Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is recognized in the adult population as a steroid-responsive biliary disease, often associated with autoimmune pancreatitis (1). IAC has been reported in some instances in the absence of pancreatic involvement (2). IAC is characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts (3). We report on a 3-year-old female patient with features of IgG4-associated cholangitis (markedly elevated serum IgG4 and heavy hepatic infiltration with IgG4-positive plasma cells), without evidence of pancreatic involvement. To the best of our knowledge, our patient is the first reported pediatric patient with IAC.
A 3-year-old female patient presented in February 2009 to the outpatient pediatric gastroenterology clinic with a 6-month history of dark urine and intermittent episodes of acholic stools. Three months before presentation she was noted to have an enlarged abdomen. She had not been noticeably jaundiced nor did she have scleral icterus until about 3 months before presentation. There were no reported fevers, joint pains, abdominal complaints, and no obvious episode of hepatitis. The patient denied diarrhea, vomiting, hematemesis, hematochezia, or lethargy. Family history is not suggestive of liver or autoimmune diseases.
Physical examination revealed a 14.7-kg child (weight at the 63rd percentile), body mass index 17.8 kg/m2 (at the 93rd percentile), with jaundice and scleral icterus. The liver extended 5 cm below the right costal margin and across the midline to the left midclavicular line. There was no splenomegaly, obvious ascites, or signs of chronic liver disease. The cardiovascular and respiratory examinations were normal.
The liver tests at her initial evaluation revealed an alanine aminotransferase (ALT) of 407 U/L (normal 7–45 U/L), an aspartate aminotransferase (AST) of 297 U/L (normal 8–50 U/L), a total protein of 8.6 g/dL, an albumin of 3.4 g/dL, total bilirubin of 4.2 mg/dL with a direct fraction of 2.8 mg/dL, alkaline phosphatase 1990 U/L (normal 169–372 U/L), gamma-glutamyl transpeptidase (GGT) 969 U/L (normal 6–29 U/L), international normalized ratio 1.3, and partial thromboplastin time of 42 seconds. Coagulation factor analysis revealed an isolated decrease in factor V (39% activity) with otherwise normal coagulation factors including a normal factor VII activity of 122%. Total IgG was 3122 mg/dL (normal <1235 mg/dL). Amylase was mildly elevated at 139 U/L (normal 21–110 U/L) at presentation; repeat values were normal amylase 76 U/L and lipase 57 U/L (10–73 U/L). A complete blood count (CBC) revealed normal leukocyte count, with a hemoglobin of 10.2 g/dL and elevated platelet count 469 × 109 U/L. Alpha-fetoprotein was 2.7 ng/mL (normal <6 ng/mL), ceruloplasmin 42.6 mg/dL (normal 14–41 mg/dL), ferritin 51 ng/mL, triglyceride 123 mg/dL, and alpha-1-antitrypsin level 240 mg/dL. Sweat chloride test was normal, anti-nuclear antibody (ANA) was elevated at 2.71 U (normal <1 U), and liver kidney microsomal (LKM) antibody was 1.3 U (normal <20 U). Further evaluation revealed perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) mildly positive, and smooth muscle antibodies (SMA) positive 1:320. She had markedly elevated IgG4 at 258 mg/dL (normal <49.1 mg/dL). Viral titers, including Epstein-Barr virus and cytomegalovirus studies, were negative. Stool was negative for blood and pathogens.
Magnetic resonance cholangiopancreatography (MRCP) showed enhanced hepatic parenchyma, mild splenomegaly, and diffuse thickening of intrahepatic ducts, but no features of primary sclerosing cholangitis (PSC) (Fig. 1)
Ultrasound-guided percutaneous liver biopsy revealed mild focal interface activity and focal lymphocytic cholangitis without significant necroinflammatory activity in the lobules (Fig. 2A). An immunoperoxidase stain for IgG4 revealed increased IgG4-positive plasma cell infiltrate in the portal tracts (>20/high-power view) (Fig. 2B).
The patient was started on prednisone 2 mg/kg/day with slow taper every 2 weeks, 25 mg/day (≈1.5 mg/kg/day) of azathioprine, and ursodeoxycholic acid 20 mg/kg/day. The patient responded initially to prednisone and azathioprine, but relapsed upon tapering prednisone and required a low maintenance dose of prednisone (Table 1). Follow-up MRCP 1 year after diagnosis showed decreased spleen size, normal pancreas, normal hepatic echotexture, and intrahepatic ducts; repeat liver biopsy showed resolution of inflammation, absent IgG4-positive immunostaining, and no progression of fibrosis. In an attempt to taper the patient off prednisone and avoid additional immunosuppressive agents, vancomycin 250 mg/5 mL once per day was added empirically to her regimen with improvement of her liver enzymes to AST 59 U/L, ALT 91 U/L, and GGT 163 IU/L. The patient's pancreatic enzymes increased to 234 U/L for lipase and 146 U/L for amylase 1 year after diagnosis, but normalized on subsequent testing.
This patient's disease appears consistent with IAC that has not previously been described in children. Her clinical and histologic picture differs from most patients with overlap syndrome (autoimmune hepatitis (AIH)/PSC) in that she had minimal hepatic parenchymal inflammation, plasmacytic infiltrate of the bile ductules that stained positive for IgG4 (>20/hpf), elevated serum IgG4 (>2 times the upper level of normal), minimal abnormality of the biliary tree on MRCP, and markedly elevated GGT and alkaline phosphatase out of proportion of AST and ALT.
IAC is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs are infiltrated with IgG4-positive lymphoplasmacytic cells (4). The biliary tree is the most common extrapancreatic site of the disease (5). IAC is mainly seen in men in the sixth and seventh decades of life presenting with obstructive jaundice, weight loss, and mild abdominal discomfort (1), and is associated with autoimmune pancreatitis in 92% of cases (4).
IgG4 accounts for only 3% to 6% of total IgG in subjects without disease (6). High-serum IgG4 is found in a few other conditions such as pemphigus vulgaris, bullous pemphigus, atopic dermatitis (7), and parasitic diseases (8). Among adult patients presenting with hepatobiliary disease, serum IgG4 levels 2 times above normal have been reported to be 99% specific for AIC (6,9). In a recent study by Umemura et al (10), immunostaining for IgG4 revealed positive staining in the hepatic sinuses in 16 of 17 patients with AIC, 2 of 17 patients with AIH, and 0 of 7 patients with PSC. IgG4-bearing plasma cell infiltration in the liver was significantly higher in patients with AIC compared to those with AIH (10). The target antigen recognized by IgG4 and the precise role of IgG4 in the pathogenesis of IAC are still uncertain (11).
One may certainly question whether this patient's elevated IgG4 level at initial presentation was merely reflective of her significantly increased total gammaglobulin level. To address this question, we have been evaluating IgG subtypes in all of the new and previously diagnosed patients with AIH, overlap syndromes, and PSC. Despite sometimes markedly elevated total IgG levels in many of these patients, we have identified only 1 other patient with increased IgG4 levels. This patient also had biopsy-proven autoimmune pancreatitis. In addition, a retrospective study was performed at our institution looking for IgG4-positive plasma cells on liver biopsies of more than 40 pediatric patients with AIH and PSC. IgG4-positive plasma cell infiltration on liver biopsy was found in <10% of patients; those patients had features of overlap syndrome, with abnormal cholangiography when available (unpublished data).
IAC appears to join AIH/PSC overlap syndrome, also termed autoimmune sclerosing cholangitis (ASC), as an autoantibody-positive cholangitis (12–14). Like IAC, overlap syndrome has features characteristic of classic PSC but is also associated with a serologic profile typical of AIH, including elevated gammaglobulin, ANA, and SMA. Histologically, overlap syndrome exhibits more parenchymal inflammation than IAC does. Bile duct abnormalities detected on cholangiography include irregularity, stricturing, and focal dilatation within the intrahepatic and/or the extrahepatic bile ducts (15). Our review of children with overlap syndrome (16) demonstrated that liver tests and parenchymal inflammation improved with immunosuppression, but, over time, PSC features became more predominant and the clinical course did not differ from that of patients with classic PSC. In addition, pancreatic disease has not been noted in patients with overlap syndrome.
Oral vancomycin use in patients with classic PSC resulted in improvement in liver tests, clinical symptoms, and, in some instances, histological markers of disease (17); although its effectiveness in patients with IAC is not clear yet, its use in our patient with an immune-mediated biliary disease was inspired from the benefit derived from its use in patients with another biliary disease (PSC).
No previous cases of IAC have been described in the pediatric age group. Our patient had normal pancreas on the MRCP, but mild fluctuation of her amylase and lipase. Patients presenting initially with IAC are prone to develop autoimmune pancreatitis and warrant close follow-up. We speculate that the incidence of IgG4-associated cholangitis in the pediatric population may be higher than previously recognized. Screening in children with suspected overlap syndrome may be indicated, especially for patients with pancreatic involvement and/or no evidence of inflammatory bowel disease, and may identify a subset of patients who are more responsive to immunosuppression. Further research and collaborative studies are needed to determine the incidence, clinical characteristics, and long-term outcome of children with IAC.
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