Kronik hepatit b tanılı hastalarda kemik metabolizma parametrelerinin bazılarının sağlıklı bireylerle karşılaştırılması
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Tarih
2006
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Selçuk Üniversitesi Tıp Fakültesi
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info:eu-repo/semantics/openAccess
Özet
Genel bilgiler: lk defa 1940 yılında Amerikalı bir endokrinolog Fuller Albright postmenopozal osteoporozu tanımlamış ve sebebininde östrojen yetersizliğine bağlı kemik yapım yetersizliği olduğunu öne sürmüştür. Osteoporoz aşırı kemik rezorbsiyonu ile karakterize, iskelet sistemi hastalığıdır. Osteoporozda düşük kemik kitlesi ve mikro mimaride bozulma ve mütakiben fraktür riskinde artış izlenir. Dünyada 200 milyondan fazla insanda osteoporoz olduğu tahmin edilmektedir. Kemik kuvvetinde azalma iskelet sistemi ile ilgili kırık riskinde artmaya yol açar ve bu da ağrı ve fonksiyon kaybı ile yaşam kalitesini bozar. skelet yapının asıl mimarları kıkırdak yapan kondrositler, kemik yapan osteoblastlar ve kemiği rezorbe eden osteoklastlardır. Kemik devam eden bir süreç içinde kemik yapan osteoblastların ve kemik rezorbe eden osteoklastların koordine ettiği bir denge içinde yapılır ve resorbe edilir. OPG, RANK ve RANKL osteoklast oluşumu, gelişimi, füzyonu, aktivasyonu ve apopitozu için üç önemli sitokindir. OPG 380 aminoasitten oluşan salgısal bir proteindir. OPG osteoblastlardan salınmaktadır. OPG'nin biyolojik etkisi hem osteoklastogenezin son basamağının yani osteoklast öncülerinden dönüşümün engellenmesi, hem de erişkin osteoklastların aktivitesinin baskılanması şeklindedir. RANKL 317 aminoasitten oluşan tip 2 transmembran bir protein formunda olduğu gibi, soluble formda da olan bir proteindir. RANKL, OPG gibi osteoblastlardan salınan diğer bir proteindir. RANKL osteoklast üzerindeki yüksek affinite reseptörü olan RANK'a bağlanarak differansiasyonu ve aktivasyonunu sağlar. RANKL, kemik rezorbsiyonunu indükleyen ve hiperkalsemiye yol açan hemen hemen tüm faktörler tarafından indüklenir. Bu etki RANKL'a bağlanarak etkisini bloke eden OPG tarafından antagonize edilir. RANKL reseptörü olan RANK membrana bağlı osteoklast üzerinde yerleşmiş olan tümör nekrozis faktör süper ailesinin bir üyesidir. Osteoporozun son dönem karaciğer yetmezliğinin potansiyel bir komplikasyonu olduğu bilinmektedir. Kronik hepatit B, C ve D virus enfeksiyonunun kemik döngüsü üzerine etkisini irdeleyen çok az sayıda çalışma mevcuttur. Bazı çalışmalarda kronik hepatite bağlı sirozlu hastalarda osteoporoz sıklığı % 53 olarak bildirilmiştir. Schiefke ve arkadaşları siroz olmayan kronik B ve C hepatit tanılı hastalarda kemik mineral dansitesinde azalma izlemişlerdir. Sirozlu hastalarda osteoporoz, kemik metabolizması ve sitokinlerle ilişkisini irdeleyen çok sayıda çalışma olmasına karşın, siroz olmayan kronik hepatit B ve C tanılı hastalarda yeterli sayıda çalışma bulunmamaktadır. Biz bu nedenle siroz olmayan kronik hepatit B tanılı 44 hastalarda kemik mineral dansite, kemik yapım ve yıkım parametreleri ve serum RANKL ve OPG düzeyleri arasındaki ilişkiyi irdeledik. Materyal ve metod: Çalışmaya. Gastroenteroloji Bilim Dalı ve Enfeksiyon hastalıkları Anabilim Dalı polikliniğine başvuran 16 kronik hepatit B tanılı hasta ve 31 sağlıklı kontrol vaka alındı. DXA, kemik dansite ölçümleri, Hologic QDR 4500W Elite serisi cihazla gerçekleştirildi. Kemik mineral dansite ölçümleri AP (anterior-posterior) pozisyonda L1, L2, L3, L4, L1-L4 lomber vertebralar, femur seviyesinde; femur boynu, büyük trokanter, intertrokanterik alan, ward's üçgeni ölçülerek gerçekleştirildi. Gece açlığından sonra hasta ve kontrol grubundan alınan sabah açlık kanları santrifüj edidikten sonra serumlarından aspartat ve alanin aminotransferaz, direk ve indirek bilirubin, gamma glutamil transpeptidaz ve alkalen fosfataz üre, kreatinin, kalsiyum, fosfor, osteokalsin, TSH, LH, FSH, östradiol, kortizol, prolaktin, anti-nükleer antikor düzeyleri ve hepatit B yüzey antijeni, hepatit B yüzey antijenine karşı antikor, hepatit B kor antijenine karşı antikor, hepatit B early antijeni, hepatit B early antijenine karşı antikor, insan immun yetmezlik virüsüne karşı antikor değerleri ölçüldü. Gruplar arasındaki korrelasyon değerlendirilmesi Spearmen korrelasyon testi kullanılarak gerçekleştirildi. Idrar kalsiyum ve fosfor değerlendirilmesi için 24 saat idrar toplanarak gerçekleştirildi. Deoksipridinolin ölçümü spot idrarda gerçekleştirildi. Gruplar arası osteoporoz risk faktörlerinin karşılaştırılması için ki-kare testi kullanıldı. P< 0.05 istatistiksel olarak anlamlı kabul edildi. Bulgular: Çalışmaya toplam 47 vaka alındı. Olguların 16 adeti kronik hepatit B (37.56±10.26) ve 31 adeti sağlıklı kontrol (36.87±9.89) grubu idi. Kronik hepatit B tanılı olguların 13'ü erkek ve 3'ü kadından oluşmakta idi. Kontrol grubunun 18'i erkek ve 13'ü kadın olarak dağılım gösterdi. Her iki grubun cinsiyet dağılımı (p=0.112) ve yaş dağılımı (p=0.824) arasında anlamlı bir fark izlenmedi. Gruplar arasında sigara (p=0.769), fizik aktivite (p=0.846), kahve tüketimi (p=0.89), ailede osteoporoz (p=0.06) ve vücut kitle indeksi (p=0.686) bakımından anlamlı fark izlenmedi. Hepatit B grubu ile sağlıklı kontrol grubu karşılaştırıldığında ortalama lomber ve femur boyun KMD değerleri, t ve z skorları arasında anlamlı fark izlenmemiştir. OPG serum düzeyi hepatit grubunda kontrol grubuna göre yüksek izlenmiş iken (p=0.029), RANKL serum düzeyi hepatit grubunda kontrol grubuna göre düşük izlenmiştir (p=0.004). Spearman's korrelasyon testi ile lomber ve femur boyun t ve z-skorları, 45 KMD değerleri, idrar deoksipridinolin ve serum osteokalsin değerleri ile RANKL ve OPG arasında korrelasyon izlenmedi. Karar: Schiefke ve arkadaşlarının yaptıkları çalışmada, siroz olmayan viral hepatit B ve C'de osteopeni ve osteoporoz sıklığını yüksek saptamışlardır. Biz ise yaptığımız çalışmada osteoporoz sıklığını sağlıklı kontrol grubundan farklı izlemedik. Hegedus ve arkadaşları, Wilson hastalarında OPG düzeyinin yüksek olmasını inflamatuvar olaya ve sürece bağlı olarak fibroblast ve immun kompetan hücrelerden artmış salınım şeklinde yorumlamışlardır. Diğer bir açıklama ise artmış kemik yıkımını kompanse etmek için osteoblastlardan OPG salımında artma şeklindedir. Bu fikir bizim bulgularımızla uyuşmamaktadır. Çünkü çalışmamızda her iki grubun ortalama KMD değerlerini normal sınırlar içinde bulduk. Sylvester ve arkadaşları, yeni tanı crohn hastası çocuklarda gerçekleştirdikleri çalışmada OPG düzeylerini artmış, RANKL düzeylerini azalmış saptamışlardır ve her iki grubun KMD değerlerini normal sınırlar içinde bulmuşlardır. Bu durumu antijenik uyarıya sekonder gamma interferon artışına ve azalmış osteoblastik aktiviteye bağlamışlardır. Bizim çalışmamızda da gamma interferon azalmış olabilir. Hepatit B grubunda ortalama osteokalsin düzeylerini normal bulduk. Bu da osteoblastik aktivitenin OPG artışı ile uyumlu olarak artmadığını göstermektedir. nterlökin- 13 RANKL serum düzeyini azaltan ve OPG düzeyini artıran ve osteoklastogenezi baskılayan sitokin olarak bilinmektedir. nterlökin-13'ün STAT6 bağlı yolak ile osteoklast ve osteoblast üzerinde bulunan RANKL/RANK/OPG sistemini etkileyen reseptörleri aktif hale getirerek, osteoklast farklılaşmasını ve kemik rezorbsiyonunu baskıladığı gösterilmiştir. Bizim çalışmamızdaki bulgularımızla örtüşen bu durum hipotezimizi, yani: OPG ve RANKL düzeyindeki değişikliklerin karaciğerdeki inflamatuvar yanıtın sonucu olduğunu desteklemektedir. Literatürde kronik hepatit B enfeksiyonunda transforming growth factor beta 1 (TGF β1) düzeyinin arttığını gösteren çok sayıda çalışma vardır. TGF-β1'in RANKL düzeyini azaltırken, OPG düzeyini artırdığı bilinmektedir. TGF-β1 osteoklastogenezi baskılamakta ve kemik döngüsünü azaltmaktadır. Bizim bulgularımız, tedavi almamış kronik hepatit B tanılı hastalarda bu sitokinin artmasından kaynaklanıyor olabilir. Ama biz çalışmamızda TGF-β1 düzeyini ölçmediğimiz için bu durum hakkında kesin bir şey söylemek mümkün değildir. TGF-β1'nın osteoklastogenezi baskılaması çalışmamızda kronik hepatit B tanılı hastalarda osteoporoz izlenmemesinin nedeni olabilir. OPG ve RANKL düzeyleri ile KMD, kemik yapım ve yıkım parametreleri arasında korrelasyon olmaması başka bir açıdan 46 bakıldığında kemik metabolizmasındaki değişiklikten ziyade karaciğerde izlenen enflamasyonun OPG ve RANKL düzeyindeki değişiklikleri meydana getirmiş olabileceğidir.
General information: In 1940, Fuller Albright described postmenapousal osteoporosis, and he claimed that the reason of bone loss was due to insufficient bone production as a result of estrogen insufficiency. Osteoporosis is a disorder of skeletal system characterised by increased bone resorbtion. Low bone mass, defect in microarchitecture, and at the end of them increased risk of skeletal fracture was seen in osteoporosis. It is estimated that more than 200 million people living in the world have osteoporosis. Reduced bone strength brings about increase in skeletal system related fracture risk which cause pain and loss of function and brings about loss of quality of life. The primary architects of skeletal system are cartilage making chondrocytes, bone making osteoblasts, and bone resorbing osteoclasts. Bone is resorbed and made continiously in a process coordinated by osteoclasts and osteoblasts respectively. OPG, RANK, RANKL are three important cytokines for osteoclast production, fusion, activation, and apopitosis. OPG is a secretory protein composed of 380 aminoacids. OPG is secreted from osteoblasts. The biologic effect of OPG is both supression of the last step in osteoclastogenesis that means prevention of conversion of osteoclast progenitors and suppression of the activity of mature osteoclasts. RANKL is found in either soluble form as 317 aminoacid type 2 transmembrane protein or soluble form. Like OPG, RANKL is secreted from osteoblasts. RANKL differanciate and activate osteoclasts through with binding to RANK which is high affinity receptor located on the osteoclast. RANKL was induced by all factors inducing bone resorbtion and causing hypercalcemia. This effect was blocked by OPG which binds to the receptor located on RANKL. RANK as a RANKL receptor is a tumor necrosis family member located on osteoclast membrane. It is known that osteoporosis is the complication of end stage liver disease (74). There are a few study that examine the relationship between bone metabolism and chronic hepatitits B,C and D infection. The incidence of osteoporosis was found 53 % in some studies performed in patients with chronic hepatitis induced chirrosis. Schiefke et. al. was found reduced BMD in non chirrotic chronic hepatitis B and C patients. There is not enough study investigating the relation between osteoporosis, bone metabolism and cytokines in non chirrotic chronic hepatitits B and C patients, although a there are a lot of related with chirrotic patients in the literature. Because of that, we investigated the relation between BMD, bone turnover parameters and OPG, RANKL serum levels in non chirrotic chronic hepatitis B patients. 48 Material and method: 16 patients admitted to the gastroenterology and infectious disease clinics with chronic hepatit B infection and 31 healthy control patient was included into the study. DXA, bone densitometry assesment was performed with Holologic QDR 4500W Elite series apparatus. Bone densitometry measurement was performed at the level of L1, L2, L3, L4, L4-5, lomber vertebrate, femur level; femur neck, great trockanter, intertrockanteric area and ward?s triangel. Serum aspartat and alanine aminotransferase, direct and indirect bilirubin, gamma glutamyl transpeptidase and alkaline phosphatase, urea, creatinine, calcium, phosphor, osteocalcin, TSH, LH, FSH, estradiol, cortisol, prolactin, antinuclear antibody level and hepatit B surface antibody, antibody against to hepatitis B surface antigen, antibody against hepatit B core antigen, hepatitits B early antigen, antibody against hepatitis B early antigen, antibody against human immuno deficiency virus was evaluated in the centrifugated serum of both patients and control group following overnight fast. 24 hours of urine was collected for calcium and phosphor evaluation. Deoxypridinoline was evaluated in random urine. Ki-kare test was used for comparison of osteoporosis risc factors between control and patient group. P<0.05 was accepted statistically significant. Result: 47 person was included into the study. 16 patient with chronic hepatitis B (37.56±10.26) and 31 healthy person (36.87±9.89) was evaluated. Chronic hepatitis B patients consist of 13 men and 3 women. Healthy control group consist of 18 men and 13 women. Age (p=0.824) and sex (p=0.112) distribution of both group was not statistically significant. There was not statistically significant difference in between groups according to cigarette smoking (p=0.769), physicial activity (p=0.846), coffee consumption (p=0.89), osteoporosis in the family (p=0.06), and body mass index (p=0.686). According to mean lomber and femur neck bone mineral density values and t and z scores; there was not statistically significant difference in between chronic hepatitis B and healthy control groups. OPG serum level was statistically significantly higher in the chronic hepatitis B group compared to healthy control (p=0.029). On the other side, RANKL serum level was found statistically significantly lower in chronic hepatitis B group compared to healthy control (p=0.004). There is not statisticaly significant correlation between lomber and femur t and z scores, bone mineral density, urine deoxypridinoline and serum osteocalcin values and RANKL and OPG. Conclusion: Schiefke et. all. found increased incidence of osteporosis and osteopenia in non-chirrotic viral hepatitis B and C patients. In our study, we have not found any 49 statistically significant different BMD values between groups. High OPG and low RANKL level was found in studies performed on the patients with Wilson?s disease and primary billier chirrosis. Hegedus et al. states in their study related with Wilson?s disease that high OPG level was due to increased secretion from immunocompetant cells as a result of inflamatory event. The other explanation was increased secretion from osteoblasts so as to compansate incresaed bone destruction. This idea was not applicable to our findings. Because, we found mean BMD values in normal range in both groups. In another study performed in pediatric age group patients with newly diagnosed crohn disease; Silvester at al. found higher OPG and low RANKL levels in patient group like our results. They concluded that these findings are due to increased gamma interferon secretion secondary to increased antigenic stimulus and reduced osteoblastic actvity. It is possible that gamma interferon may also be decreased in our study. We found normal mean osteocalcin levels in hepatitis B group. This means that osteoblastic activity does not increase concordant with increase in the serum level of OPG. IL-13 is known as a cytokine that reduce serum RANKL levels, increase serum OPG levels, and depress osteoclastogenesis. It has been shown that IL-13 suppres osteoclast differantiation and bone resorbtion via activating the receptors using STAT6 pathway which effect OPG/RANKL/RANK system located on osteoblasts and osteoclasts. This finding that is compatible with our findings supports our hypothesis that; change in the serum levels of OPG and RANKL was due inflamation in the liver. There are many study in the literature that disclose incresed level of TGF-β1 in chronic hepatitis B patients. It is known that TGF- β1 increase serum OPG level, while reduce serum RANKL level. It also depress bone turnover and osteoclastogenesis. Our findings may probably results from the increased level of this cytokine in newly diagnosed chronic hepatitis B infected patients. Unfortunatelly we have not measured serum levels of this cytokine in our study so we couldn?t able to talk about definitive effect of TGF- β1. The resason that we didn?t see osteoporosis in our hepatitis B patients may be due to incresaed level of TGF-β1. We have not found any correlation between OPG and RANKL serum levels and BMD and bone metabolism parameters in our study which may be due to secondary to inflamation of chronic hepatitis B instead of bone metabolism.
General information: In 1940, Fuller Albright described postmenapousal osteoporosis, and he claimed that the reason of bone loss was due to insufficient bone production as a result of estrogen insufficiency. Osteoporosis is a disorder of skeletal system characterised by increased bone resorbtion. Low bone mass, defect in microarchitecture, and at the end of them increased risk of skeletal fracture was seen in osteoporosis. It is estimated that more than 200 million people living in the world have osteoporosis. Reduced bone strength brings about increase in skeletal system related fracture risk which cause pain and loss of function and brings about loss of quality of life. The primary architects of skeletal system are cartilage making chondrocytes, bone making osteoblasts, and bone resorbing osteoclasts. Bone is resorbed and made continiously in a process coordinated by osteoclasts and osteoblasts respectively. OPG, RANK, RANKL are three important cytokines for osteoclast production, fusion, activation, and apopitosis. OPG is a secretory protein composed of 380 aminoacids. OPG is secreted from osteoblasts. The biologic effect of OPG is both supression of the last step in osteoclastogenesis that means prevention of conversion of osteoclast progenitors and suppression of the activity of mature osteoclasts. RANKL is found in either soluble form as 317 aminoacid type 2 transmembrane protein or soluble form. Like OPG, RANKL is secreted from osteoblasts. RANKL differanciate and activate osteoclasts through with binding to RANK which is high affinity receptor located on the osteoclast. RANKL was induced by all factors inducing bone resorbtion and causing hypercalcemia. This effect was blocked by OPG which binds to the receptor located on RANKL. RANK as a RANKL receptor is a tumor necrosis family member located on osteoclast membrane. It is known that osteoporosis is the complication of end stage liver disease (74). There are a few study that examine the relationship between bone metabolism and chronic hepatitits B,C and D infection. The incidence of osteoporosis was found 53 % in some studies performed in patients with chronic hepatitis induced chirrosis. Schiefke et. al. was found reduced BMD in non chirrotic chronic hepatitis B and C patients. There is not enough study investigating the relation between osteoporosis, bone metabolism and cytokines in non chirrotic chronic hepatitits B and C patients, although a there are a lot of related with chirrotic patients in the literature. Because of that, we investigated the relation between BMD, bone turnover parameters and OPG, RANKL serum levels in non chirrotic chronic hepatitis B patients. 48 Material and method: 16 patients admitted to the gastroenterology and infectious disease clinics with chronic hepatit B infection and 31 healthy control patient was included into the study. DXA, bone densitometry assesment was performed with Holologic QDR 4500W Elite series apparatus. Bone densitometry measurement was performed at the level of L1, L2, L3, L4, L4-5, lomber vertebrate, femur level; femur neck, great trockanter, intertrockanteric area and ward?s triangel. Serum aspartat and alanine aminotransferase, direct and indirect bilirubin, gamma glutamyl transpeptidase and alkaline phosphatase, urea, creatinine, calcium, phosphor, osteocalcin, TSH, LH, FSH, estradiol, cortisol, prolactin, antinuclear antibody level and hepatit B surface antibody, antibody against to hepatitis B surface antigen, antibody against hepatit B core antigen, hepatitits B early antigen, antibody against hepatitis B early antigen, antibody against human immuno deficiency virus was evaluated in the centrifugated serum of both patients and control group following overnight fast. 24 hours of urine was collected for calcium and phosphor evaluation. Deoxypridinoline was evaluated in random urine. Ki-kare test was used for comparison of osteoporosis risc factors between control and patient group. P<0.05 was accepted statistically significant. Result: 47 person was included into the study. 16 patient with chronic hepatitis B (37.56±10.26) and 31 healthy person (36.87±9.89) was evaluated. Chronic hepatitis B patients consist of 13 men and 3 women. Healthy control group consist of 18 men and 13 women. Age (p=0.824) and sex (p=0.112) distribution of both group was not statistically significant. There was not statistically significant difference in between groups according to cigarette smoking (p=0.769), physicial activity (p=0.846), coffee consumption (p=0.89), osteoporosis in the family (p=0.06), and body mass index (p=0.686). According to mean lomber and femur neck bone mineral density values and t and z scores; there was not statistically significant difference in between chronic hepatitis B and healthy control groups. OPG serum level was statistically significantly higher in the chronic hepatitis B group compared to healthy control (p=0.029). On the other side, RANKL serum level was found statistically significantly lower in chronic hepatitis B group compared to healthy control (p=0.004). There is not statisticaly significant correlation between lomber and femur t and z scores, bone mineral density, urine deoxypridinoline and serum osteocalcin values and RANKL and OPG. Conclusion: Schiefke et. all. found increased incidence of osteporosis and osteopenia in non-chirrotic viral hepatitis B and C patients. In our study, we have not found any 49 statistically significant different BMD values between groups. High OPG and low RANKL level was found in studies performed on the patients with Wilson?s disease and primary billier chirrosis. Hegedus et al. states in their study related with Wilson?s disease that high OPG level was due to increased secretion from immunocompetant cells as a result of inflamatory event. The other explanation was increased secretion from osteoblasts so as to compansate incresaed bone destruction. This idea was not applicable to our findings. Because, we found mean BMD values in normal range in both groups. In another study performed in pediatric age group patients with newly diagnosed crohn disease; Silvester at al. found higher OPG and low RANKL levels in patient group like our results. They concluded that these findings are due to increased gamma interferon secretion secondary to increased antigenic stimulus and reduced osteoblastic actvity. It is possible that gamma interferon may also be decreased in our study. We found normal mean osteocalcin levels in hepatitis B group. This means that osteoblastic activity does not increase concordant with increase in the serum level of OPG. IL-13 is known as a cytokine that reduce serum RANKL levels, increase serum OPG levels, and depress osteoclastogenesis. It has been shown that IL-13 suppres osteoclast differantiation and bone resorbtion via activating the receptors using STAT6 pathway which effect OPG/RANKL/RANK system located on osteoblasts and osteoclasts. This finding that is compatible with our findings supports our hypothesis that; change in the serum levels of OPG and RANKL was due inflamation in the liver. There are many study in the literature that disclose incresed level of TGF-β1 in chronic hepatitis B patients. It is known that TGF- β1 increase serum OPG level, while reduce serum RANKL level. It also depress bone turnover and osteoclastogenesis. Our findings may probably results from the increased level of this cytokine in newly diagnosed chronic hepatitis B infected patients. Unfortunatelly we have not measured serum levels of this cytokine in our study so we couldn?t able to talk about definitive effect of TGF- β1. The resason that we didn?t see osteoporosis in our hepatitis B patients may be due to incresaed level of TGF-β1. We have not found any correlation between OPG and RANKL serum levels and BMD and bone metabolism parameters in our study which may be due to secondary to inflamation of chronic hepatitis B instead of bone metabolism.
Açıklama
Anahtar Kelimeler
Kronik hepatit B, Chronic hepatitis B, Kemik metabolizma parametreleri, Bone metabolism parameters
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Dikbaş, O. (2006). Kronik hepatit b tanılı hastalarda kemik metabolizma parametrelerinin bazılarının sağlıklı bireylerle karşılaştırılması. Selçuk Üniversitesi, Yayımlanmış uzmanlık tezi, Konya.
