Neonatal Sclerosing Cholangitis Associated with Autoimmune Phenomena

Abstract

Sclerosing cholangitis (SC) is an idiopathic disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts. Bile duct obliteration eventually causes biliary cirrhosis. Sclerosing cholangitis has a pathognomonic cholangiographic appearance. Alternating areas of strictures and dilatations in the intrahepatic and often the extrahepatic bile ducts give the classic “beading” pattern. The disease can occur in association with other conditions, such as inflammatory bowel disease (IBD), congenital and acquired immune deficiencies, and Langerhans' cell histiocytosis (1,2). As modern imaging techniques of the bile ducts (such as percutaneous transhepatic cholangiography [PTC] and endoscopic retrograde cholangiopancreatography [ERCP]) came into routine use, the diagnosis of SC is now made more frequently in the pediatric population (1–3). To the best of our knowledge, only 18 cases have been described in neonates (1,4–6). Debray et al. described 15 patients with neonatal SC. All of them had cholestatic jaundice during the first month, which progressed to cirrhosis (1,5). Baker et al. (4) reported two similar cases, both in children of consanguineous parents. Another case, the first in an Arab population, has recently been described (6). We present a case of neonatal SC, to our knowledge the first to be described in association with autoimmune phenomena. CASE REPORT An 8-month-old male infant was referred to our hospital because of persistent neonatal jaundice. His parents are Moslem Arabs who are first cousins and had two healthy daughters before this delivery. The patient's aunt (father's sister) died in childhood of an unknown liver disease (no details are available). The patient was delivered at term, weighing 3 kg. When he was 3 days of age, jaundice developed with acholic stools and hepatosplenomegaly. Laboratory results showed conjugated hyperbilirubinemia and mildly elevated liver enzymes (alanine aminotransferase [ALT] 190 IU/l, aspartate aminotransferase [AST] 363 IU/l, and alkaline phosphatase 360 IU/l). Serology for hepatitis A virus, hepatitis B virus, and TORCH (toxoplasmosis, other congenital viruses, rubella, cytomegalovirus, and herpes simplex virus) was negative. The child was observed locally and continued to have jaundice. No further admissions were recorded, apart from one resulting from a urinary tract infection at 2 months of age. When referred at the age of 8 months, the child weighed 6.5 kg (<3rd percentile), length was 64 cm (<3rd percentile), triceps skinfold 5 mm (<5th percentile), and midarm circumference 135 mm (<5th percentile). On physical examination the child was malnourished, and there was deep jaundice and finger clubbing with no other stigmata of chronic liver disease including signs of bleeding. The liver was firm with a 9-cm span and a firm edge palpable 6 cm below the costal margin. The spleen was palpable 5 cm below the costal margin. Laboratory Results Hemoglobin was 9.7 g/dl with a mean corpuscular volume of 74 fl. Total bilirubin was 19.4 mg/dl (direct, 18 mg/dl). The AST was 331 IU/l (normal <40 IU/l), ALT 223 IU/L (normal <50 IU/l), alkaline phosphatase 1183 IU/l (normal <420 IU/l), and γ-glutamyl transferase (GGT) 673 IU/l (normal <40). Total protein was 8.5 g/dl with serum albumin of 3.5 g/dl. Prothrombin time was normal. The erythrocyte sedimentation rate (ESR) was 90 mm/hr. Stool examination revealed no erythrocytes or leukocytes. Abdominal ultrasound showed an enlarged, homogenous liver, small gallbladder, enlarged spleen, patent nondilated common bile duct, and normal blood flow in the portal vein. Hepatoiminodiacetic acid (HIDA) scan showed no evidence of extrahepatic bile duct obstruction, with dye appearing normally in the duodenum after 2 hours. Sweat test results, serum amino acid concentrations, and urinary reducing substances were normal; Pi phenotype was MM. Hepatitis A, B, and C virus screening results were negative; IgG levels were elevated (1994 mg/dl; normal < 900 mg/dl); IgM and IgA levels were normal. The anti-smooth muscle antibodies (ASMA) titer was 1:320 with negative antinuclear antibodies (ANA), anti neutrophil cytoplasm antibodies (ANCA), and liver-kidney microsomal (LKM) antibodies. Complement studies showed normal results. Liver biopsy was performed with the specimen showing nodular transformation with bile duct proliferation and neutrophil infiltration; nodules were surrounded by fibrous septa. The hepatocytes showed marked swelling due to cholestasis, and multinucleated cells were seen. These findings were compatible with secondary biliary cirrhosis and not characteristic of chronic active hepatitis or autoimmune cholangitis. Percutaneous transcholecystic transhepatic cholangiography (PTTC) was performed with gallbladder filling and then passage of the dye to the biliary tree. Characteristic beading of the intra-and extrahepatic bile ducts was observed with the common bile duct and the pancreatic duct also affected (Fig. 1). HLA class I typing was performed by serology, and HLA class II allele-specific molecular typing was performed using sequence-specific oligo probes (SSOPs). The patient's phenotype was A1, A2, CW17, CW7, B44, B41, and class II alleles DRB1*0301 (formerly DR3), DRB1*0403, DRB3*0202, DRB4*01, DQB1*02, and DQB1*0301. Maternal autoantibody screening results and immunoglobulin levels were normal.FIG. 1.: Percutaneous transcholecystic transhepatic cholangiography (PTTC) through the gallbladder shows (A) beading of the intrahepatic, common hepatic, and common bile ducts and (B) beading of the pancreatic duct.Figure 1: ContinuedManagement Treatment was started with ursodeoxycholic acid (20 mg/kg) and high doses of fat-soluble vitamins. Two months later the patient had gained weight to the third percentile for his age (8.3 kg), direct bilirubin decreased to 6.1 mg/dl, ESR decreased to 46 mm/hr, and hepatic enzyme levels decreased as well (AST 230 IU/L, ALT 147 IU/l, alkaline phosphatase 504 IU/l, and GGT 485 IU/l). At routine follow-up 1 year later, the child was gaining weight and the jaundice had cleared. Hepatosplenomegaly remained. Laboratory results included AST 140 IU/l, ALT 102 IU/l, alkaline phosphatase 410 IU/l, GGT 104 IU/l, IgG 1440 mg/dl, and ASMA 1:160. DISCUSSION The occurrence of SC in the neonatal period is very rare and has been described in several patients only, none of whom had associated autoimmune phenomena (1,4–6). It appears that neonatal SC is a separate subgroup of childhood SC. These patients are unique in the clinical manifestations, natural history, and, perhaps, pathogenesis of the disease. Previous studies describing patients with neonatal SC found that the parents were related in approximately a third of the cases (1,5). In the case presented, the parents were first cousins with a case of early, fatal liver disease in the close family, possibly due to SC. The cause of SC is as yet unknown but undoubtedly, genetic and immunologic factors are important. The increased incidence of HLA B8 and DR3 found in nonneonatal SC is established (7). A previous study from Israel in adult patients did not find any correlation between specific HLA antigens and the disease apart from the DRB3*0202 haplotype in 75% of the patients (8). The HLA typing in this patient was positive for DRB1*0301 (DR3) but did not show B8 antigen. However, he was positive for DRB3*0202 antigen which is common in Israeli patients with PSC. HLA DR molecules present self or foreign antigens to CD4 T-helper lymphocytes, thereby initiating an immune response resulting in tissue damage. As yet, the nature of this antigen is unknown, and the exact mechanism involving specific HLA molecules in the pathogenesis of the disease remains to be elucidated. In all cases of neonatal SC, the most important diagnosis to rule out is biliary atresia. There is some evidence of an association between HLA and biliary atresia that may provide support for genetically determined susceptibility (9,10). Further studies that characterize bile duct epithelial cell–host immune interactions and genetic participation will enhance our understanding of a possible common pathogenic basis for both biliary atresia and neonatal SC. Previous studies have indicated that some of the children with SC manifest a clinical picture similar to that of autoimmune hepatitis (1–3,11). These patients have elevated IgG levels, high aminotransferase levels, and normal complement levels. In some of these patients, ANAs and high titers of ASMA were found. These autoimmune phenomena have never been described in neonatal SC. The patient described here is the first patient with neonatal-onset SC with autoimmune features. He had elevated IgG levels with inversion of the normal albumin-globulin ratio, and a high titer of ASMA, along with normal complement levels, but no histologic signs of autoimmune cholangitis. The importance of these findings is as yet unclear, but they may be markers of undefined immunologic abnormalities in neonatal SC. Maternal origin for the autoimmunity was ruled out. The gold standard for diagnosing SC is radiologic imaging of the bile ducts (12). The histologic picture in a liver specimen is not specific and can include features of cirrhosis, bile duct proliferation, and an inflammatory infiltrate (12). All children with SC described so far had involvement of the intrahepatic bile ducts, and most of them had involvement of the extrahepatic bile ducts as well. Our patient showed involvement of the intrahepatic bile ducts as well as the common bile duct and the pancreatic duct. This latter finding has been reported in neonatal SC (5). None of the neonatal patients with SC described in the past had conditions known to be related to SC, such as IBD or Langerhans' cell histiocytosis. Our patient had no clinical sign of IBD, and several stool samples showed no evidence of colonic inflammation; therefore, further investigation of the colon was not performed. It is known that SC may precede the presentation of IBD (2), so it is possible that longer follow-up will reveal evidence of IBD in the neonatal SC. We found no clinical or laboratory evidence of other diseases associated with SC. Liver transplantation is the only treatment available in pediatric patients with SC that progress to cirrhosis. Determining its optimal timing is complicated, because disease progression is unpredictable. Most investigators agree that prolonged jaundice is a parameter directly related to poor prognosis (1,2,12). This is not the case in neonatal SC. In all the patients described so far, the jaundice cleared during the first year of life, although in all, the disease progressed to cirrhosis. Recurrence of jaundice after the neonatal period may indicate poor prognosis, but there are no guidelines regarding the timing for transplantation. This child responded well to ursodeoxycholic acid, which we speculate may prevent further deterioration in neonatal SC if initiated early enough. In summary, imaging of the bile ducts should be considered in infants with cholestatic liver disease in the absence of other causes. Autoimmune features, such as elevated ASMA titer or elevated levels of immune globulins, could serve as clues to the diagnosis of a new subgroup of SC in neonates and young children with cholestatic jaundice.