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7 Review / Derleme 47 DO I: /MMJ The Association between Music Preferences and Psychiatric Problems in Adolescents Ergenlerde Müzik Tercihi ile Psikiyatrik Sorunlar Arasındaki İlişki Özalp EKİNCİ 1, Volkan TOPÇUOĞLU 2, Özgür Bilgin TOPÇUOĞLU 3, Osman SABUNCUOĞLU 4, Meral BERKEM 4 1 Child Psychiatry Clinic, Antakya Childrens Hospital, Hatay, Turkey 2 Department of Psychiatry, School of Medicine, Marmara University, İstanbul, Turkey 3 Department of Neurology, Erenköy Psychiatric and Neurological Disorders Hospital, İstanbul,Turkey 4 Department of Child and Adolescent Psychiatry, School of Medicine, Marmara University, İstanbul, Turkey Abstract 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 Özet 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) Anah tar Ke li me ler: 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 development 1-3. Music can also provide a background for romance and serve as the basis for establishing relationships in diverse settings 4. It is estimated that an ordinary adolescent spends over two hours listening to music everyday 5,6. The daily time spent in listening to music music may be even more than that of watching television for adolescents 4. 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/iletişim: : Özalp Ekinci, M.D., Child Psychiatry Clinic, Antakya Childrens Hospital, Hatay, Turkey ozalpekinci@yahoo.com Submitted/Başvuru Tarihi: Ac cep ted/ka bul Ta ri hi: Marmara Medical Journal, Pub lis hed by Ga le nos Pub lis hing. / Marmara Üniversitesi Tıp Fakültesi Der gi si, Ga le nos Ya yı ne vi ta ra fın dan ba sıl mış tır.

8 48 Ekinci et al. Music Preferences and Psychiatric Problems in Adolescents Marmara Medical Journal 2012;25:47-52 related to suicidality, self harm, depression, drug abuse, recklessness, antisocial behavior, school problems, arrests and family dysfunction 3,7-9 while rap was shown to be linked with alcohol abuse, illegal-drug use, aggressive behavior and arrests 8,10,11. Dance, hip-hop, techno and reggae music were reported to be related mainly to alcohol and illegal drug use 10,12. 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 music 13. 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 respectively 3. This classification has also been used by others 2,14. 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 fans 15. 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 police 16. 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 suicide 16. Newer music styles have been on the market since the year Emo music, an abbreviation for emotional music, is defined as a musical outpouring of emotions, usually associated with relationship break-ups or other tragic events 4. 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 eclectic 3. 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 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 impulses 17. Other studies also showed that adolescents preferring heavy metal music have an increased tendency to homicide 18, experience more psychological turmoil 8, and exhibit more anger and emotional problems 19 than those without such a preference. Personality traits of youth preferring pop music were also studied. Swartz and Fouts 3 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 music 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 males 27. 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 music 3. 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 problems 9. 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 years 4. 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

9 Marmara Medical Journal 2012;25:47-52 Ekinci et al. Music Preferences and Psychiatric Problems in Adolescents 49 Ozzie Osbourne were unsuccesfully sued by the parents of suicide victim adolescents because their music was being played while the adolescents died 9. 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 years 10. 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 environment 1,2,28,29. 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 students 9. 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 themes 30. 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 tendencies 32. 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 mood 7. 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 music 9,34,35. 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 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 pop 12,34,36. The association of heavy music preference and alcohol, cannabis and tobacco usage have been shown widely in Western countries including US 28,30, Australia 9 and European countries 10,12,37. 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 behavio r 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 styles 38, 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 aggressive 34. 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 music 15. Another study among university students also showed that the preference for rap and heavy metal music was associated with significant hostile attitudes 46. 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 gangs 36. Music Videos Research on the relationship between music preferences with adolescent mental health has detected another dimension of current popular music: the music videos 4. 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 week 4,47. 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

10 50 Ekinci et al. Music Preferences and Psychiatric Problems in Adolescents Marmara Medical Journal 2012;25:47-52 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 videos 49. 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 violence 47,50,51. 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 Demi 52 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 music 52. Rosenbaum and Prinsky 53 reported that a high incidence of adolescents with preference for heavy metal music were hospitalized for psychiatric problems. Doak 54 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 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 mood 35. 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 cities 55,56. 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 lives 55. Another popular style, Turkish Folk music, has more positive themes and seems to be linked to the expression of identity and nationality 56. 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 Turkey 57. 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 law 58. 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 adolescents 59. 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 depression 60. 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 Rosenbaum 61 suggested that adolescents do not

11 Marmara Medical Journal 2012;25:47-52 Ekinci et al. Music Preferences and Psychiatric Problems in Adolescents 51 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 Dodson 62 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. 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13 Derleme / Review 53 DO I: /MMJ 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 TANIR 1, Şayeste DEMİREZEN 1, Mehmet Sinan BEKSAÇ 2 1 Biyoloji Bilim Dalı, Genel Biyoloji Anabilim Dalı, Fen Fakültesi, Hacettepe Üniversitesi, Ankara, Türkiye 2 Kadın Hastalıkları ve Doğum Anabilim Dalı, Tıp Fakültesi, Hacettepe Üniversitesi, Ankara, Türkiye Özet 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) Anah tar Ke li me ler: Wnt proteinleri, Beta-katenin, Fz, LRP5/6, Erişkin kök hücreler, Kanser Abstract 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 Gi riş Organizmalarda hem embriyonik hem de erişkin dönemdeki birçok önemli biyolojik süreçte aktivite gösteren üç adet Wnt sinyal yolu tanımlanmıştır 1. 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-pos ta: sayeste@hacettepe.edu.tr Başvuru Tarihi/Submitted: Ka bul Ta ri hi/ac cep ted: Marmara Üniversitesi Tıp Fakültesi Der gi si, Ga le nos Ya yı ne vi ta ra fın dan ba sıl mış tır. / Marmara Medical Journal, Pub lis hed by Ga le nos Pub lis hing.

14 54 Tanır ve ark. Wnt/Beta-Katenin Hedef Hücre Zarı Biyomolekülleri Marmara Medical Journal 2012;25:53-7 Polarity pathway, (PCP pathway)] denir 2. 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 denir 3. Bazı araştırıcılar bu iki yolu birlikte tanımlayarak standart olmayan (non-canonical pathway) veya β-katenin bağımsız sinyal yolu olarak da adlandırmaktadırlar 1,4. Üçüncü sinyal yolu ise Wnt/β-katenin sinyal yoludur. Bu sinyal yolu standart (canonical) ya da klasik yol olarak da literatürde yer almaktadır 1. Wnt/β-katenin sinyal yolu tümör oluşumu ve birçok ciddi hastalıklarla olan sıkı ilişkisi nedeniyle araştırıcılar tarafından en çok çalışılan Wnt sinyal yoludur 5,6. Wnt/β-katenin sinyal yolunun tanımlandığı ilk yıllarda hücre siklusunun düzenlenmesinde, hücre proliferasyonu, farklılaşması ve adezyonunda önemli görevler üstlendiği ortaya konulmuştur 7,8. Son yıllarda ise bu görevlerinin yanı sıra tümör oluşumunda, sinaps oluşumu, adipogenez ve anjiogenez gibi önemli biyolojik olaylarda da rol oynadığı saptanmıştır 5,8-11. 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 alır 12. 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 sentezlenir 6,12. Sentezlenen Wnt proteini çeşitli post-translasyonel modifikasyonlar geçirerek bu hücreler tarafından ekstraselüler matrikse salınır 13. Ekstraselüler matrikste difüzyon ile hedef hücre zarına gelen Wnt proteini hedef hücre zarında bulunan Fz ve LRP5/6 isimli reseptörlerine bağlanır 14,15. Wnt proteininin reseptörlerine bağlanması ile oluşan Wnt-Fz- LRP5/6 üçlü kompleksi sinyal yolunun başlaması için oluşmuş olan esas yapıdır (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. 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 almıştır 17. 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 geçmiştir 18. Wnt genleri omurgalı ve omurgasız birçok canlıda saptanmış; ancak tek hücreli bir ökaryot olan Saccharomyces cerevisiae de ve prokaryotlarda bulunamamıştır 12,19,20. Son yıllarda yapılan çalışmalarda bitkilerde de Wnt sinyal mekanizmasında görev alan biyomoleküllerin homologları tespit edilmiştir 21,22. 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 bulunmaktadır 1,23. Wnt genlerinin ürünü olan Wnt proteinleri kd molekül ağırlığında ve yaklaşık 350 amino asit uzunluğundadır 23. Bu proteinler adet korunmuş sistein rezidülerine sahiptir 12,23. 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 oynar 24. Wnt proteinleri uzun yıllar boyunca hücreden izole edilememiştir 12,13. Yapılan deneylerde Wnt proteinleri hücre zarı ve ekstraselüler matriks bileşenlerinden heparan sülfat glikozaminoglikanlarla bağlı olarak izole edilmiş ve in vitro koşullarda aktivite göstermemiştir 13. 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 göstermiştir 25. 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 gösterilmiştir 12,23,26. 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 bildirilmektedir 26. Ayrıca WNT4 geninin anlatımında meydana gelen değişikliklerin de over ve meme kanserlerinin yanı sıra polikistik böbrek hastalıklarında rolü olduğu ifade edilmektedir 27. LRP5/6 Wnt Fz Sinyal yolu aktif Üçlü kompleks Wnt LRP5/6 Şekil 1. Wnt/β-katenin sinyal yolunun hedef hücre zarındaki mekanizması (p=fosfat) (43. referanstan değiştirilerek çizilmiştir). P P P Fz

15 Marmara Medical Journal 2012;25:53-7 Tanır ve ark. Wnt/Beta-Katenin Hedef Hücre Zarı Biyomolekülleri 55 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 kullanılmasıdır 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 olmaktadır 28,29. 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 sağlamıştır Hücre Zarı Reseptör Proteinleri a. Frizzled (Fz) Wnt/β-katenin sinyal yolu Wnt proteininin hücre zarındaki reseptörlerine bağlanmasıyla başlamaktadır 16. Sinyal yolunun başlamasında görev alan bu reseptörlerden ilk olarak Frizzled proteini tanımlanmıştır 5. Bu proteini kodlayan FRIZZLED (FZ, FZD) geni 1996 yılında Drosophila ile yapılan epidermal hücre polaritesi çalışmaları sırasında saptanmıştır 31. Daha sonra yapılan araştırmalarla insan genomunda da 10 adet FZD geni (FZD1- FZD10) bulunmuştur 11,31,32. FZD genlerinin ürünü olan Fz proteinleri yaklaşık amino asit uzunluğunda, kda molekül ağırlığında olan transmembran proteinlerdir 33. 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) denir 34. 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 gösterilmiştir 34,35. Bu da, bu amino asit dizisinin sinyal yolunun sitoplazma içindeki işleyişinde önemli rol oynadığını göstermektedir 36. Fz reseptörünün N-terminal ucu ise ekstrasellüler matrikse uzanır ve 10 adet sistein rezidüsünden oluşan, korunmuş sisteince zengin bölge [cystein-rich domain (CRD)] içerir 37. 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 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 oynamaktadır 16,38. 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 olmaktadır 37,38. 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 edilmiştir 39. 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 saptanmıştır 40,41. 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 gözlenmiştir 42. 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 alır 43,44. 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 girer 43. 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 kullanılmaktadır 43,44. 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 davranmasıdır 45. Bu

16 56 Tanır ve ark. Wnt/Beta-Katenin Hedef Hücre Zarı Biyomolekülleri Marmara Medical Journal 2012;25:53-7 kompleksin yapısında bulunan LRP5/6 reseptörünün sitozol içinde kalan kısmı amino asitten oluşur ve prolin ile serin amino asitleri bakımından zengindir. Bu kısım 5 adet korunmuş PPPSPXS (Prolin-prolin-prolin-serin-prolin) motifi içerir 43,45. 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 sürülmektedir 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 gösterilmiştir 10,46. 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 göstermektedir 47. Son yıllarda yapılan çalışmalar LRP5/6 antikorlarının tedavide kullanılabileceğini göstermektedir 48. Örneğin, meme tümör hücreleri ile yapılan bir çalışmada ortama eklenen LRP5/6 antikorlarının ve antagonistlerinin meme tümör hücrelerinde apoptozisi indüklediği ve hücre proliferasyonunu azalttığı gözlenmiştir 49. 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 kaldırılmıştır 50. 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. Kaynaklar 1. van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development 2009; 136: doi: /dev Veeman MT, Axelrod JD, Moon RT. A second canon: functions and mechanisms of β-catenin-independent Wnt signaling. Dev Cell 2003; 5: doi: / _10] 3. Kühl M, Sheldahl LC, Park M, et al. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 2000; 16: doi: /s (00)02028-x 4. Kikuchi A, Yamamoto H. Tumor formation due to abnormalities in the beta-catenin-independent pathway of Wnt signalling. Cancer Sci 2008; 99: doi: /j x 5. Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 2003; 129: doi: /s Donma MM, Donma O. 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Sailing with the Wnt: charting the Wnt processing and secretion route. Exp Cell Res 2009; 315: doi: /j.yexcr Tamai K, Semenov M, Kato Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 2000; 407(6803): doi: / Cadigan KM, Liu YI. Wnt signaling: complexity at the surface. J Cell Sci 2006; 119(Pt 3): Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982; 31: Nusse R, Brown A, Papkoff J, et al. A new nomenclature for int-l and related genes: the Wnt gene family. Cell 1991; 64: Adell T, Thakur AN, Müller WE. Isolation and characterization of Wnt pathway-related genes from Porifera. Cell Biol Int 2007; 31: Kusserow A, Pang K, Sturm C, et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature 2005; 433(7022): Li J, Nam KH. Regulation of brassinosteroid signaling by a GSK3/SHAGGY-like kinase. Science 2002; 295(5558): Vert G, Nemhauser JL, Geldner N, et al. Molecular mechanisms of steroid hormone signaling in plants. Annu Rev Cell Dev Biol 2005; 21: Miller JR. The Wnts. Genome Biol 2001;3:reviews Kikuchi A, Yamamoto H, Kishida S. Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal 2007; 19: Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipidmodified and can act as stem cell growth factors. Nature 2003; 423(6938): Niemann S, Zhao C, Pascu F, et al. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet 2004; 74: doi: / Peltoketo H, Allinen M, Vuosku J, et al. Characterization and expression of the human WNT4; lack of associated germline mutations in high--to moderate--risk breast and ovarian cancer. Cancer Lett 2004; 213: doi: /j.canlet He B, You L, Uematsu K, et al. A monoclonal antibody against Wnt- 1 induces apoptosis in human cancer cells. Neoplasia 2004; 6: You L, He B, Xu Z, et al. An anti-wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res 2004; 64: doi: / can Wei W, Chua MS, Grepper S, et al. Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells. Mol Cancer 2009; 8: doi: /

17 Marmara Medical Journal 2012;25:53-7 Tanır ve ark. Wnt/Beta-Katenin Hedef Hücre Zarı Biyomolekülleri Bhanot P, Brink M, Samos CH, et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996; 382(6588): doi: /382225a0 32. Wang YK, Samos CH, Peoples R, et al. A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q Hum Mol Genet 1997; 6: Huang HC, Klein PS. The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol 2004; 5: doi: /gb Wawrzak D, Luyten A, Lambaerts K, et al. Frizzled PDZ scaffold interactions in the control of Wnt signaling. Adv Enzyme Regul 2009; 49: Punchihewa C, Ferreira AM, Cassell R, et al. Sequence requirement and subtype specificity in the high-affinity interaction between human frizzled and dishevelled proteins. Protein Sci 2009; 18: doi: /pro Umbhauer M, Djiane A, Goisset C, et al. The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/betacatenin signalling. EMBO J 2000; 19: doi: /emboj/ Dann CE, Hsieh JC, Rattner A, et al. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 2001; 412(6842): doi: / Povelones M, Nusse R. The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J 2005; 24: doi: /sj.emboj Kirikoshi H, Sekihara H, Katoh M. Expression profiles of 10 members of Frizzled gene family in human gastric cancer. Int J Oncol 2001; 19: Nagayama S, Fukukawa C, Katagiri T, et al. Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene 2005; 24: doi: /sj.onc Wu QL, Zierold C, Ranheim EA. Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia. Blood 2009; 113: doi: /blood Fukukawa C, Hanaoka H, Nagayama S, et al. Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10. Cancer Sci 2008; 99: He X, Semenov M, Tamai K, et al. LDL receptor-related proteins 5 and 6 in Wnt/b-catenin signaling: arrows point the way. Development 2004; 131: Schweizer L, Varmus H. Wnt/Wingless signaling through beta-catenin requires the function of both LRP/Arrow and frizzled classes of receptors. BMC Cell Biol 2003; 4:4-15. doi: / MacDonald BT, Yokota C, Tamai K, et al. Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J Biol Chem 2008; 283: doi /jbc.m Cuzzo LM, Ross-Cisneros FN, Yee KM, et al. Low-density lipoprotein receptor-related protein is decreased in optic neuropathy of Alzheimer disease. J Neuroophthalmol 2011;31: doi: /wno.0b013e31821b602c 47. Milat F, Ng KW. Is Wnt signalling the final common pathway leading to bone formation? Mol Cell Endocrinol 2009; 310: Ettenberg SA, Charlat O, Daley MP, et al. Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligandbinding regions by LRP6 antibodies. Proc Natl Acad Sci U S A 2010; 107: doi: /pnas Liu CC, Prior J, Piwnica-Worms D, et al. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci USA 2010; 107: doi: /pnas Guo Y, Rubin EM, Xie J, et al. Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model. Clin Orthop Relat Res 2008; 466: doi: /s y

18 58 Review / Derleme DO I: /MMJ 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 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. (Marmara Medical Journal 2012;25:58-63) Key Words: Pregnancy, Hyperemesis gravidarum, Intrahepatic cholestasis of pregnancy, Preeclampsia and eclampsia, HELLP syndrome, Acute fatty liver of pregnancy. Özet 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) Anah tar Ke li me ler: 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 6 th week of gestation, and it is raised by approximately 50% at the 36 th 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 considered 1. 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/iletişim: Dr. Emel Ahishali, M.D., Department of Gastroenterology, Dr. Lutfi Kırdar Kartal Education and Research Hospital, Cevizli, Istanbul, Turkey emelahishali@yahoo.com Submitted/Başvuru Tarihi: Ac cep ted/ka bul Ta ri hi: Marmara Üniversitesi Tıp Fakültesi Der gi si, Ga le nos Ya yı ne vi ta ra fın dan ba sıl mış tır. / Marmara Medical Journal, Pub lis hed by Ga le nos Pub lis hing.

19 Marmara Medical Journal 2012;25:58-63 Emel Ahıshalı Liver Diseases Associated with Pregnancy 59 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 changed 2-4. 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 4 th -10 th week, and alleviates by 16 th -18 th week. However, it may persist until the third trimester in 15-20% of patients, and until parturition in 5-10% of patients 1,5. The pathogenesis is not clearly known, but it is believed to be multifactorial with possibly endocrine, immunological and psychological factors playing roles in the etiology 1,5. 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 12 th -14 th week of gestation, which coincides with the initiation of nausea and vomiting 6-8. 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 women 6. T cell mediated immune reactivation, immunoglobulins and the complement system are also considered to play an important role in HG etiology 5. Among the risk factors that have been reported to be associated with HG development are a young maternal age, a multiple pregnancy, molar pregnancy, nulliparity, a female fetus, hyperthyroidism, psychiatric illness, presence of family history, specific nutrient deficiencies and chronic infection of helicobacter pylori 1,9-11. 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 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 hypokalemia Complications are rare in HG, but retinal hemorrhage, Wernicke s encephalopathy, esophageal tear or rupture, pneumothorax and splenic avulsion may be encountered 1,10. Diagnosis is mainly based on clinical findings; it is diagnosed by the typical initiation of the symptoms at 4 th -10 th 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 cholestasis 1,4,13. 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 dehydration 6,7,9,14. It has also been reported that non-pharmacological treatments like hypnosis and acupuncture are also effective 7,9,15,16. HG generally self-recovers near the 20 th week of gestation independently of treatment. HG may cause fetal growth Table I. Liver function tests in normal pregnancy 3 Non-pregnant 1 st trimester 2 nd trimester 3 rd trimester AST (IU/L) ALT (IU/L) Bilirubin (mg/dl) GGT (IU/L) ALP(IU/L) Bile acids (μmol/l) AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyl transferase; ALP, alkaline phosphatase.

20 60 Emel Ahıshalı Liver Diseases Associated with Pregnancy Marmara Medical Journal 2012;25:58-63 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 treatment 1,4,10. 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 ICP 17,18. 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 proteins 19,20. 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 damage 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 encountered 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 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. γ- glutamyl 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 increased 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 37 th 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 cholestasis 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 % 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 20 th 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 proteinuria 22,23. 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 history 4,10. 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 delivery 22. 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