocial factors, as well as cultural factors. Cross-cultural
differences in norms, ethnicity, religious beliefs, and sex
stereotyping can influence empathic engagement during clinical
encounters1. Awareness of cultural peculiarities can improve
90
Gönüllü et al.
Table I. Items and factor loadings of the items in the student version of the JSPE
Items
Perspective
taking
I believe that empathy is an important therapeutic factor in medical treatment (20)
0.771
Patients value a physician’s understanding of their
feelings which is therapeutic in its own right (10)
0.762
Physicians’ understanding of the emotional status of their patients, as well as that
of their families, is one important component of the physician–patient relationship (16)
0.760
Physicians should try to think like their patients in order to render better care (17)
0.652
Physicians should try to stand in their patients’ shoes
when providing care to them (9)
0.639
Empathy is a therapeutic skill without which the physician’s success is limited (15)
0.638
Understanding body language is as important as verbal
communication in physician–patient relationships (4)
0.593
Physicians should try to understand what is going on in their patients’ minds by
paying attention to their nonverbal cues and body language (13)
0.557
Patients feel better when their physicians understand their feelings (2)
0.549
A physician’s sense of humor contributes to a better clinical outcome (5)
Patients’ illnesses can be cured only by medical or surgical treatment; therefore,
physicians’ emotional ties with their patients do not have a significant
influence in medical or surgical treatment (11)
I believe that emotion has no place in the treatment of medical illness (14)
0.392
Compassionate
care
Standing in the
patient’s shoes
0.829
0.744
Attention to patients’ emotions is not important in history taking (7)
0.669
Asking patients about what is happening in their personal lives is not
helpful in understanding their physical complaints (12)
0.494
Attentiveness to patients’ personal experiences does not influence treatment outcomes (8)
0.491
I do not enjoy reading nonmedical literature or the arts (19)
0.450
Physicians’ understanding of their patients’ feelings and the feelings of their patients’
families does not influence medical or surgical treatment (1)
0.438
It is difficult for a physician to view things from patients ‘perspectives (3)
1.149
Because people are different, it is difficult to see things from patients’ perspectives (6)
0.400
Table II. The gender and year differences for the factor scores of the student version of the JSPE
Perspective taking
Gender
Year
Male
5.40±0.97
[5.50 (1.00-7.00)]
Female
5.64±0.88
[5.80 (2.60-7.00)]
p
Compassionate care
p
2.42±1.02
[2.29 (1.00-6.57)]
0.001
2.14±0.86
[2.00 (1.00-5.33)]
Standing in the patient’s shoes
3.75±1.36
[4.00 (1.00-7.00)]
<0.001
3.63±1.34
[3.50 (1.00-7.00)]
1
5.54±0.91
[5.70 (1.40-7.00)]
2.42±0.85
[2.29 (1.00-5.29)]
3.73±1.35
[4.00 (1.00-7.00)]
2
5.56±1.03
[5.80 (1.00-7.00)]
2.05±0.93
[1.86 (1.00-5.43)]
3.44±1.34
[3.50 (1.00-7.00)]
3
5.44±0.89
[5.50 (1.00-7.00)]
4
5.42±0.98
[5.40 (2.50-7.00)]
2.37±0.96
[2.29 (1.00-5.17)]
3.74±1.26
[4.00 (1.00-7.00)]
5
5.56±0.92
[5.70 (2.30-7.00)]
2.15±1.03
[2.00 (1.00-6.57)]
3.64±1.40
[4.00 (1.00-7.00)]
0.341
2.29±1.04
[2.00 (1.00-5.71)]
p
<0.001
3.91±1.36
[4.00 (1.00-7.00)]
0.286
0.082
Gönüllü et al.
empathic understanding which is the essence of a meaningful
patient-physician relationship2. Empathy is influenced by a
number of factors apart from cultural factors, including variation
in the selection and education of medical students, the availability
of appropriate role-models and the medical curriculum.
In Turkey, there is no adapted or original scale to determine
medical students’ levels of empathy. In this study, the student
version of JSPE was adapted to the Turkish population. The student
version of JSPE has three factors; perspective taking, compassionate
care, and standing in patient’s shoes. Perspective taking which is
the most important component of empathy, can be acquired and
used in everyday life and there is an outcome consistent with that
reported for the general population23. The other two components
of empathy are both specific to the patient-physician relationship2.
In this study, we examined the reliability and validity of the Turkish
version of the student version of JSPE, and our findings supported
the three-dimensional structure that emerged in the American
sample except Item 18 that loaded on “compassionate care”
component with a factor loading of below 0.40. The main reason
for this situation could be related to translation or cultural
differences. The reliability of the student version of JSPE for the
“perspective taking” factor was as high as in its original English
form, and the others were adequate. The internal consistency of
"standing in patient's shoes" factor has a Cronbach alpha of 0.60
for two items. This Cronbach alpha value can be considered not too
bad, when compared with the values of other items. Thus, our
findings indicate that the Turkish student version of JSPE has
satisfactory psychometric properties as a measure of empathy in
Turkish medical students and could be used to identify crucial
factors to effective empathy education in future studies.
Although the student version of JSPE has a three-dimensional
structure, we could not find any articles examining the group
differences (such as gender, year, etc.) in terms of these three
components2,4,12-15.
We found that the empathy scores for “perspective taking” were
higher for females, whereas those for “compassionate care” and
“standing in the patient’s shoes” were higher for males. As the
“perspective taking” is a skill that can be gained and used in
everyday life, there is a popular belief that women are more prone
to value interpersonal relationships and have more competent
understanding of emotions and caring attitude1,2,7,9,14. The finding
obtained in this study verified and strengthened this assumption.
However, the higher scores for “compassionate care” and “standing
in the patient’s shoes” components in favour of male students could
be explained by the structure of these components which were
both specific to the patient-physician relationship. Also, the empathy
scores could be affected by other extrinsic factors which are
attributed to empathy, such as the interpersonal style in caring, rolemodeling, socialization. As a result, these findings are difficult to
explain and more empirical evidence and researches are needed.
The decline of the empathy scores of students during their
medical school years has been demonstrated previously. According
to the present study, when the years were compared crosssectionally, there is a decline in the medical school years in Turkey
too. Statistically significant declines were observed on the
91
“compassionate care” factor scores and post hoc tests showed that
first years had higher scores than second, third and fifth years.
These findings are consistent with previous findings of Hojat et al.11
although their study showed a significant decline in mean empathy
scores in the third year of medical school. They found statistically
significant declines especially in 5 items of the JSPE of which 4
measure the “compassionate care” component. Newton et al.24
also reported a drop in vicarious emotional empathy (measured by
Balanced Emotional Empathy Scale- BEES) during medical school.
These findings suggest that an erosion of empathy occurs
during medical education. Further research is needed to
investigate the reasons and timing of this erosion. Lack of role
models, changes in the health care system, a high volume of
materials to learn, time pressure, patient and environmental
factors can affect the medical students’ visions of the importance
of human interactions and empathy in patient encounters. It is
very important for medical educators to discern exactly the causes
of the decline and to make profound changes in medical
education by developing appropriate educational programs. In
this context, we are also planning to conduct a longitudinal study
to follow the same group of students in different stages of medical
education in order to examine changes in each stage.
Further studies are also needed among Turkish medical
students with larger samples and with other medical schools in
the country. These studies will help us to better understand and
characterize the effects of medical education on Turkish medical
students’ empathic skills.
In conclusion, this study has shown that the student version of
JSPE can be applied to the medical school students in Turkey with
the exception of Item 18, “Physicians should not allow themselves
to be influenced by strong personal bonds between their patients
and their family members” in the original scale. The underlying
reason could be a translation error that it has lost its accuracy after
it had been translated into Turkish or there may have been cultural
differences. As a result to determine the reason further researches
should be done. Also the gender and medical school year findings
of this study need further research to justify the results.
Student version of Turkish JSPE can be used efficiently to
determine the empathy levels of the medical students in terms of
“perspective taking”, “compassionate care” and “standing in the
patient’s shoes” components.
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Psikiyatr Derg 2005;16:83-9.
18. Cronbach LJ. Coefficient alpha and the internal structure of tests.
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20. Pai AL, Mullins LL, Drotar D, Burant C, Wagner J, Chaney JM.
Exploratory and confirmatory factor analysis of the child uncertainty
in illness scale among children with chronic illness. J Pediatr Psychol
2007;32:288-96.
21. Muthén LK, Muthén BO. Mplus User’s Guide 5th ed. Los Angeles: CA;
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23. Davis MH. Measuring Individual Differences in Empathy: Evidence for
a Multidimensional Approach J Pers Soc Psychol 1983;44:113-126
24. Newton BW, Barber L, Clardy J, Cleveland E. Is there hardening of the
heart during medical school? Acad Med 2008;83:244-9.
93
Case Report / Olgu Sunumu
DOI: 10.5472/MMJ.2012.02287.1
Anisocoria due to the Datura Plant
Datura Bitkisine bağlı Anizokori
Muhsin ERASLAN
Ophthalmology Clinic, Sinop Atatürk State Hospital, Sinop, Turkey
Abstract
Özet
Unilateral unresponsive dilatation of the pupil is an alarming finding and may
be secondary to a wide range of ocular and neurological disorders. Ocular side
effects, particularly pupillary dilation with blurring of vision may be alarming
because they can indicate potentially lethal conditions related to some kinds of
plants with local and systemic effects. It may also be only a topical side effect
without any systemic disorder. We herein report a case of mydriasis related to
the datura plant. The right pupil of the patient was dilated and unresponsive
to both the pupillary light reflex (direct, consensual) and the accommodation
reflex. There was no accompanying headache, diplopia, or other neurological
symptom. Topical pilocarpine 2% induced normal constriction of the left pupil
but had no effect on the right, confirming the pharmacological basis of the
right mydriasis. Pupil size and accommodation gradually returned to normal
after three days without any treatment. In some conditions as in this case the
pupil dilation with blurring of vision is only a topical side effect of some kinds
of plants without any systemic disorder. A detailed history and this simple
topical pilocarpin test provided us vaulable information and eliminated the
need for unnecessary expensive neuro-imaging and the use of unnecessary
medication.It also prevented us from squandering the time of the emergency
services.. (Marmara Medical Journal 2012;25:93-5)
Key Words: Mydriasis, Unilateral, Anisocoria, Datura, Gardener’s pupil
Tek taraflı pupil dilatasyonu çok geniş bir dağılımdaki oküler ve nörolojik
bozukluklara ikincil gözlenebilir. Oküler yan etkiler, özelikle görme
bulanıklığı ve pupil dilatasyonu, bazı bitki ürünlerinin neden olabileceği
lokal ve sistemik etkiler ile gelişen ve ölümcül olma potansiyeli bulunan
durumların uyarıcısı olabilir. Fakat sistemik bozukluğun gözlenmediği
sadece topikal yan etkiler de oluşabilir. Burada datura bitkisine bağlı oluşan
bir midriyazis vakası sunuldu. Sağ pupil dilate haldeydi. Sağ pupil hem ışık
refleksine (direk ve indirek) ve hem de akomodasyon refleksine cevapsızdı.
Hastada eşlik eden bir başağrısı, diplopi veya diğer bir nörolojik semptom
yoktu. Topikal %2 lik pilokarpin ile sol pupillada konstriksiyon ortaya
çıkarken sağda hiçbir etki gözlenmemesi midriyazisin farmakolojik temelini
doğrulamaktaydı. Bunun gibi bazı olgularda görme bulanıklığı ile birlikte
olan pupil dilatasyonu birkaç tür bitkinin neden olduğu, sistemik herhangi
bir bozukluk olmadan sadece topikal olarak gözlenen bir yan etki olabilir.
Detaylı anamnez ve basit topikal pilokarpin testi bize önemli bilgiler verir ve
gereksiz ve pahalı radyolojik görüntüleme yöntemlerinden, gereksiz
medikal tedavilerden korunmuş olunur ve acil durumlarda zaman kaybı
önlenmiş olunur. (Marmara Üniversitesi Tıp Fakültesi Dergisi 2012;25:93-5)
Anahtar Kelimeler: Midriyazis, Tek taraflı, Anizokori, Datura, Bahçıvan
Pupillası
The 3rd World Congress on Controversies in Ophthalmology (COPHy) Anterior Segment, Retina, Glaucoma. Istanbul, Turkey, March 22 - 25, 2012
Introduction
Unilateral unresponsive pupil dilation may be secondary to a
wide range of ocular and neurological disorders. Ocular disorders
which cause unilateral mydriasis include third nerve palsy, Adie's
pupil, traumatic mydriasis, and pharmacologic mydriasis. We
report a case of mydriasis related to datura plant products. This
condition is called "Gardener’s pupil" in the literature and is a
pharmacological mydriasis caused by exposure to plants
containing alkaloids such as scopolamine, hyoscyamine, or
atropine1,2. This report emphasises the importance of accurate
history taking when evaluating a fixed and dilated pupil.
Correspondence to/İletişim: Muhsin Eraslan, M.D., Ophthalmology Clinic, Sinop Atatürk State Hospital, Sinop, Turkey
94
Muhsin Eraslan
Case Report
A healthy 27 year old white male presented with a unilateral fixed
dilated pupil, associated with blurred vision, noted 2 hours earlier.
There was no accompanying headache, diplopia, or other
neurological symptom. The past medical history was unremarkable.
Inadvertent self medication was denied.
General and neurological examination was normal. Visual acuity
measured 10/10 for distant vision in both eyes. Examination of
the anterior segments and fundus were unremarkable. Ocular
movements were full, and the eyes were orthophoric. However, the
right pupil was dilated and unresponsive to both the pupillary light
reflex (direct, consensual) and the accommodation reflex (Figure 1).
Instillation of topical pilocarpine 2% induced normal constriction
of the left pupil but had no effect on the right, confirming the
pharmacological basis of the right mydriasis3 (Figure 2). The patient
was a gardener and during the history taking, he recalled that 4 hours
ago a leaf of a datura plant had accidentally gotten into his eye while
working in the garden.
On the second day’s examination, the right pupil was middilated (Figure 3). And the patient brought some types of plants that
have the potential to be the source. One of them was the datura
plant which is the most popular of the ornamental plants that
contain anticholinergic substances (Figure 4). Pupil size and
accommodation gradually returned to normal on the third day
without any treatment. Written permission was obtained from the
patient to publish his photographs and other information.
Discussion
Figure 1. Before instillation of topical pilocarpin
"Gardener's pupil" is a pharmacological mydriasis that occurs after
inadvertent exposure to plants containing tropane alkaloids1,2.The
"trumpet plant," also known as moonflower, Datura or Brugmansia
arborea, is one of the most popular of the ornamental plants that
contain anticholinergic substances. Some of these species are
common ornamental garden plants as well as indoor plants because
of their beautiful trumpet-shaped blossoms4. Most of these plants are
members of the same genus and grow in the wild. Datura is,
however, poisonous, containing these tropane alkaloids.
Tropane alkaloids are commonly described as anti-cholinergic
compounds, due to their ability to bind to muscarinic acetylcholine
receptors and hence act as competitive antagonists at these
receptors5. The tropane alkaloids that are present in Datura spp are
Figure 2. After instillation of topical pilocarpin
Figure 3. Second day examination
Figure 4. Datura plant
Muhsin Eraslan
hyoscyamine, atropine and scopolamine. The mechanism of action
of tropane alkaloids relates to their competitive antagonism at
muscarinic acetylcholine receptors, preventing the binding of
acetylcholine. According to the specificity and selectivity of
muscarinergic acetylcholine receptors in different organs, the
functions of smooth muscles and exocrine gland cells, as well as the
heart rate, respiration and functions in the central nervous system are
modulated. According to the organ, different subtypes of muscarinic
receptors have been described, denoted M1 to M5, all belonging to
the class of G- protein coupled receptors4. Approximately 60% to
75% of the muscarinic receptors in the human iris sphincter and
ciliary body are the M3 subtype. Lower levels (5% to 10%) of the m2
and m4 receptors are present in these tissues. The m1 receptor (7%)
has been detected in the ciliary processes and iris sphincter and the
m5 receptor (5%), which is usually found only in the central nervous
system, was present in the iris sphincter. The m3 subtype is the
predominant muscarinic receptor in the anterior segment of the
human eye and these alkoloids directly affect these receptors6.
These tropane alkoloids are readily absorbed by the aqueos
humuor through the cornea and conjunctiva. The iris has both
circular and radial muscles that work in a complementary manner to
control the pupil diameter. In tropane alkaloid-induced mydriasis, the
mechanism of action involves blocking the contraction of the circular
pupillary sphincter muscle, which is normally stimulated by
acetylcholine release, thereby allowing the radial pupillary dilator
muscle to contract and dilate the pupil These alkoloids also induce
cycloplegia by paralyzing the ciliary muscles and abolish the
accomodation reflex. Tropane alkaloids degrade slowly, typically
wearing off in 2 to 3 days.
Ocular toxicity occurs through inadvertent topical exposure, while
systemic side effects (primarily tachycardia due to a vagolytic effect)
occur through absorption of the alkaloids from the lachrymal
passages. Systemic effects are more pronounced upon oral ingestion.
Sometimes ocular side effects may also be only a topical side effect
without any systemic disorder such as in our case. The onset of
symptoms occurs 1-4 hours after contact or ingestion of plant
material or seeds7. The duration of symptoms is often 24-48 hours
Ocular disorders which cause unilateral mydriasis include third nerve
palsy, Adie's pupil, traumatic mydriasis, and pharmacologic mydriasis.
The simple measure of instillation of topical pilocarpine 2% establishes
the pharmacological nature of the condition and eliminates the need
for expensive neuro-imaging. Although accidental mydriasis is
commonly due to parasympatholysis, it may also occur secondary to
increased adrenergic stimulation. Care should therefore be exercised
while interpreting a pilocarpine test8.
Differentiation between paralytic mydriasis and pharmacologic
mydriasis can be made by using a pilocarpine 2% eye drop test. A
dilated pupil from paralytic mydriasis will constrict with 2%
pilocarpine, whereas a dilated pupil from pharmacologic mydriasis
will not constrict. Pilocarpine is competitively inhibited by alkaloids
(atropine, etc.), paralyzing the iris sphincter. Although a traumatic
pupil would stay dilated in response to pilocarpine 2%, making it
95
difficult to differentiate this condition from pharmacologic mydriasis,
the anisocoria would not have improved over the day in a traumatic
pupil as it did in our patient. If the degree of toxicity is low, mydriasis
may be overcome with pilocarpine drops. However, if the pupil does
not constrict after pilocarpine 2% instillation, one can avoid costly
investigations and reassure the patient that the pupillary dilation was
due to a chemical exposure.
In this case, third nerve palsy was ruled out because the patient
did not present with any neurologic symptoms. In addition, there
was no ptosis or motility deficit. The improvement of the anisocoria
over time also suggested that the etiology was exposure to some
type of chemical. If further work up of a third nerve palsy was to be
considered, an MRI would have been the next step to rule out a
compressive cause due to a third nerve palsy.
Adie's pupil is the result of an injury to the ciliary ganglion, which
can occur after viral infection, trauma, or cancer. Adie's pupil will
often have segmental constriction and light-near dissociation. Adie's
pupil can be demonstrated by a drop of topical pilocarpine 0.1%.
This very small concentration of pilocarpine will cause constriction of
the pupil due to denervation sensitivity.
Ocular side effects, particularly pupillary dilation with blurring of
vision may be alarming for the potentially lethal conditions related to
some kind of plants with local and systemic effects8. It may also be
only a topical side effect without any evidence of a significant
systemic disorder. This report emphasises the importance of accurate
history taking when evaluating a fixed and dilated pupil. Retailers of
such poisonous plants should detail the local and systemic effects of
accidental exposure, rather than merely labelling a plant (nonspecifically) as poisonous. The history taking and this simple topical
pilocarpin test eliminates the need for unnecessary expensive neuroimaging and the use of unnecessary medication, and also prevents us
from squandering the time of emergency room staff.
References
1.
2.
3.
4.
5.
6.
7.
8.
Voltz R, Hohlfeld R, Hertel H. Gardener’s mydriasis. Lancet
1992;339:752. doi 10.1016/ 0140-6736(92)90660-U
Reader AL. Mydriasis from Datura wrightii. Am J Ophthalmol
1977;84:263-4.
Thompson HS, Newsome DA, Lowenfeld IE. The fixed dilated pupil.
Sudden iridoplegia or mydriatic drops? A simple diagnostic test. Arch
Ophthalmol 1971;86:21-7.
Scientific Opinion of the Panel on Contaminants in the Food Chain
on a request from the European Commission on Tropane alkaloids
(from Datura spp.) as undesirable substances in animal feed. The
EFSA Journal 2008; 691:1-55.
Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In:
Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 11th ed. New-York: McGrawHill Companies, Inc 2006:183-200.
Gil DW, Krauss HA, Bogardus AM, WoldeMussi E. Muscarinic
receptor subtypes in human iris-ciliary body measured by
immunoprecipitation. Invest Ophthalmol Vis Sci 1997;38:1434-42.
Goldfrank LR. Toxicologic Emergencies, 5th ed., Norwalk, CT:
Appleton and Lange, 1994:7-8.
Raman S V, Jacob J. Mydriasis due to Datura inoxia. Emerg Med J
2005;22:310-1 doi: 10.1136/emj.2003.013060
96
Olgu Sunumu / Case Report
DOI: 10.5472/MMJ.2012.02019.1
Erişkin Yaş Başlangıçlı Langerhans Hücreli Histiyositoz:
Olgu Sunumu
Adult Onset Langerhans' Cell Histiocytosis: A Case Report
Zehra AŞIRAN SERDAR1, Sevda GİZENTİ1, Şirin YAŞAR1, Işık GÖNENÇ2, Pembegül GÜNEŞ3
1Dermatoloji
2Kadın
Kliniği, Haydarpaşa Numune Eğitim ve Araştırma Hastanesi, İstanbul, Türkiye
Hastalıkları ve Doğum Kliniği, Haydarpaşa Numune Eğitim ve Araştırma Hastanesi , İstanbul, Türkiye
3Patoloji,
Haydarpaşa Numune Eğitim ve Araştırma Hastanesi, İstanbul, Türkiye
Özet
Abstract
Langerhans hücreli histiyositoz (LHH), kemik iliği kökenli dendritik hücre
yapısındaki histiyositlerin anormal proliferasyonu sonucu oluşan nedeni
bilinmeyen bir hastalık grubudur. Görülme sıklığı milyonda 0,5-5,4
arasındadır. Çocukluk çağında daha sık olmasına karşın erişkin yaşta çok
nadir görülmektedir. Literatürde olgu sunumları şeklinde erişkin yaş
başlangıçlı LHH olguları bildirilmektedir. Burada deri ve akciğer
tutulumunun birlikte olduğu 66 yaşında kadın hasta sunulmaktadır.
Anahtar Kelimeler: Langerhans hücreli histiyositoz, Erişkin yaş başlangıçlı,
Pulmoner tutulum
Langerhans' cell histiocytosis(LCH) is a group of diseases of unknown cause
resulting from abnormal proliferation of bone marrow-originated dendritic
cells called histiocytes. The incidence is between 0.5-5.4 per million. More
common in childhood, it is extremely rare in adults. Cases of adult-onset LCH
are presented as case reports in literature. Here, we present the case of a 66year-old female patient with both skin and pulmonary involvement. (Marmara
Key Words: Langerhans' cell histiocytosis, Adult-onset, Pulmonary involvement
Giriş
Langerhans hücreli histiyositoz (LHH), atipik histiyositik
hücrelerin lokal veya yaygın olarak kemik, akciğer, hipotalamus,
karaciğer, lenf nodları, mukokütanöz dokular ve endokrin organlar
gibi çeşitli dokularda birikmesi sonucunda hasara neden olan,
nedeni bilinmeyen klonal, pleomorfik, neoplastik karakterde bir
hastalıktır1-4. LHH hücre infiltrasyon derecesine göre HashimatoPritzker hastalığı (HPD), eozinofilik granulom (EG), Hand-SchüllerChristian hastalığı (HSC) ve Letterer-Siwe hastalığı (LSD) olarak
isimlendirilen 4 farklı klinik tablo şeklinde isimlendirilmektedir5.
LHH Çalışma Grubu’nun organ tutulumuna göre yaptığı
sınıflamada ise tek sistem tutulumlu ve multisistem tutulumlu
hastalık olarak 2 ana grupta incelenmiştir6. LHH her yaş
gurubunda görülmekle beraber özellikle 1-3 yaş aralığında sık
rastlanır ancak erişkinlerde iyi tanımlanamayan nadir olgular
şeklinde görülür4,7,8. Yapılan çalışmalarda LHH’ lu olgularda %3-5
oranında akciğer tutulumu saptanmıştır. Akciğer tutulumu olan
hastaların sıklıkla 20-40 yaş arası kadın hastalar olduğu ve %90100 sıklığında sigara içtiği gözlemlenmiştir9.
Burada erişkin yaş başlangıçlı, deri ve akciğer tutulumunun
birlikte olduğu, 66 yaşında kadın hasta sunuldu.
İletişim/Correspondence to: Dr. Işık Gönenç, Kadın Hastalıkları ve Doğum Kliniği, Haydarpaşa Numune Eğitim ve Araştırma Hastanesi, Haydarpaşa, İstanbul, Türkiye
Serdar ve ark.
Erişkin Yaşta Langerhans Hücreli Histiyositoz
97
Olgu Sunumu
Şekil 1. Saçlı deride eritemli zeminde skuamlı papüller
Şekil 2. İnframamarian bölgeden sternuma uzanan eritemli skuamlı
papüllerin yakından görünümü
Şekil 3. Lumbosakral bölgede eritemli skuamlı papüller
Altmış altı yaşında kadın hasta, 2-3 yıldan beri, saçlı deri ve
sırtta, üzeri kabuklanan kızarık yaralar ve nefes darlığı şikayeti ile
kliniğimize başvurdu. Hastanın özgeçmişinde; over kanseri
nedeniyle total abdominal histerektomi ve bilateral salpingoooferektomi operasyonu geçirdiği, 20 paket/yıl sigara içtiği, 3-4
yıldır nefes darlığı şikayeti nedeniyle başka bir merkezde toraks için
yapılan bilgisayarlı tomografi (BT) incelemesi sonucunda LHH
şüphesiyle takibe alındığı öğrenildi.
Hastanın kemik ağrısı, diyare, ateş ve halsizlik gibi şikayetleri
bulunmamaktaydı.Hastanın dermatolojik muayenesinde; saçlı
deride her iki pariyetal bölgede eritemli zeminde üzeri skuamlı
papüllerden oluşan plak lezyonlar ile lumbosakral bölgede eritemli
skuamlı papüller izlendi. Her iki inguinal bölgede eritem ve
üzerinde ince deskuamasyon saptandı (Şekil1, 2, 3).
Fizik muayenede servikal, aksiller ve inguinal lenfadenopati ve
hepatosplenomegali tespit edilmedi. Lumbosakral bölgede
eritemli skuamlı papüllerden alınan Tzanck smear incelemede;
geniş eozinofilik sitoplazmalı, eksantrik nükleuslu Langerhans
hücreleri görüldü (Şekil 4).
Histopatolojik incelemede epidermiste parakeratoz, polimorf
nüveli lökositlerin oluşturduğu krut, ülserasyon ve nekroz alanı,
ülserasyon altına uyan bölgede papiller dermisi dolduran diffüz hücre
infiltrasyonu izlendi. İnfiltrasyon gösteren hücreler monoton atipi
göstermekteydi ve hücreler geniş eozinofilik sitoplazmalı eksantrik
nükleuslu hücrelerdi. Yapılan immünhistokimyasal incelemede bu
hücreler S-100 ile pozitif boyandı. Ayırıcı tanı açısından yapılan HMB
45 ve Melen A boyaması negatif idi (Şekil 5, 6, 7).
Yapılan tetkiklerde hemogram, Alanin aminotransferaz (ALT),
Aspartat aminotransferaz (AST), Gama glutamil transpeptidaz
(GGT), hipofiz hormonları büyüme hormonu (GH), insülin benzeri
büyüme faktörü-1 (IGF1), tiroid uyarıcı hormon (TSH),
triiyodotronin (T3), tiroksin (T4), folikül uyarıcı hormon (FSH),
lüteinizan hormon (LH), parathormon (PTH), prolaktin, fosfor, bazal
kortizol düzeyleri normal olarak değerlendirildi. Kan osmolaritesi,
idrar osmolaritesi ve periferik kan yayması normal sınırlardaydı.
Radyolojik incelemelerde kafa grafileri ve uzun kemik grafileri,
hipofiz manyetik rezonans (MR) inceleme ve batın ultrasonografisi
Şekil 4. Tzanck smear incelemede geniş eozinofilik stoplazmalı,
eksantrik nükleuslu Langerhans hücreleri, 10x10, Giemza
98
Serdar ve ark.
(USG) normal olarak değerlendirildi. Hastanın akciğer grafisinde
şüpheli infiltrasyon nedeniyle yapılan toraks BT’de her iki akciğer
parankiminde yaygın hava kistleri izlendi.
Bronkoalveolar lavajda; lenfosit %12 (22/mm3), nötrofil %24
(44/mm3), makrofaj %60 (110/mm3), eozinofil %4 (8/mm3)
saptanırken, CD4/CD8: 0,4 CD45: %32,9 olarak saptandı.
Hastaya bu bulgular ışığında deri ve pulmoner tutulumun birlikte
olduğu LHH tanısı konuldu. Tedavide topikal olarak günde iki kez
klobetazol propiyonat %0,05 krem verildi. Göğüs hastalıkları kliniği
ile konsulte edilerek salmeterol +flutikazon ve tiotropiyum bromür
semptomatik tedavi olarak başlandı. Sigarayı bırakması ve düzenli
takip önerildi. Birinci yılın sonunda hastanın deri lezyonlarında artış
saptanmadı. Ancak deri lezyonlarının aynen devam ettiği gözlendi.
Göğüs hastalıkları takibinde akciğerde lezyonların ve semptomların
gerilemediği bu nedenle mevcut semptomatik tedavinin devam
etmesi gerektiği ve sistemik tedavi ihtiyacı olmadığı bildirildi.
Hastadan fotoğraflarının basılması için yazılı izin alınmıştır.
Tartışma
Şekil 5. Papiller dermisi dolduran diffüz hücre infiltrasyonu, 4x10,H&E
Şekil 6. Geniş eozinofilik stoplazmalı eksantrik nukleuslu hücreler,
40x10, H&E
Şekil 7. İmmunhistokimyasal boyamada S-100 pozitif hücreler, 4x10, CD 1a
LHH, kemik iliği kökenli dendritik hücre yapısındaki
histiyositlerin anormal proliferasyonu sonucu oluşan nedeni
bilinmeyen bir hastalık grubudur. Görülme sıklığı milyonda 0,5-5,4
arasındadır. Erkeklerde kadınlardan iki kat fazla görülür1.
Etyopatogenezinde viral enfeksiyonlar (HHV-6, CMV, parvovirüs ),
genetik faktörler, immün disregülasyon sorumlu tutulmaktadır8.
LHH’da tek organ tutulumu kemikten sonra 2. sırada deri olarak
bildirilmektedir10. Hastalığın ayırıcı tanısında kontakt dermatit,
dermatofitozlar, follikülit, dissemine granüloma anulare, varisella,
kutanöz lenfomalar, eroziv genital hidradenitis, nodüler skabiyez,
juvenil ksantogranülom ve ksantomlar yer almaktadır3,5. Erişkin
LHH’ da akciğer tutulumu diğer organlarla karşılaştırıldığında
%58,4 gibi yüksek oranda karşımıza çıkar9. Tüm LHH hastalarına
bakıldığında %3-5 oranında akciğer tutulumu olduğu
görülmüştür. Akciğer tutulumu olan hastaların sıklıkla 20-40 yaş
arası kadın hasta olduğu ve %90-100 oranında sigara içtiği
gözlemlenmiştir5.
Hastalar genellikle deri bulguları, nefes darlığı, çok su içme ve
sık idrara çıkma gibi şikayetlerle başvurabilirken, kemik ağrıları,
lenfadenopati ve kilo kaybı da görülebilir8.
Hastamızda seboreik dermatit benzeri lezyonlar ve akciğer
tutulumuna bağlı nefes darlığı şikayeti bulunmaktaydı. Literatürde
pulmoner LHH’ un %25 oranında asemptomatik seyrettiği en sık
semptomların ise öksürük ve nefes darlığı olduğu bildirilmiştir11.
Hastalığın tanısı klinik, histopatolojik ve immünhistokimyasal
analizle konulur. Ayrıca hastalarda diğer sistem tutulumları
açısında batın USG, kemik grafileri, PA AC grafisi ve yüksek
rezolüsyonlu bilgisayarlı toraks tomografisi (HRCT) ve beyin MR
istenmelidir7. Akciğer tutulumu açısında BT görüntüleri tipiktir,
diffüz bilateral simetrik ve daha çok üst zonları tutan başlangıçta
nodüler daha sonra retikülonodüler ve kistik lezyonlar mevcuttur,
kostafrenik bölgedeki parankim korunmuştur11. Hastamızda
yapılan toraks BT’de her iki akciğer parankiminde yaygın hava
kistleri izlenmiştir.
Hastamızda sistem tutulumları açısından yapılan tetkiklerde
akciğer dışında tutulum saptanmadı.
Tedavi hastalığın yaygınlığına ve organ tutulumuna göre
değişmektedir. LHH Çalışma Grubu’nun organ tutulumuna göre
yaptığı sınıflamada5:
Serdar ve ark.
1. Tek sistem tutulumlu hastalık
• Tek bölge
o Monoostotik kemik tutulumu
o İzole deri tutulumu
o Soliter lenf nodu tutulumu
• Çoklu bölge
o Poliostotik kemik tutulumu
o Multifokal kemik tutulumu
o Multiple lenf nodu tutulumu
2. Multisistem tutulumlu hastalık
• Düşük riskli grup
o Dissemine hastalık riskli organ (akciğer, karaciğer, dalak ve
hemopoetik sistem) tutulumu yok
• Yüksek riskli grup
o En az bir riskli organ tutulumu
Olgumuz, deri ve akciğer tutulumu olması nedeniyle, LHH
Çalışma Grubu’nun organ tutulumuna göre yaptığı sınıflamada
multisistem tutulumlu hastalığın yüksek riskli grubu olarak
değerlendirildi. Multisistem tutulumla giden hastalarda amaç
mortaliteyi azaltmak, reaktivasyonları ve geç sekelleri önlemektir.
Dissemine hastalık olup riskli organ tutulumu olmayan hastalarda
semptomatik tedaviyle çok iyi sonuçlar alınır. Bu hastalarda
dissemine hastalık açısından takip önemlidir.
Multisistem
tutulumlu LHH hastalarında yapılan çalışmalar etoposit, vinblastin
gibi tekli ajan kullanımının çoklu ajanlı tedavilere göre
(etoposit+vinblastin+prednizolon) özellikle riskli organ tutulumu
olan hastalarda daha yüksek mortaliteyle seyrettiğini, bu nedenle
bu hastalarda kombine kemoterapilerin daha yararlı olduğunu
bildirmektedir. Yine bu grupta tedaviye yanıtın 6-12 hafta gibi geç
dönemde gelişebileceği %75 oranında mortal seyrettiği, hastalıksız
sağ kalım süresinin ise %20’den az olacağı bildirilmektedir.
Tedavide deri tutulumunda topikal streoid, nitrojen mustard,
PUVA, CO2 lazer, talidomid ve isotretinoin tedavi seçenekleri
arasındadır7. Hastamıza, tedavi olarak deri tutulumu açısından topikal
olarak günde iki kez klobetazol propiyonat %0,05 krem verildi.
Pulmoner LHH genellikle kendiliğinden gerileme eğiliminde
olduğundan takip önerilmektedir. Hastalığın tetikleyici faktörü
bilinmemekle birlikte akciğer tutulumunda sigaranın en önemli
etken olduğu bildirilmektedir11. Bu nedenle hastalara sigarayı
bırakmaları önerilmelidir. Semptomatik nodüler pulmoner LHH’ da
prednizolon 0,5-1 mg/kg/gün 6-12 ay süresince verilebilir12 . Yaygın
sistemik tutulumda sistemik kemoterapotik ajanlardan metotreksat,
99
prednizolon,vinblastin ve etoposit kullanılmalıdır6. Hastamız Göğüs
Hastalıkları Kliniği ile konsulte edildiğinde multisistem yüksek riskli
grup olmasına rağmen hastanın akciğer tutulumunun az olması ve
hayatı tehdit edici lezyonlarının ve fonksiyon bozukluğunun
olmaması nedeniyle salmeterol +flutikazon ve tiyotropiyum bromür
semptomatik tedavi olarak başlandı. Sigarayı bırakması ve düzenli
olarak takiplerine gelmesi önerildi.
LHH, erişkin yaşta nadir görülmesi nedeniyle klinik olarak seboreik
dermatit, kontakt dermatit, dermatofitozlar, follikülit, dissemine
granuloma annulare, varisella, kütanöz lenfomalar ile karışabilir3.
Olgumuz, LHH’un geç erişkin yaşta da başlayabileceği ve eritemli
skuamlı papülleri olan olguların ayrıcı tanısında mutlaka düşünülmesi
gerektiğini vurgulamak amacıyla literatür bilgileri eşliğinde tartışıldı.
Kaynaklar
1.
Lipton JM. Histiocytic disorders. In:Hoofman R, Benz EJ, Shattil SJ, et
al. editors. Basic Principals and Practice. 3rd ed. New York: Churchill
Livingstone, 2000:783-93.
2. Akdemir O, Çolak A. Langerhans hücresi histiositozisi. Turkiye
Klinikleri J Surg Med Sci 2007;3:1-4.
3. Aydoğan K, Tunalı S, Koran Karadoğan S, Balaban Adım S, Turan H.
Adult-onset Langerhans cell histiocytosis confined to the skin. J Eur
Acad Dermatol Venereol 2006;20: 890-2.
4. Aricò M, Girschikofsky M, Généreau T, et al. Langerhans cell
histiocytosis in adults. Report from the International Registry of the
Histiocyte Society. Eur J Cancer 2003; 39 : 2341-8.
5. James WD,Berger TG, Elston DM.Macrophage and monocyte
disorders.In: William D James, Timothy G Berger, Dirk M Elston,
Richard B Odom, editors. Andrews' Diseases of the Skin: Clinical
Dermatology.10th ed. Philadelphia : Saunders Elsevier, 2006:714- 24.
6. Abla O, Egeler M, Weitzman S. Langerhans cell histiocytosis: current
concepts and treatments. Canc Treat Rev 2010;36: 354-9.
doi:10.1016/j.ctrv.2010.02.012
7. Çil T, Gökalp D, Tuzcu A, Işıkdoğan A, Bahçeci M. Yetişkin Langerhans
hücreli histiyositoz. Turkiye Klinikleri J Med Sci 2007;27: 633- 5.
8. Caputo R, Gelmetti C. Langerhans cell histiocytosis. In: Wolff K,
Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, editors.
Fitzpatrick′s Dermatology in General Medicine. 7th ed. New York:
McGraw Hill, 2008:1419.
9. Sahin F, Özen KP, Vural F, et al. Retrospective analysis of seven patients
with adult-onset Langerhans cell histiocytosis syndromes: A single
center experience. Turk J Hematol 2007; 24: 75-9.
10. Campanati A, Simonetti O, Marconi B, et al.. Purely cutaneous
Langerhans' cell histiocytosis in an adult woman. Acta Derm Venereol
2009; 89: 299-301.
doi:10.2340/00015555-0614
11. Çelik B, Furtun K, Bilgin S. Pulmoner Langerhans hücreli histiyositoz
olgu sunumu. Tur Toraks Der 2010;11: 84-6.
12. Tazi A. Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J
2006; 27: 1272-85.
100
DOI: 10.5472/MMJ.2012.02158.1
Occurrence in a Case of Philadelphia Negative Acute
Lymphoblastic Leukemia following Treatment for
Ewing’s Sarcoma
Ewing Sarkom Tedavisi Sonrası Gelişen Philadelphia Negatif Akut Lenfoblastik
Lösemi Olgusu
Abdullah KATGI1, Selda KAHRAMAN1, Pınar ATACA2, Özden PİŞKİN1, Mehmet Ali ÖZCAN1, Güner Hayri ÖZSAN1,
Fatih DEMİRKAN1, Bülent ÜNDAR1
1Sub-department
2Department
of Hematology, Department of Internal Medicine, School of Medicine, Dokuz Eylül University, İzmir, Turkey
of Internal Medicine, School of Medicine, Dokuz Eylül University, Izmir, Turkey
Abstract
Özet
Therapy-related leukemias are 10-20% of all acute leukemia cases.
Therapy-related acute lymphoblastic leukemia (ALL) is less frequent than
therapy-related acute myeloid leukemia (AML) or myelodysplastic
syndrome (MDS). In this paper, we present a patient with Ewing’s sarcoma
(ES) in the soft tissue of his right breast cured by chemotherapy and
radiotherapy. He developed Ph(-) ALL four years following the therapy.
Key Words: Ph(-) ALL, Secondary leukemia, Ewing’s sarcoma
Tedavi ilişkili akut lösemiler tüm akut lösemili olguların %10-20'sini oluşturur.
Tedavi ilişkili akut lenfoblastik lösemi (ALL) görülme sıklığı akut miyeloid lösemi
(AML) veya akut myelodisplastik sendrom (MDS)'a göre daha nadirdir. Bu
yazıda dört yıl önce sağ memedeki kitleden Ewing sarkom (ES) tanısı alan
kemoterapi ve radyoterapi ile tam kür sağlanan olguda gelişen Ph(-) ALL olgusu
sunulacaktır. (Marmara Üniversitesi Tıp Fakültesi Dergisi 2012;25:100-2)
Anahtar Kelimeler: Ph(-) ALL, Sekonder lösemi, Ewing sarkom
Introduction
Long term survival has been recently achieved by evolution in
treatment strategies for many solid neoplasms. In particular, patients
treated with chemotherapy regimens commonly including
alkylating agents and anthracyclines, and further exposed to
radiotherapy, are at increased risk of developing leukemia. Therapyrelated leukemias are 10-20% of all acute leukemia cases1,2.
Therapy-related acute lymphoblastic leukemia (ALL) is less frequent
than therapy-related acute myeloid leukemia (AML) or
myelodysplastic syndrome (MDS). In one series it is shown that
therapy-related ALL occurs in 1-2% of all ALL patients3. In this paper,
we present a patient with Ewing’s sarcoma (ES) in the soft tissue of
his right thorasic wall, cured by chemotherapy and radiotherapy. He
developed ALL four years following the therapy. We obtained
written informed consent from the patient.
Case Report
A 19-year old male was admitted to the oncology clinic with a
painless, hard 7.5x3.4 cm mass in his right hemithorax lateral wall
in August 2004. He was diagnosed by thorax magnetic resonance
Correspondence to/İletişim: Selda Kahraman, M.D., Subdepartment of Hematology, Department of Internal Medicine, School of Medicine, Dokuz Eylül University, İzmir, Turkey
imaging (MRI) as having hemangioma, and partial embolization
was applied. During the follow up, he was readmitted with
enlargement of the mass to 17x15 cm. No metastasis was detected
in the thorax-abdomen and cranial computerized tomography (CT)
screening. However, there was an increased uptake in the 6th costal
arcus in the bone scintigraphy, evaluated as bone invasion. The
incisional biopsy of the mass, revealed ES in February 2005. There
was no invasion of the bone marrow He was classified as high risk
extraosseous ES (tumor>100mL) and chemotherapy regimen
etoposide, vincristine, dactinomycin, ifosfamide, doxorubicin
(EVAIA) was initiated as in the European Intergroup Cooperative
Ewing’s Sarcoma Studies (EICESS-92) protocol. He received three
courses of etoposide of 150 mg/m² each 1.5 vincristine 0.5 mg/m²
dactinomycin, 2,000 mg/m² ifosfamide and 30 mg/m²
doxorubicin. There was more than 50% regression in the tumour
size in the control thorax CT in June 2005, when radiotherapy was
arranged. He received 54 Gy/25 fractions over 5 weeks
radiotherapy fort he primary region and 45Gy/25fractions over 5
weeks radiotherapy fort he right hemithorax. 2 courses of EVAIA
chemotherapy protocol were administered before he had total
resection of the mass in December 2005. During the postoperative
period he received two more courses of EVAIA protocol, which was
completed in April 2006. He was followed in complete remission
until March 2010. He was referred to the hematology clinic with a
complete blood count reported as platelets: 20.000 µL, WBC:
8.800 µL (69.6% neutrophil, 16.9% lymphocytes, 1.1% monocyte,
1.8% eosinophil, 0.1% basophil) hemoglobin: 11 gr/dL. In his
periferic blood smear analysis, rare platelets, schistocytes and
lymphoblasts (35% of all leukocyte) was detected. The blood
lactate dehyrogenase (LDH) level was increased to 862 U/L
(normal: 125-243 U/L). Bone marrow aspiration was hypercellular
and 55% of the cells was established as blasts. The blasts were
positive in periodic acid schiff (PAS) stain, but negative in
myeloperoxidase (MPO) or esterase stain. In the bone marrow flow
cytometric analysis, the dominant cells that match the blastic cell
morphology were sorted by forward scatter and side scatter
detectors. The mature granular cell population was excluded in
sorting. The flow cytometric expressions in immature lymphoid
cells were determined as CD 10 (98 %), CD 19 (98%), CD 22
(96%), CD 34 (89%) ve HLA-DR (98%). T cell surface antigen and
BCR-ABL gene were not detected with quantitative reverse
transcriptase-polymerase chain reaction (QRT-PCR) in all nuclear
cells. In the cytogenetic studies, 20 metaphases were examined by
giemsa stain without cytogenetic anomaly. According to the
findings, he was diagnosed as precursor B cell ALL in April 2010.
Alternating hyper-CVAD chemotherapy courses A and B were
initiated. Course A consisted of 300 mg/m² cyclophosphamid, 25
mg/m² doxorubicine, 4mg vincristin, and 280mg dexaemethason.
Course B consisted of 1 g methotrexate and 6 g/m² cytarabine.
After the first A and B courses, a complete (morphologic) remission
was achieved in the bone marrow aspiration analysis. In the next
courses, we rearranged the protocol with etoposide instead of
doxorubicine because the cumulative dose of anthracyline was
Katgı et al.
Ph(-) ALL following Treatment for Ewing's Sarcoma
101
totally 390mg/m². He completed 4 courses of Hyper-CVAD A and
B protocol and 6 courses of prophylactic intrathecal chemotherapy:
(12,5 mg methotrexate and 40 mg cytarabine) in December 2010.
After 15 months of maintenance therapy with 100mg 6mercaptopurine daily, 25mg methotrexate weekly and 1mg
vincristine plus 100mg prednisolon monthly, he was followed up
and still in remission. With no HLA-matched donor, he was
consequently included in a non-relative allogeneic donor
transplantation list .
Discussion
ES is a neuroectodermal tumor occuring mostly in the second
decade and originating from bone or soft tissue4. Even though two
over three patients with the localized disease are followed in
remission by current treatment approaches, the prognosis of
metastatic disease is still very poor5. Secondary malignancy risk
increases significantly in ES cases. There are two major hypothesis
explaining the occurrence of ES: it may be caused by the genetic
predisposition may play a role as in other cancers, or effects of
chemotherapeutic agents used for treatment6.
It has been stated that secondary leukemias are induced after
treatments with alkylating agents and topoisomerase inhibitors.
The detection of leukemias secondary to topoisomerase
inhibitors occurs shortly after chemotherapy for primary tumours
(average of 14 months) however, alkylating agents have a longer
leukemia latent period7. Our case was treated with both
etoposide and doxorubicine and the leukemias was diagnosed 4
years after the temination of the ES treatment, which is
compatible with other studies.
Sultan et al.8 described 35 secondary malignancy cases from
metaanalysis of all ES patients (1166 cases) who were diagnosed
between January 1973 and December 2005 in the USA. Twentythree of 35 were solid tumors and the remaining were
hematological malignancies. One ALL case was reported 5 years
after ES detection.
In general, secondary ALL is rare. In a metaanalysis of 3934
acute leukemia patients (2964 AML, 901 ALL and 69 acute
biphenotypic leukemia) secondary ALL was established in 2.3% of
the patients compared with secondary AML in 6% of the patients.
10.5% secondary ALL patients in the secondary malignancy group
was reported9.
Many chemotherapeutic agents are thought to cause
secondary ALL. Some studies in secondary ALL pointed out the
relation with chromosomal anomalies. In alkylating agent induced
ALL, myelodysplasia is more frequent, the latent period is long
and cytogenetic anomalies in chromosome 5 and/or 7 are
detected. On the other hand, topoisomerase II inhibitor induced
ALL occurs with chromosome 11q23 translocations with a short
latent period7. In our case, treatment with both agents did not
cause any cytogenetic anomaly.
In summary, secondary ALL due to chemotherapeutic agents
account for 2-3% of all ALL’s. Our patient is one of the rare ALL
102
Katgı et al.
Ph(-) ALL following Treatment for Ewing's Sarcoma
patients occurring after the treatment of ES. The latent time period
until the determination of ALL varies from 13 months to 8 years. The
latent period is longer in alkylating agents compared to
topoisomerase II inhibitors. The latent period was 4 years in our case
where the patient was treated by both regimens which is
compatible with other studies. Treatment-related malignancies
should be considered in the routine follow-up of patients treated
with alkylating agents and topoisomerase II inhibitors.
References
1.
2.
3.
Leone G, Mele L, Pulsoni A, Equitani F, Pagano L. The incidence of
secondary leukemias. Haematologica 1999;84:937-45.
Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C.
Genetic pathways in therapy-related myelodysplasia and AML. Blood
2002;99:1909-12.
Ishizawa S, ML Slovak , Popplewell L, et al. High frequency of pro-B
acute lymphoblastic leukemia in adults with secondary leukemia with
11q23 abnormalities. Leukemia 2003;17: 1091-5.
4.
5.
6.
7.
8.
9.
Hancorn K, Sharma A, Shackcloth M. Primary extraskeletal Ewing's
sarcoma of the lung. Interact Cardiovasc Thorac Surg 2010;10:803-4.
doi:10.1510/icvts.2009.216952
Esiashvili N, Goodman M, Marcus RB. Changes in incidence and
survival of Ewing Sarcoma patients over the past 3 decades:
Surveillance epidemiology and end results data. J Pediatr Hematol
Oncol 2008; 30: 425- 30. doi:10.1097/MPH.0b013e31816e22f3
Navid F, Billups C, Liu T, Krasin MJ, Rodriguez-Galindo C. Second
cancers in patients with the Ewing sarcoma family of tumours. Eur J
Cancer 2008; 44: 983- 91. doi:10.1016/j.ejca.2008.02.027
Cho J, Hur M, Moon HW, Yun YM, Lee CH, Lee HG. A case of therapyrelated ALL with MLL gene rearrangement following treatment of
breast cancer. Korean J Lab Med 2010 Jun;30:255-9.
doi:10.3343/kjlm.2010.30.3.255
Sultan I, Rihani R, Hazin R. Second malignancies in patients with
Ewing sarcoma family of tumors; A population-based study. Acta
Oncologica 2010; 49: 237-44. doi:10.3109/02841860903253538
Pagano L, Pulsoni A, Tosti ME, et al. Acute lymphoblastic leukaemia
occurring as second malignancy: report of the GIMEMA archive of
adult acute leukaemia. Br J Haematol 1999;106:1037-40.
103
DOI: 10.5472/MMJ.2012.02184.1
Thymoma Associated with Loeys-Dietz Syndrome Type 1
Timomanın Eşlik Ettiği Loeys-Dietz Sendromu Tip 1
Hayrullah ALP1, Fatih ŞAP1, Hakan ALTIN1, Zehra KARATAŞ1, Tamer BAYSAL1, Sevim KARAASLAN1, Sevgi PEKCAN2
1Sub-Department
2Sub-Department
of Pediatric Cardiology, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey
of Pediatric Pulmonology, Department of Child Health and Pediatrics, Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey
Abstract
Özet
Loeys-Dietz syndrome is a rare autosomal dominant disorder characterized by
the involvement of cardiovascular, craniofacial and skeletal systems. The main
etiology of the disease is the mutation in the transforming growth factor betareceptor type 1 and 2 genes. Today, Loeys-Dietz syndrome has been classified
into two subtypes due to the presence of craniofacial involvement. These
patients have progressive aortic enlargement which increases the risk of
dissection and rupture. So, delay in the diagnosis may be associated with poor
prognosis. We present a new case with thymoma diagnosed as Loeys-Dietz
syndrome type 1. Also, this is the first report of a tumor in Loeys-Dietz
syndrome according to the current literature review. (Marmara Medical Journal
2012;25:103-6)
Key Words: Loeys-Dietz syndrome, Thymoma, Aortic root aneurysm, Aortic
dilatation
Loeys-Dietz sendromu kardiovasküler, kraniofasiyal ve iskelet sisteminin
tutulduğu nadir bir otozomal dominant hastalıktır. Esas etyoloji,
transforming growth faktör beta-reseptör tip 1 ve 2 genlerindeki
mutasyonlardır. Günümüzde, Loeys-Dietz sendromu kraniofasiyal
bulguların varlığına göre iki alt gruba ayrılmıştır. Aort genişlemesi olan
hastalar diseksiyon ve rüptür açısından risk taşırlar. Sonuçta, tanıdaki
gecikme kötü prognoz ile sonuçlanabilir. Timomanın eşlik ettiği ve LoeysDietz tip 1 sendromu tanısı konulan yeni bir vakayı sunduk. Ayrıca, vaka
sunumu literatürde bir tümörün eşlik ettiği ilk Loeys-Dietz sendromudur.
Anahtar Kelimeler: Loeys-Dietz sendromu, Timoma, Aort kökü anevrizması,
Aort dilatasyonu
Introduction
Loeys-Dietz syndrome (LDS) is a newly identified genetic
disorder of the connective tissue, described by Loeys et al. in 20051.
Th diagnostic triad of the syndrome is the following: 1) arterial
tortuosity, aneurysms or dissections 2) hypertelorism and 3) bifid
uvula or cleft palate1-3. It is caused by heterozygous mutations in
the genes encoding type 1 or type 2, transforming growth factor
beta-receptors traced to chromosomes 9q33-34 and 3p244.
Affected individuals exhibit a variety of features, mainly involving
the musculoskeletal, cardiovascular and central nervous systems.
The clinical findings of the musculoskeletal system includes
symptoms such as arachnodactyly, joint laxity, pectus deformity,
scoliosis, dolichosternomelia, talipes equinovarus, camptodactyly
and cervical spine instability4. Chiari malformation and
hydrocephalus are associated anomalies of the central nervous
system. However, the life-threatening complications, which
determine the prognosis, are the results of cardiovascular system
findings including aortic root aneurysm, arterial tortuosity,
aneurysms of other vessels, patent ductus arteriosus and atrial
septal defects4. Up to now, two subtypes of LDS have been
delineated4. The patients with LDS type 1 have both craniofacial
Correspondance to/İletişim: Hayrullah Alp, M.D. Sub-Department of Pediatric Cardiology, Department of Child Health and Pediatrics, Meram School of Medicine, Necmettin
Erbakan University, Konya, Turkey Phone: +90 332 223 64 29 Fax: +90 332 223 65 85 E-mail: [email protected]
104
Alp et al.
Loeys-Dietz Syndrome Type 1
and cardiovascular disorders. The most common characteristic of
craniofacial clinical features are hypertelorism and cleft palate or
bifid uvula1-4. In contrast, patients with LDS type 2 may have a bifid
uvula but do not have a cleft palate, craniosynostosis or
hypertelorism4. Additional manifestations of LDS include malar
hypoplasia, exotropia, blue sclera and retrognathia4. The
phenotypes of patients with LDS closely resemble Marfan,
Shprintzen-Goldberg, Beals, Larsen or vascular Ehlers-Danlos
syndromes1,2. However, LDS is characterized by a unique
constellation of clinical and pathologic manifestations. We have
reported a case of LDS type 1 syndrome with thymoma. Current
review of the literature suggested no case with a tumor in LDS.
Case Report
The patient was a 17-year old male who referred to our clinic
for evaluation of cardiac murmur. He was born at term after an
uncomplicated pregnancy from non-consanguineous parents. He
had a mild developmental delay during infancy and childhood.
He was operated for bilateral inguinal hernias at the age of five.
His height and weight were 50-75th percentile and his head
circumference was >97th percentile, respectively. On initial
examination, he had dolichocephaly, hypertelorism, bifid uvula,
high-arched palate and malar hypoplasia (Figure 1a, b). Other
examination findings were bilateral foot and hand contractures
characterized by camptodactyly with arachnodactyly. Also, there
was a second degree cardiac murmur detected on physical
examination. The chest radiography revealed an expansion on the
superior mediastinum (Figure 2). Echocardiography showed that
the bicuspid aortic valve and aortic root diameter measured 44
mm. Diagnostic cardiac catheterization displayed bicuspid aortic
valve without steneous or aortic insufficiency and dilated aorta
with the following diameters: root 44 mm, arcus 43 mm and
descending 40 mm respectively (Figure 3a, b). On cardiac
catheterization and magnetic resonance imaging, no dilatation
was detected in other arteries. Due to the mild mental retardation,
magnetic resonance imaging of the brain was performed and it
revealed Chiari 1 malformation (Figure 4). Magnetic resonance
imaging of the thorax demonstrated a well-defined superior
mediastinal mass and normal lung regions (Figure 5). An
ultrasonography guided biopsy of intrathoracic tumor was
performed showing a thymoma type B1 (Figure 6), according to
the World Health Organization (WHO) classification. Beta-blocker
treatment was given for the unexpected complications, dissection
and rupture, and he was referred to the department of thoracic
surgery for the surgery of thymoma. Also, a signed permission
form was taken from the parents for all images of the patient
prior to publication.
Figure 2: Expansion of the superior mediastinum due to thymoma on
the chest radiography
Figure 1a, b: (a) Dolichocephaly, hypertelorism and malar hypoplasia,
(b) bifid uvula and high-arched palate
Figure 3a, b: (a) Bicuspid aortic valve and wide aorta with the
diameters of root 44 mm, (b) arcus 43 mm and descending 40 mm
respectively on diagnostic cardiac catheterization
Alp et al.
105
Discussion
Figure 4: Chiari 1 malformation on magnetic resonance imaging.
Figure 5: Magnetic resonance imaging of the thorax demonstrated a
well-defined superior mediastinal mass.
Table I. Comparison of clinical and laboratory findings of LDS type 1
described by Loeys et al. and of our patient
Loeys et al.1
Patient
Cardiovascular
Aortic root aneurysm
98%
+
Craniofacial
Hypertelorism
Cleft palate/bifid uvula
Malar hypoplasia
Craniosynostosis (dolichocephaly)
90%
90%
60%
48%
+
+
+
+
Skeletal system
Arachnodactyly
Camptodactyly
70%
38%
+
+
Neurocognitive
Chiari 1 malformation
Mental retardation
10%
15%
+
+
1Loeys BL, Chen J, Neptune ER et al. A syndrome of altered cardiovascular, craniofacial,
neurocognitive and skeletal development causes by mutations in TGFBR1 or TGFBR2.
Nat Genet 2005;37:275-81.
Loeys-Dietz syndrome is a newly recognized genetic disorder1.
We have demonstrated clinical features of this disorder including;
dolichocephaly, hypertelorism, bifid uvula, high-arched palate,
malar hypoplasia, camptodactyly and arachnodactyly with the
radiographic findings; bicuspid aortic valve, wide aortic root,
aortic dilatation and Chiari 1 malformation which were diagnosed
in the present patient with LDS. Comparison of the key clinical
features of LDS type 1, reported by Loeys et al. in 20051 and the
present case are given in Table I.
The sex predominance and prevalence of this genetic
syndrome has not been established yet. LDS may be commonly
misdiagnosed as Marfan, Shprintzen-Goldberg, Beals, Larsen or
vascular Ehlers-Danlos syndromes.
Marfan syndrome is caused by mutations in the fibrillin-1 gene
located on chromosome 15q212,5. Symptoms are skeletal,
ocular; especially ectopia lentis which are not associated with LDS;
and cardiovascular manifestations in patients with Marfan
syndrome3,5.
Shprintzen-Goldberg syndrome is one of the marfonoid
craniosynostosis syndromes with skeletal, ocular, cranial and
connective tissue defects. Also, this syndrome is not associated
with cleft palate, arterial tortuosity or risc of the aneurysm or
dissection other than of the aortic root5,6.
Beals syndrome, otherwise known as congenital contractural
arachnodactyly occurs as a result of a mutation in the fibrillin 2
gene. This syndrome is not associated with cardiac or ocular
pathologies as in LDS7.
Larsen syndrome is caused by mutations in the flaming B gene
encoded in the 3p14 region. The characteristic clinical features are
craniofacial findings and multiple joint dislocations8. However,
cardiac and spine abnormalities in association with joint
contractures can be present in Larsen syndrome9.
Vascular Ehlers-Danlos syndrome (type 4) is autosomal
dominant in type 3 collagen and characterized by fragile skin with
life-threatening complications10. This syndrome can overlap with
the features of LDS type 2.
As the site of maturation for T-cells, the thymus plays a central
role in adaptive immunity11. Although primary tumors of the
thymus are rare, the most common histologic type is thymoma. The
cause of thymoma is unknown11. Complete surgical resection is vital
for the successful management of thymic malignancies and
chemotherapy and radiation therapy play an important role in the
management of recurrent disease12. Our patient was referred to the
department of thoracic surgery for surgery of the thymoma. This is
the first report of a tumor in LDS syndrome. However, due to the
reported of no malignancy in these patients, it cannot be suggested
that there may be a predisposition for tumors in LDS patients.
Probably, the thymoma was detected coincidentally in LDS.
Aortic dilatation in patients with LDS may appear in various
age groups and major complications of the disease are aortic
dissection or rupture1,2,4,5,10,13,14. Physicians should have been
alerted by the expansion on superior mediastinum which may be
106
Alp et al.
associated with aortic dilatation or malignancy, as in our case, on
the chest radiography. However, it cannot be estimated whether
aortic root dilatation occurs in early or late decades of life. So, to
follow up these patients for unexpected complications is
important. Surgery, such as valve-sparing root replacement,
reconstruction of the descending thoracic or abdominal aorta
may be performed2.
In conclusion, LDS syndrome causes an aggressive aortic
aneurism or in the other arteries, with a predisposition to rupture
or dissection at younger ages. So, early true diagnosis and
differentiation from other similar syndromes are the basis for
optimal management and meticulous surveillance.
References
1.
2.
3.
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered
cardiovascular, craniofacial, neurocognitive and skeletal development
causes by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-81.
Williams JA, Loeys BL, Nwakanma LU, et al. Early surgical experience
with Loeys-Dietz: a new syndrome of aggressive thoracic aortic
aneurysm disease. Ann Thorac Surg 2007;83:757-63.
Rodrigues VJ, Elsayed S, Loeys BL, Dietz HC, Yousem DM.
Neuroradiologic manifestations of Loeys-Dietz syndrome type 1.
AJNR 2009;30:1614-9.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by
mutations in the TGF-beta receptor. N Engl J Med 2006;355:788-98.
LeMaire SA, Pannu H, Tran-Fadulu, V Carter SA, Coselli JS, Milewicz
DM. Severe aortic and arterial aneurysms associated with a TGFBR2
mutations. Nat Clin Pract Cardiovasc Med 2007;4:167-71.
doi:10.1038/ncpcardio0797
Kosaki K, Takahashi D, Udaka T, Kosaki R, Matsumoto M, Ibe S.
Molecular pathology of Shprintzen-Goldberg syndrome. Am J Med
Genet A 2006;140:104-8. doi: 10.1002/ajmg.a.31006
Hecht F, Beals RK. New syndrome of congenital contractural
arachnodactyly originally described by Marfan in 1896. Pediatrics
1972;49:574-9. doi: 10.1542/peds.1972-1800
Larsen LJ, Schottsstaedt ER, Bost FC. Multiple congenital dislocations
associated with characteristic facial abnormalities. J Pediatr
1950;37:574-81. doi: 10.1016/S0022-3476(50)80268-8
Kiel EA, Frias JL, Victorica BE. Cardiovascular manifestations in the Larsen
syndrome. Pediatrics 1983;71:942-6. doi: 10.1542/peds.1983-1844
Drera B, Ritelli M, Zoppi N, et al. Loeys-Dietz syndrome type l and ll:
clinical findings and novel mutations in two Italian patients. Orphanet
J Rare Dis 2009;2:24. doi: 10.1186/1750-1172-4-24
Engels EA. Epidemiology of thymoma and associated malignancies. J
Thorac Oncol 2010;5:260-5. doi: 10.1097/JTO.0b013e3181f1f62d
Rajan A, Giaccone G. Targeted therapy for advanced thymic tumors.
J Thorac Oncol 2010;5:361-4. doi: 10.1097/JTO.0b013e3181f21114
Onrat ST, Emmiler M, Sivaci Y, Söylemez Z, Ozgöz A, Imirzalioğlu N.
A patient with ascending aortic dilatation, similar to phenotypes of
connective tissue disorders. Genet Mol Res 2009;8:426-34.
Tug E, Loeys B, De Paepe A, Aydin H, Gideroglu K. A Turkish patient
of typical Loeys-Dietz syndrome with a TGFBR2 mutation. Genet
Couns 2010;21:225-32.
107
Photo Quiz
DOI: 10.5472/MMJ.2012.02189.0
A 25-year-old Man with Acute Maculo-Papular Rash and
Target Lesions
Vitorino Modesto dos SANTOS1, Antonio Augusto Dall'Agnol MODESTO2, Milena Oliveira AMUI3
1Catholic University (UCB) and Armed Forces Hospital (HFA), Internal Medicine, Brasília-DF, Brazil
2Family and Community Medicine, Community Medicine, São Paulo-SP, Brazil
3Uniube, Internal Medicine, Uberaba-MG, Brazil
A 25-year-old student had an erythematous eruption on his face,
trunk and upper extremity. Initial maculo-papules evolved to target
lesions with a vesicular center surrounded by alternating pale and dark
rings. The eruption appeared at the dorsum of the hand and
progressed proximally, four days after a flu-like episode, without use of
drugs or medicines for a minimum of six-months. The changes were
restricted to the skin, painless and mildly itching. More conspicuous
lesions appeared on his right scapula, left shoulder, and the dorsum
of the left hand (Figure 1). Previously, he was in good health, without
a history of allergy or skin or mucosal disturbances. He denied
alcoholism, tobacco smoking, use of illicit drugs, and vaccination. His
girl friend had fever, fatigue, pharyngitis and lymphadenopathy
shortly before the onset of his actual disease. Physical examination
revealed the aforementioned skin changes, in addition to discrete
bilateral posterior cervical lymphadenopathy, and a moderate nontender liver and spleen enlargement. The patient was eutrophic and
afebrile, with no ocular, oral, nasal, genital or anal lesions. In addition
to routine laboratory tests, he underwent a skin biopsy aiming to clear
the diagnosis. Blood determinations revealed leukocytosis,
lymphocytosis and 12% reactive lymphocytes. Except for a transient
elevation of the aminotransferase levels, biochemical data were
normal. Hepatosplenomegaly and lymph node enlargement rapidly
regressed to normal, as well as the lymphocyte count. The skin lesions
improved gradually and healed in about two weeks.
Figure 1
What is your diagnosis?
A. Behçet’s disease
B. Erythema elevatum diutinum
C. Erythema gyratum repens
D. Erythema multiforme
E. Sweet syndrome
Correspondence to/İletişim: Vitorino Modesto dos Santos, M.D.,Catholic University (UCB) and Armed Forces Hospital (HFA), Internal Medicine, Brasília-DF, Brazil
108
Santos et al.
Photo-Quiz
ANSWER to PHOTO QUIZ
Erythema multiforme minor (EMM)
Discussion
Erythema multiforme is an acute or recurrent eruption due to
a hypersensitivity reaction. This condition can be idiopathic, but
infections and drugs are the main precipitating factors1. EMM was
suspected, based on: edematous papules and typical target
lesions; involvement of less than 10% of body surface area; lack of
lesions in mucous membranes; and absence of epidermal
detachment1. Findings from the skin biopsy were also indicative
of EMM (apoptotic keratinocytes, hydropic degeneration of the
basal layer of the epidermis, intercellular edema, dermal
perivascular lymphocytic infiltrate, and absence of vasculitis)1.
Microorganisms were not detected by cultures or histopathology
studies. These laboratorial and histopathology data contributed to
rule out alternative hypotheses. Differential diagnosis of EMM
includes diverse other entities such as dermatitis herpetiformis,
necrotizing vasculitis, pemphigoid, pemphigus, serum sickness,
systemic lupus erythematosus, and urticaria. As observed in this
patient, EMM can heal spontaneously in two to three weeks, but
supportive or symptomatic care may be necessary, such as
antihistamines and corticosteroids for itching lesions. Clinical and
laboratory data led to suspicion of mononucleosis, but the
heterophile antibody test and Ebstein-Barr virus specific tests were
not confirmatory2. Serologic tests for cytomegalovirus, herpes
simplex, adenovirus, HIV, hepatitis A, influenza A and B,
mycoplasma, syphilis and toxoplasma were negative. Although
clinical data, aminotransferase and lymphocyte changes strongly
suggested mononucleosis,2 idiopathic EMM was not discarded.
Behçet’s disease (BD) is a multisystem inflammatory chronic
condition characterized by vasculitis and vascular thrombi, with
conspicuous cutaneous and mucosal changes3. BD is related to
geographical and genetic factors, in addition to immunological
disturbances. Most cases occur in men (20-40 years) from Turkey,
Japan, Korea, China, Iran, Iraq, and Saudi Arabia3,4. Criteria for the
diagnosis of BD include: recurrent oral ulcers; skin lesions
(erythema nodosum, pseudofolliculitis, ulcers); vascular lesions
(aneurysm, phlebitis, thrombosis); positive pathergy test;
recurrent genital ulcers; and eye lesions (retinal vasculitis, uveitis,
vitreous cells)3,4. Histopathology features include leukocytoclastic
vasculitis, perivascular lymphocytic infiltrates and neutrophilic
vascular reaction. Corticosteroids, colchicine, dapsone,
thalidomide, cyclosporine, azathioprine, etanercept, and
rebamipide constitute main options for treatment3,4.
Erythema elevatum diutinum (EED) is a rare chronic entity
actually included in the group of leukocytoclastic vasculitis5. This
condition is typically manifested by symmetrical red, brownishpurple, or yellow-brown papules, plaques and nodules on the skin
overlying joints and buttocks. Areas less commonly affected are
the trunk, palms and soles. Moderate pruritus and arthralgias may
occur. EED can be idiopathic, but the association with
hematological malignancies, IgA monoclonal gammapathy,
infections, autoimmune diseases, and cancer is usually reported.
The histopathologic data characteristic for the diagnosis of EED
are dermal neutrophilic infiltrates and leukocytoclastic vasculitis5.
Dapsone constitutes the treatment of choice for EED.
Erythema gyratum repens (EGR), is a rare condition
characterized by progressively migratory concentric and elevated
erythematous pruritic skin lesions, spreading as serpiginous bands
with scaly borders over the trunk and extremities6. Palmoplantar
keratoderma and blood eosinophilia may be observed in some
patients. The histopathologic findings are nonspecific and the
pathogenesis remains unclear. In the vast majority of cases, EGR
occurs associated with pulmonary, esophageal, pancreatic and
breast cancers, or mycosis fungoids. This paraneoplastic disorder
usually regresses after control of the underlying malignancy6.
Sweet syndrome (SS) or acute febrile neutrophilic dermatosis
is an acute condition characterized by fever, neutrophilia, and
painful erythematous, solid, and bullous lesions affecting the skin
and mucous membranes3,7. Idiopathic or classical SS more often
affects women, and has been related to upper respiratory or
gastro-intestinal infections, inflammatory intestinal disease, and
pregnancy. The SS can be drug-induced, as well as associated with
Behçet disease, rheumatoid arthritis, erythema nodosum,
sarcoidosis, and thyroid diseases. Of note, is the association of SS
with hematologic malignancies and carcinomas (genitourinary,
breast, gastro-intestinal)3,7. Histopathology features of SS include
epidermal spongiosis, subepidermal edema and vesicles, dense
and diffuse neutrophilic infiltrate in the upper dermis, and
absence of vasculitis3,7.
References
1.
2.
3.
4.
5.
6.
7.
Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am
Fam Phys 2006;74:1883-8.
Zawar V, Chuh A, Sankalecha S. Erythema multiforme-like lesions in
the course of infectious mononucleosis. J Dermatol Case Rep
2009;3:44-6. doi:10.3315/jdcr.2009.1035
Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses: part I. An
Bras Dermatol 2011;86:11-25.
Kerkeni N, Zaraa I, Ayachi J, El Euch D, Mokni M, Ben Osman A.
Behçet’s disease: A profile of mucocutaneous features. Acta
Dermatovenerol Alp Panonica Adriat 2010;19:11-5.
El Fekih N, Belgith I, Fazaa B, et al. Erythema elevatum diutinum: an
"idiopathic" case. Dermatol Online J 2011;17:7.
Delage M, Naouri M. Images in clinical medicine. Erythema gyratum
repens. N Engl J Med 2010;362:1814.
dos Santos VM, Nery NS, Bettarello G, Neiman IM, de Brito FC, Souza
CFR. Photoclinic. Bullous Sweet syndrome in chronic myeloid
leukemia. Arch Iran Med 2010;13:561-2.

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