ABSTRACT
Objective:
Neonatal cholestasis is a condition that begins in the first months of life and is accompanied by a direct increase in bilirubin and jaundice as a result of deterioration in bile production or excavation. Early and accurate diagnosis is important for treatment success and prognosis. In this study, we aimed to examine the demographic characteristics, etiological factors, clinical signs, treatment and final conditions of patients monitored for neonatal cholestasis and to determine the etiological factors of liver transplant patients.
Methods:
Patients who were diagnosed with cholestasis in the neonatal period (<6 months) and followed up in our clinic for at least six months between January 2005 and January 2018 were included in the study. The clinical course and final status of the patients were recorded retrospectively.
Results:
The median age of onset of jaundice in 131 patients (61.1% male) enrolled in the study was 6 days (range: 1-180 days). Ninety-nine (75.6%) patients were in the intrahepatic cholestasis group, and 32 (24.4%) were in the extrahepatic cholestasis group. In the intrahepatic cholestasis group, total parenteral nutrition-related cholestasis (27.3%) was the most common, and biliary atresia (71.9%) was the most common in the extrahepatic cholestasis group. Other main reasons were systemic (19.1%), metabolic (12.2%), hereditary cholestatic diseases (9.9%) and infectious (7.6%) causes. The median time of Kasai portoenterostomy in patients with biliary atresia was 64 days (range: 28-180 days). The highest (44%) mortality rate was in the patients with systemic disease-related cholestasis. Liver transplantation (n=21, 16%) was the most frequently performed in patients with biliary atresia.
Conclusion:
Early diagnosis and timely treatment are very important for the optimal prognosis in neonatal cholestasis. The presence of acholic stools, maturity, early onset of jaundice and high gamma-glutamyl transferase levels should suggest biliary atresia. Early surgical treatment is warranted once the diagnoses was made, and liver transplantation is a treatment method that increases survival rate in these patient groups.
INTRODUCTION
Neonatal cholestasis is a condition that starts in the first months of life and progresses with direct (conjugated) bilirubin increase and jaundice as a result of impaired bile production or excretion (1). Its incidence is known as 1 in 2,500 live births (2). As a result of increased conjugated bilirubin and bile acids, toxin components cause liver damage and cause hepatobiliary dysfunction. Therefore, in a patient presenting with jaundice, it is critical to distinguish whether the jaundice is cholestatic or not.
Newborn babies, especially premature ones, are prone to cholestasis. The reasons of this are because of the irregularity in canalicular structure and function, the increase in hypomotility and paracellular permeability, and the decrease in hepatic immaturity and bile flow. Hepatic maturation is complete around the end of the first year. Therefore, there is no consensus regarding the age range of neonatal cholestasis. In most studies, it was considered to be about the first six months (3).
The most common cause of neonatal cholestasis is intrahepatic cholestasis (60-70%), and most of these cases are idiopathic neonatal hepatitis (INH) (4). INH covers a group of patients whose etiology cannot be found or whose specific diagnosis cannot be made by existing examinations rather than a diagnosis. Although it has been determined in studies that more than half of the cholestatic infants are patients with INH, the rate of INH diagnosis has decreased in recent years thanks to clinical and molecular developments (5). Infections [toxoplasmosis, rubella, cytomegalovirus (CMV), herpes virus, TORCH and syphilis], endocrinopathies (hypothyroidism, hypopituitarism, adrenal insufficiency), systemic diseases, genetic-chromosomal disorders, metabolism diseases, total parenteral nutrition (TPN), hereditary cholestatic diseases and anatomical disorders are other causes of intrahepatic cholestasis (6). Most patients with extrahepatic cholestasis are diagnosed with biliary atresia (BA). In etiological studies reported from different centers, BA accounted for about 25-35% of all neonatal cholestasis cases, while other major causes were genetic disorders (25%), metabolic diseases (20%) and alpha-1 antitrypsin deficiency (10%) (7). In recent years, the frequency of TPN-related neonatal cholestasis cases has also increased as a result of increased life rates of premature and low birth-weighted newborns.
Early and accurate diagnosis of neonatal cholestasis patients is very important for treatment success and prognosis. Evaluation of these patients is difficult due to the variety of cholestatic syndromes and the lack of clinical manifestations specific to diseases. But thanks to clinical and molecular advances, differential diagnosis can be made more easily in recent years.
In this study, it was planned to examine the neonatal cholestasis cases followed in our clinic with their demographic characteristics, etiological factors, clinical signs, treatment and final status and to compare these data with other studies in the literature.
GİRİŞ
Neonatal kolestaz, hayatın ilk aylarında başlayan, safra yapımı veya ekskresyonunun bozulması sonucu direkt (konjuge) bilirubin artışı ve sarılıkla seyreden bir durumdur (1). İnsidansı 2.500 canlı doğumda 1 olarak bilinmektedir (2). Konjuge bilirubin ve safra asitlerinin artması sonucu, toksin bileşenler karaciğerde hasara yol açmakta ve hepatobiliyer disfonksiyona neden olmaktadır. Bu nedenle sarılık ile başvuran bir hastada, sarılığın kolestatik olup olmadığının ayırt edilmesi kritik öneme sahiptir.
Prematürler başta olmak üzere yenidoğan bebekler kolestaza yatkındırlar. Perinatal dönemde, kanaliküler yapı ve fonksiyonda düzensizlik, hipomotilite ve paraselüler permeabilite artışı olmakta, hepatik immatürite ve safra akışında azalma görülmektedir. Bu nedenle yenidoğan bebekler kolestaza yatkındır. Hepatik maturasyon yaklaşık ilk bir yılda tamamlanmaktadır. Bu nedenle neonatal kolestazın yaş aralığı ile ilgili bir görüş birliği yoktur. Çoğu çalışmada yaklaşık ilk altı ay olarak kabul edilmiştir (3).
Neonatal kolestazın en sık nedeni intrahepatik kolestaz (%60-70) olup bu olguların da büyük kısmını idiyopatik neonatal hepatit (İNH) oluşturmaktadır (4). İNH, bir tanıdan çok etiyolojisi bulunamayan ya da mevcut tetkiklerle spesifik tanı konulamayan hasta grubunu kapsamaktadır. Yapılan çalışmalarda, kolestatik infantların yarısından çoğunun İNH’li hastalar olduğu belirlenmiş olsa da klinik ve moleküler gelişmeler sayesinde son yıllarda İNH tanı oranı azalmıştır (5). Enfeksiyonlar [toksoplazmozis, rubella, sitomegalovirüs (CMV), herpes virüs, TORCH ve sifiliz], endokrinopatiler (hipotroidi, hipopituarizm, adrenal yetmezlik), sistemik hastalıklar, genetik-kromozomal bozukluklar, metabolik hastalıklar, total parenteral nütrisyon (TPN), herediter kolestatik hastalıklar ve anatomik bozukluklar diğer intrahepatik kolestaz nedenleridir (6). Ekstrahepatik kolestazlı hastaların çoğu biliyer atrezi (BA) tanısı almaktadır. Farklı merkezlerden bildirilen etiyolojik çalışmalarda BA, tüm neonatal kolestazlı olguların yaklaşık %25-35’ini oluştururken, diğer başlıca nedenler ise genetik bozukluklar (%25), metabolik hastalıklar (%20) ve alfa-1 antitripsin eksikliğidir (%10) (7). Son yıllarda prematür ve düşüm doğum ağırlıklı yenidoğanların yaşam oranlarının artması sonucu TPN ile ilişkili neonatal kolestaz olgularının da sıklığı artmaktadır.
Neonatal kolestazlı hastalara erken ve doğru tanı konulması, tedavi başarısı ve prognoz açısından çok önemlidir. Bu hastaların değerlendirilmesi, kolestatik sendrom çeşitliliği ve klinik bulguların hastalıklara spesifik olmaması nedeniyle zordur. Ancak klinik ve moleküler gelişmeler sayesinde ayırıcı tanı son yıllarda daha kolay yapılabilmektedir.
Bu çalışmada, kliniğimizde takip edilen neonatal kolestazlı olguların; demografik özellikleri, etiyolojik faktörleri, klinik bulguları, tedavi ve son durumlarıyla incelenmesi ve bu verilerin literatürdeki diğer çalışmalarla karşılaştırılması planlanmıştır.
METHODS
Patients diagnosed with neonatal cholestasis (0-6 months old) and followed for at least six months in the Karadeniz Technical University Faculty of Medicine Pediatric Gastroenterology, Hepatology and Nutrition Department between January 2005 and January 2018 were included in this study. Cholestasis was considered to be conjugated bilirubin levels above 1 mg/dL when serum total bilirubin levels were below 5 mg/dL, or conjugated bilirubin was more than 20% of total when total bilirubin levels were above 5 mg/dL (5,8). Demographic characteristics, etiological factors, clinical signs, treatment and final status of patients were examined and etiological factors were determined in the liver transplant cases.
Causes of cholestasis were grouped as extrahepatic and intrahepatic cholestasis. Intrahepatic cholestasis; i) INH, ii) metabolic diseases, iii) hereditary cholestatic syndromes, iv) infectious diseases, v) systemic diseases, vi) toxins (TPN, drugs), vii) anatomical disorders of the biliary tract, viii) undiagnosed extrahepatic cholestasis was classified as i) BA, ii) choledochal cysts, iii) biliary hypoplasia, iv) cholelithiasis (9).
Ethics committee approval was obtained from the Karadeniz Teknik University Faculty of Medicine Scientific Research Ethics Committee for the study (approval number: 2016/128, approval date: 21.09.2016). Our study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Consent was obtained from the patients.
YÖNTEMLER
Bu çalışmaya; Karadeniz Teknik Üniversitesi Tıp Fakültesi Çocuk Gastroenteroloji, Hepatoloji ve Beslenme Bilim Dalı’nda, Ocak 2005-Ocak 2018 yılları arasında neonatal kolestaz tanısı alan (0-6 aylık) ve en az altı ay süreyle takip edilen hastalar dahil edildi. Kolestaz, serum total bilirubin düzeyi 5 mg/dL altındayken konjuge bilirubin düzeyinin 1 mg/dL üzerinde olması veya total bilirubin düzeyi 5 mg/dL’nin üzerindeyken konjuge bilirubinin, totalin %20’sinden fazla olması olarak kabul edildi (5,8). Hastaların; demografik özellikleri, etiyolojik faktörleri, klinik bulguları, tedavi ve son durumları incelenip, karaciğer nakli yapılan olguların etiyolojik faktörleri belirlendi.
Kolestaz nedenleri, ekstrahepatik ve intrahepatik kolestaz olarak gruplandırıldı. İntrahepatik kolestaz; i) İNH, ii) metabolik hastalıklar, iii) herediter kolestatik sendromlar, iv) enfeksiyöz hastalıklar, v) sistemik hastalıklar, vi) toksinler (TPN, ilaç), vii) safra yollarının anatomik bozuklukları, viii) tanı konulamayan kolestatik hasta grubu şeklinde, ekstrahepatik kolestaz ise i) BA, ii) koledok kistleri, iii) biliyer hipoplazi, iv) kolelitiazis şeklinde sınıflandırıldı (9).
Çalışma için Karadeniz Teknik Üniversitesi Tıp Fakültesi Bilimsel Araştırmalar Etik Kurulu’ndan etik kurul onayı alınmıştır (onay no: 2016/128, onay tarihi: 21.09.2016). Çalışmamız Helsinki Deklarasyonu Etik Prensipleri’ne uygun olarak yapılmıştır. Hastalardan onam formu alınmıştır.
İstatistiksel Analiz
İstatistiksel analizler “SPSS® for Windows version 22.0” kullanılarak yapıldı (IBM Corp., Released 2013, IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY, USA). Değerlendirme sonuçlarının tanımlayıcı istatistikleri; kategorik değişkenler için sayı ve yüzde, devamlı değişkenler için ortalama ± standart sapma minimum, maksimum, ortanca olarak verildi. Bağımsız gruplarda kategorik değişkenlerin oranları arasındaki farkların analizinde ise ki-kare testi kullanıldı. İstatistiksel alfa anlamlılık seviyesi p<0,05 olarak kabul edildi.
Statistical Analysis
Statistical analysis was performed using “SPSS® for Windows version 22.0” (IBM Corp., Released 2013, IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY, USA). Descriptive statistics of evaluation results; number and percentage for categorical variables, mean ± standard deviation for continuous variables were given as minimum, maximum, and median. Chi-square test was used to analyze the differences between the ratios of categorical variables in independent groups. Statistical significance level of alpha was accepted as p<0.05.
RESULTS
A total of 131 patients were enrolled in the study [61.1% male, median age; 35 days (range: 1-180 days)]. Patients’ median age of onset of jaundice; it was 6 days (range: 1-180 days). Forty-three patients (32.8%) had prematurity and parents of 43 patients (32.8%) had a consanguineous marriage. The findings other than jaundice were hepatomegaly (n=102, 77.9%), splenomegaly (n=48, 36.6%), acholic stool (n=46, 35.1%), umbilical hernia (n=9, 6.9%), limb anomaly (n=7, 5.3%) and atypical facial appearance (n=7, 5.3%). The demographic and clinical features of the patients at the time of application are shown on Table 1.
Patients were divided into two groups according to their diagnosis. Extrahepatic cholestasis was detected in 32 (24.4%) patients and intrahepatic cholestasis was detected in 99 (75.6%) patients. Recent diagnoses of patients are shown in Table 2.
BA (n=23) constituted 71.9% of patients with extrahepatic cholestasis and 17.6% of all patients with cholestasis. Kasai portoentrostomy was performed in 22 (95.7%) of the patients with BA after the diagnosis was made by intraoperative cholangiography. The mean age of Kasai portoentrostomy was 68.6±33.5 (median: 64 days, range: 28-180) days. Since one patient (4.3%) presented late (225th day), liver transplantation was performed in the follow-up before Kasai operation could be performed. Liver transplantation was performed in 10 (43.5%) of 22 patients who underwent Kasai operation (all living donors). All of the transplant patients (n=11, 47.8%) are alive and their median age at present is 6.8 years (range: 0.9-13.5 years). Three (25%) of the 12 patients who did not have a transplant, died due to decompensated cirrhosis while waiting on the transplant list. When liver function was evaluated in nine living patients (39.1%), seven patients (30.4%) had compensated cirrhosis, and two patients (8.7%) had decompensated cirrhosis. Among all BA patients, there were three (13%) patients with excitus, and 20 (87%) patients who survived. Other causes of extrahepatic cholestasis (n=9) were biliary cyst (n=5), biliary hypoplasia (n=2), and cholelithiasis (n=2). Cystectomy was performed in five patients with biliary cyst, external drainage was performed on a patient with biliary hypoplasia, cholecystectomy was performed on a patient with cholelithiasis, and other patients were followed up with medical treatment.
Most patients in the intrahepatic cholestasis group had TPN-associated cholestasis (n=27, 27.3%). The cases of 21 (77.8%) and premature indications for TPN; necrotizing enterocolitis (NEC) (n=13, 48.1%), short bowel syndrome (n=7, 36%), sepsis (n=5, 18.5%), Pierre-Robin variant (n=1, 3.7%) and anatomical problems (n=1, 3.7%). Patients were given cyclic fat support (n=27, lipid 1 g/kg/day three days a week), ursodeoxycholic acid (n=22, 15 mg/kg/day), N-acetylcysteine (n=4, 5 mg/kg/hour-5 days), omega-3 (n=1, 1-2 mL/kg) therapy as a treatment protocol. In follow-up, five patients had died due to sepsis (two with fungal sepsis, three with catheter-related sepsis). The average follow-up period of living patients (n=22, 77.8%) was 5.6 years (range: 1-11.5 years) and liver function tests were normal in their last applications.
In the metabolic diseases group (n=16, 16.2%); four patients (25%) galactosemia (homozygous Q188R mutation), four patients (25%) tyrosinemia, two patients (12.5%) cystic fibrosis (CFTR gene; p.F508del homozygous mutation), one patient (6.3%) was diagnosed with Wollman’s disease. Five patients (31.3%) were described as possible metabolic diseases due to non-specific changes in their metabolic tests, a history of close kinship, a history of infant death, coagulopathy, and ascites. A lactose-free diet for patients with galactosemia, a diet for patients with tyrosinemia and NTBC (1 mg/kg), and medical treatment for patients with cystic fibrosis (pancreatic enzyme replacement, medium-chain triglyceride fat support and vitamin A, D, E, K) were initiated. In follow-up, 10 patients underwent medical treatment as well as a new diet, and three patients (n=4, 25%) who had Wollman’s disease and were considered a possible metabolic disease died. One of the two patients with tyrosinemia had a liver transplant due to hepatocellular carcinoma and the other due to decompensated cirrhosis (one from a cadaver, one from a live donor from the mother).
Patients with hereditary cholestatic syndrome (n=13, 13.1%); seven (53.8%) progressive familial intrahepatic cholestasis (PFIC, ABCB4 gene in three patients; p.Ala953Asp homozygous mutation-PFIC-3 and ABCB11 gene; p.E1302 homozygous mutation-PFIC-2, ATP8B1 gene in one patient; 18q21.31 homozygous mutation -PFIC-1), six of them (46.2%) were diagnosed with Alagille syndrome. A total of five patients had liver transplantation. The median age of transplant PFIC patients (n=4, 57.1%) at the time of transplant was 29.5 months (range: 5-66 months), all alive, and their current median age of 8.8 years (range: 3.7-13.5 years). One of the patients with Alagille syndrome (16.7%) underwent liver transplantation (living donor) at the age of two months, but died eight months after transplantation due to organ rejection. Two of the five patients (83.3%) who were not transplanted died while waiting on the list for transplant. The median follow-up period of surviving patients (n=3) is 9.7 years (range: 9.2-10.2 years).
Patients in the infectious group (n=10, 10.1%) accounted for 7.6% of all patients with cholestasis [congenital CMV (n=4, 40%), toxoplasma infection (n=1, 10%) and sepsis-associated cholestasis (n=5, 50%)]. Four of the patients with sepsis had pyelonephritis Escherichia coli (E.coli), and one had nosocomial sepsis. Two of these patients died [20%, CMV (n=1), nosocomial sepsis (n=1)].
Patients in the cholestasis group associated with systemic disease (n=25, 25.3%) constituted the 19.1% of all patients with cholestasis. Eight of these patients (32%) had genetic-chromosomal disease [arthrogryposis-renal dysfunction-cholestasis (ARC) (n=3), Down syndrome (n=1), trisomy 13 (n=1) and genetic syndrome (n=3, multiple congenital anomalies)], endocrinopathy in seven (28%) [congenital hypothyroidism (n=5), hypopituitarism (n=1), adrenal insufficiency (n=1)], in nine (36%) hematologic-immunological diseases [chronic hemolytic disease (n=4), neonatal hemochromatosis (n=2), hemophagocytic lymphohistiocytosis (HLH, n=1), common variable immunodeficiency (n=1), autoimmune giant cell hepatitis and autoimmune hemolytic anemia (n=1)] and in one (4%) had congenital heart disease (left ventricular hypertrophy, aortic valve dysplasia, pulmonary stenosis). In general, the highest mortality (n=11, 44%) was in this group, and genetic-chromosomal disease (three patients with genetic syndrome and ARC) in six patients, endocrinopathy (congenital hypothyroidism) in one, hematological-immunological disease in three patients (one was HLH, one had neonatal hemochromatosis, the other was immunodeficiency) and one had congenital heart disease. In this group, only one patient (autoimmune giant cell hepatitis + autoimmune hemolytic anemia) received liver transplantation (living donor) at the age of four months due to decompensated cirrhosis. The transplanted patient is alive and the average follow-up period is 6 years.
Patients in the cholestasis group associated with anatomical disorders (n=2, 2%) constituted 1.5% of all patients with cholestasis. The median onset of jaundice in these patients was 35 days (range: 1-68 days). One of the patients died five days after being diagnosed with Caroli syndrome. While the other patient was being followed up with the diagnosis of congenital hepatic fibrosis and autosomal recessive (AR) polycystic kidney disease, liver transplantation (live donor) was performed due to decompensated cirrhosis, and the patient died due to sepsis after transplantation.
INH group (n=2, 2%) comprised 1.5% of all patients with cholestasis. Patients with unfitting clinical and laboratory findings to a specific disease group and with undetermined cholestasis etiology were evaluated as INH. All patients had hepatomegaly and splenomegaly on physical examination. One (50%) of INH patients received liver transplantation at the age of seven months (living donor). The liver functions of the other patient are normal and follow-up continues.
Four patients (4%) who could not be diagnosed constituted 3.1% of all patients with cholestasis. One of these patients (25%) died at the age of two months and the etiology was not found. The median follow-up period of the surviving patients was 5.8 years (range: 0.9-10.7 years). Liver functions of three patients who were living in the follow-up were completely normalized.
When BA and other diseases are compared; while there was no significant difference in terms of gender and kinship, a significant difference was found in the age of onset of acholic defecation, jaundice, gestational week and gamma-glutamyl transferase (GGT) (p<0.001, p=0.028, p=0.001 and p=0.001, respectively) (Table 3).
When the last conditions of the patients are evaluated; liver transplantation was performed in 21 (16%) of 131 patients (20 living, one cadaver donor) (Table 4). 99 (75.6%) of all patients were alive (61.1% with their own liver, 14.5% after transplantation) 32 of them (24.4%) were exitus (22.9% with their own liver and 1.5% after transplantation). Both five-year and 10-year survival rates of BA patients were 86%. Five-year and 10-year survival rates of systemic disease-related cholestasis cases with the highest mortality were determined as 56%. The final status of the patients is shown in Table 5.
TARTIŞMA
Kolestazlı hastaların değerlendirilmesi, kolestatik sendrom çeşitliliği ve klinik bulguların non-spesifik olması nedeniyle zordur. Hepatobiliyer sistemin mekanizmalarının daha net anlaşılmasıyla ayırıcı tanı son dönemde daha iyi yapılabilmektedir. Çalışmamızda yer alan 131 hastanın etiyolojisine bakıldığında; (i) olguların büyük çoğunluğunda intrahepatik kolestaz saptandığı (%75,6) ve bununda büyük kısmının TPN ile ilişkili kolestaz olduğu (%27,3), (ii) ekstrahepatik kolestazlı olguların büyük çoğunluğunun BA olduğu (%71,9), (iii) BA hastalarının Kasai portoenterostomi zamanının ortanca 64 gün olduğu, (iv) karaciğer nakline giden olguların büyük kısmını BA’nın oluşturduğu (%52,4), (v) sistemik hastalıkla ilişkili kolestaz olgularının mortalitesinin yüksek olduğu (%44) gözlenmiştir.
Çalışmamızda neonatal kolestaz etiyolojisi, literatürdeki diğer çalışmalara benzer şekilde %60-70 oranında intrahepatik kolestaz olarak belirlenmiştir. İntrahepatik kolestaz olgularının da büyük kısmını çalışmanın yapıldığı döneme bağlı olarak İNH ve TPN ilişkili kolestaz oluşturmaktadır (4). Son yıllarda klinik ve moleküler gelişmeler sonucunda İNH tanı oranı azalmıştır (5). TPN kolestazının sıklığı, bizim çalışmamızda da olduğu gibi prematüre ve düşük doğum ağırlıklı bebeklerin yenidoğan bakımlarının daha iyi yapılması ve komplikasyonların daha iyi tedavi edilebilmesi nedeni ile giderek artmaktadır. Yapılan çalışmalarda risk faktörlerinin büyük kısmını NEK, sepsis ve majör barsak cerrahileri oluşturmaktadır (10). En iyi tedavi yöntemi, mümkün olan en kısa zamanda enteral beslenmenin başlanması ve parenteral nütrisyonun kesilmesi olup omega-3 takviyesi ve lipidin azaltılması önerilen diğer uygulamalardır (11). TPN kolestazında uzun dönemde, karaciğer yetmezliği ve siroz nedeniyle organ nakline gerek duyulsa da, bizim olgularımızda karaciğer nakil ihtiyacı olmamıştır. Kaybedilen hastaların büyük çoğunluğu kateter ya da kan akımı ile ilişkili sepsis nedeni ile kaybedilmiştir.
Ekstrahepatik kolestazın en sık ve en önemli nedeni BA’dır (12). Merkezlerin hasta yoğunluğuna göre değişmekle birlikte tüm kolestazların %20-35’ini BA oluşturmaktadır. Ülkemizde yapılan bir çalışmada; tüm kolestazların %16,8’ini ekstrahepatik kolestaz oluştururken, ekstrahepatik kolestazın ise %75’ini BA’nın oluşturduğu tespit edilmiştir (13). Başka bir çalışmada ise; tüm neonatal kolestazı olan hastalarda BA oranı %25,9 (438/1.692) olarak bulunmuştur (5). BA’da erken tanı ve tedavi prognoz açısından çok önemlidir. Erken tanı konulup erken yaşta Kasai portoenterostomi yapılan olgularda, karaciğer nakil ihtiyacının daha az olduğu gözlenmiştir (12). Merkezimizde Kasai portoenterostomi zamanı ortanca 64 gündü. Diğer çalışmalar ile merkezimiz kıyaslandığında, Kasai operasyonu yaşının birçok merkez ile benzer olduğu görülmüştür. Amerika’daki bir organ nakil merkezinde 63 gün, Londra merkezli başka bir çalışmada ise 66 gün olarak rapor edilmiştir (14,15).
Akolik dışkı her ne kadar BA için spesifik olsa da kesin tanı için safra yollarının intraoperatif kolanjiyografi tetkiki ile görüntülenmesi gerekmektedir. Bugüne kadar BA için çeşitli objektif skorlama sistemleri oluşturularak gereksiz intraoperatif kolanjiyografi ihtiyacı azaltılmaya çalışılmış ve non-invaziv olarak tanı konmaya çalışılmıştır. Amerika’da yapılan bir çalışmada; akolik dışkı, GGT yüksekliği (>204 U/L) ve normal ağırlık Z skorunun BA ile ilişkili olduğu tespit edilmiştir (12). Ülkemizde yapılan bir çalışmada ise; ultrasonografi bulguları, GGT yüksekliği (>197 U/L) ve akolik dışkının BA ile ilişkili olduğu rapor edilmiştir (16). Bizim çalışmamız da, literatürdeki bu çalışmalara benzer şekilde akolik dışkı ve GGT yüksekliğinin BA için anlamlı olduğunu tespit etmiştir.
Metabolik hastalıkların en önemli hedef organlarından biri karaciğerdir. Neonatal dönemde, galaktozemi, tirozinemi ve kistik fibrozisli hastalar akut karaciğer yetmezliği bulguları ile başvurabilmektedir. Bir çalışmada; metabolik hastalığı ve kolestazı olan 74 hastanın %36,5’i (27/74) galaktozemi, %8,1’i (6/74) tirozinemi tanısı almıştır. Aynı çalışmada genel taramada ise kistik fibrozis tanısı %0,89 (15/1.692) oranında görülmüştür (4). Bizim çalışmamızda; metabolik hastalık oranı %12,1 olarak belirlenmiş olup en sık galaktozemi ve tirozinemi tespit edilmiştir. Çoğu OR kalıtılan bu hastalıklarda, aile öyküsü ve akrabalığın ayrıntılı sorgulanması önemli olup erken tanı ve tedavi önem arz etmektedir.
Özellikle son yıllarda moleküler çalışmaların artması ile herediter kolestatik sendromların tanısında artış gözlenmiştir. Hastalarda sarılığa ek olarak kaşıntı, ishal, büyüme geriliği gibi bulgular PFİK açısından, iskelet anomalileri, tipik yüz görünümü, pulmoner stenoz ve göz bulguları ise Alagille sendromu açısından anlamlı bulgulardır (17). Bu hastalarda hem karaciğer yetmezliğine bağlı hem de oluşan komplikasyonlara bağlı (özellikle PFİK tanılı hastalarda kaşıntı, büyüme gelişme geriliği vs.) karaciğer nakli endikasyonu oluşabilmektedir. Literatürdeki çalışmalara benzer şekide bizim çalışmamızda da, karaciğer nakli BA’dan sonra en sık bu hastalara yapıldı.
Enfeksiyöz hastalıklara bağlı kolestaz literatüre bakıldığında, ülkemizde yapılan bir çalışmada %2,6 (5/190) oranında görülürken çalışmamızda %7,7 oranında görülmüştür (13). Amerika’da yapılan geniş çaplı taramada enfeksiyona bağlı kolestaz %11,5 (194/1.692) oranında görülmüş olup enfeksiyöz gruptaki hastaların %33,5’ini CMV enfeksiyonu, %3,6’sını toksoplazma enfeksiyonu, %24,7’sini sepsis ve %9,8’ini idrar yolu enfeksiyonu (İYE) oluşturmaktaydı (4). Kolestaz, bakteriyel sepsise de eşlik edebilir. Bakteriyel ürünler ve endotoksinlerin yol açtığı mediyatörler, hepatik dolaşımda değişiklik ve safra akımında azalmaya yol açarak kolestaza sebep olmaktadır. Tiker ve ark.’nın (18) yaptığı bir çalışmada; en sık kolestaz nedeni sepsis (E.coli-İYE ilişkili) olarak tespit edilmiş ve kolestaz bulgularının ortalama 10. günde geliştiği gözlenmiştir.
Neonatal kolestaz, karaciğer hastalığının bir bulgusu olsa bile karaciğeri tutan diğer sistemik hastalıklar da kolestazla bulgu verebilir. Bunun için kolestatik bir hasta geldiğinde eşlik edebilecek anomaliler açısından kardiyak, renal ve eğer nörolojik bulgu varsa santral sinir sistemi malformasyonları açısından araştırılması önerilir. Çalışmamıza benzer şekilde Sarı ve ark. (13) yaptığı çalışmada; ekokardiyografi (eko) sonuçlarında çoğunlukla atriyal septal defekt, patent foramen ovale ve periferik pulmoner stenoz bulunmuştur. Bu eko bulguları, bazen hastalığa rastlantısal olarak eşlik edebilirken bazen de etiyolojiye yönelik ipucu verebilir. Özellikle, Alagille sendromlu hastalarda periferik pulmoner stenoz görülmesi anlamlıdır. Renal bulgulara bakacak olursak; polikistik böbrek bulgularının olması Caroli hastalığı açısından, renal parankim ekosunda artış ise metabolik hastalıklar açısından önemlidir.
Neonatal kolestaz, çocuklarda yapılan karaciğer nakil nedenlerinin yarısından fazlasını oluşturmakta olup en sık neden BA (%40-%50) olarak bilinmektedir. McDiarmid ve ark. (19); 1.187 karaciğer nakil hastasının %33,5’inin bir yaşın altında olduğunu ve bu hastaların %65,6’sını BA’nın oluşturduğunu tespit etmişlerdir. Haberal ve ark.’nın (20) çocuklarda yaptığı başka bir çalışmada; 101 karaciğer nakli yapılmış ve en sık endikasyon BA (n=24, %23,7) olarak tespit edilmiştir. Bir başka karaciğer nakil merkezinde ise Zeytunlu ve ark. (21); 1.001 karaciğer nakil hastasını incelemiş (183 çocuk hasta) ve çocuk hastalarda en sık nakil endikasyonunu kolestatik hastalıklar (%69), kolestatik hastalıklarda ise en sık BA ve PFİK olarak tespit etmişlerdir. Bizim çalışmamızda da benzer şekilde, en sık nakil endikasyonu BA ve herediter kolestatik hastalıklardır.
Çalışmanın Kısıtlılıkları
Çalışmamız retrospektif ve hasta dosya kayıtlarına dayalı bir çalışmadır. Ayrıca çalışmaya başlanılan ilk yıllardaki teknik imkansızlıklar (metabolik ve genetik inceleme yöntemlerinin yetersizliği) sonucu tanı konamamış veya idiyopatik kolestazlı hastalar mevcuttur.
DISCUSSION
Evaluation of patients with cholestasis is difficult due to the variety of cholestatic syndromes and nonspecific clinical findings. With a clearer understanding of the mechanisms of the hepatobiliary system, differential diagnosis can be made better recently. Considering the etiology of 131 patients in our study; (i) intrahepatic cholestasis was detected in the majority of cases (75.6%) and most of this was TPN-related cholestasis (27.3%), (ii) the majority of cases with extrahepatic cholestasis had BA (71.9%), (iii) Kasai portoenterostomy in BA patients, it was observed that the median time was 64 days, (iv) the majority of the cases undergoing liver transplantation were BA (52.4%), (v) the mortality of cholestasis cases associated with systemic disease was high (44%).
In our study, the etiology of neonatal cholestasis was determined to be 60-70% intrahepatic cholestasis, similar to other studies in the literature. The majority of intrahepatic cholestasis cases are INH and TPN-related cholestasis, depending on the period during which the study was conducted (4). In recent years, the rate of INH diagnosis has decreased as a result of clinical and molecular developments (5). As in our study, the frequency of TPN cholestasis is increasing due to better neonatal care of premature and low birth weight babies and better treatment of complications. Most of the risk factors in the studies are NEC, sepsis and major intestinal surgeries (10). The best treatment method is to start enteral nutrition as soon as possible and stop parenteral nutrition, and omega-3 supplementation and lipid reduction are other recommended applications (11). Although organ transplantation is required for long-term TPN cholestasis due to liver failure and cirrhosis, in our cases, there was no need for liver transplantation. The cause of death of the vast majority of patients who have died is sepsis associated with catheter or blood flow.
The most common and most important cause of extrahepatic cholestasis is BA (12). Although the centers vary depending on the patient density, BA accounts for 20-35% of all cholestasis. A study conducted in our country found that 16.8% of all cholestasis cases constitute extrahepatic cholestasis, while 75% of extrahepatic cholestasis is BA (13). In another study, the BA rate was found to be 25.9% (438/1,692) in all neonatal cholestasis patients (5). Early diagnosis and treatment in BA is very important for prognosis. In cases where early diagnosis was made and Kasai portoenterostomy was performed at an early age, it was observed that the need for liver transplantation was less (12). The median time for Kasai portoenterostomy in our center was 64 days. Compared to other studies, our center found that the age of operation Kasai is similar to that of many centers. It was reported as 63 days in an organ transplant center in America and 66 days in another study based in London (14,15).
Although acholic stools are specific for BA, the bile ducts must be visualized by intraoperative cholangiography for definitive diagnosis. Until now, various objective scoring systems have been created for BA to reduce the need for unnecessary intraoperative cholangiography, and a diagnosis has been attempted non-invasively. In a study conducted in America; acholic stools, high GGT (>204 U/L) and normal weight Z score were found to be associated with BA (12). In a study conducted in our country; it has been reported that ultrasonography findings, high GGT (>197 U/L) and acholic stools are associated with BA (16). Our study also found that acholic stool and GGT height were significant for BA, similar to these studies in the literature.
The liver is one of the most important target organs of metabolic diseases. In the neonatal period, patients with galactosemia, tyrosinemia and cystic fibrosis can apply with signs of acute liver failure. In a study, 36.5% (27/74) of 74 patients with metabolic disease and cholestasis were diagnosed with galactosemia, 8.1% (6/74) of them were diagnosed with tyrosinemia. In the same study, the diagnosis of cystic fibrosis was found at a rate of 0.89% (15/1,692) in the general screening (4). In our study, the rate of metabolic disease was determined as 12.1% and galactosemia and tyrosinemia were most commonly detected. In most AR inherited diseases, detailed questioning of family history and close kinship is important, and early diagnosis and treatment are important.
Especially in recent years, an increase in the diagnosis of hereditary cholestatic syndromes has been observed with the increase in molecular studies. In addition to jaundice, signs such as itching, diarrhea, growth retardation in patients are significant in terms of PFIC; skeletal abnormalities, typical facial appearance, pulmonary stenosis, and eye signs are significant in terms of Alagille syndrome (17). In these patients, both due to liver failure and due to complications (itching, growth retardation, especially in patients diagnosed with PFIC, etc.) indication of liver transplantation may occur. Similar to the studies in the literature, in our study, liver transplantation was performed most often to these patients after BA.
When the literature is examined, cholestasis due to infectious diseases was observed with a rate of 2.6% (5/190) in a study conducted in our country, while it was seen at a rate of 7.7% in our study (13). In the large-scale screening conducted in the United States, cholestasis due to infection was observed at a rate of 11.5% (194/1692), and in the infectious group, 33.5% of the patients were CMV infection, 3.6% toxoplasma infection, 24.7% sepsis and 9.8% urinary tract infections (UTI) (4). Cholestasis may also accompany bacterial sepsis. Mediators caused by bacterial products and endotoxins cause cholestasis, leading to changes in hepatic circulation and a decrease in bile flow. In a study conducted by Tiker et al. (18), the most common cause of cholestasis is sepsis (E.coli-UTI-related) and cholestasis findings developed on the 10th day on average.
Even if neonatal cholestasis is a sign of liver disease, other systemic diseases involving the liver may also present with cholestasis. Therefore, when a cholestatic patient admits, it is recommended to investigate cardiac, renal and, if there are neurological findings, in terms of central nervous system malformations that may accompany. Similar to our study, in the study of Sarı et al. (13); echocardiography (echo) results mostly found atrial septal defect, patent foramen ovale, and peripheral pulmonary stenosis. These echo findings may sometimes accompany the disease incidentally and sometimes give clues about the etiology. In particular, peripheral pulmonary stenosis is significant in patients with Alagille syndrome. If we examine the renal findings, polycystic kidney findings are important for Caroli’s disease, and and renal parenchymal echo findings are important for metabolic diseases.
Neonatal cholestasis accounts for more than half of the causes of liver transplantation in children, and the most common cause is known as BA (40%-50%). McDiarmid et al. (19) found that 33.5% of 1,187 liver transplant patients were under 1 year of age and 65.6% of these patients were BA. In another study conducted by Haberal et al. (20) in children, 101 liver transplants were performed and the most common indication was BA (n=24, 23.7%). In another liver transplant center, Zeytunlu et al. (21) examined 1,001 liver transplant patients (183 pediatric patients) and found the most common transplant indication in pediatric patients as cholestatic diseases (69%) and the most common BA and PFIC in cholestatic diseases. Similarly in our study, the most common indications for transplantation are BA and hereditary cholestatic diseases.
Study Limitations
Our study is retrospective and based on patient file records. In addition, there are patients with idiopathic cholestasis who have not been diagnosed as a result of technical impossibilities (lack of metabolic and genetic examination methods) in the first years of the study.
CONCLUSION
The causes of cholestasis vary in the neonatal period. Early diagnosis and timely treatment are crucial for mortality, morbidity and optimal prognosis. Presence of acholic stools, maturity, early onset of jaundice and high GGT levels should primarily suggest BA. In particular, the diagnosis of BA and metabolic diseases that require early surgery is important, and liver transplantation is a treatment method that increases the survival rate in these groups of patients.
