Autoimmune Liver Disease in Three Children with Sickle Cell Disease

INTRODUCTION Sickle-cell disease (SCD) is an inherited disorder of hemoglobin causing chronic hemolytic anemia with recurrent hemolytic crises. Liver involvement is common in affected patients, most of whom present with hepatomegaly, elevated serum transaminases or cholestasis as a consequence of hepatic crises, hepatic sequestration, post-transfusion viral hepatitis, hemosiderosis, pigment gallstones, congestive heart failure or unrelated diseases (1-4). Progression of liver injury to cirrhosis may occur in 7.5 to 29% of those with chronic liver disease, usually in adulthood (1,5). There have been only two reports describing an association between SCD and autoimmune hepatitis (6,7). Because of the rarity of this association, we report our experience with three children with SCD and autoimmune hepatitis to alert clinicians to this association. In one of the children, bile duct damage compatible with sclerosing cholangitis developed subsequently. CASE REPORTS Patient 1 Diagnosis of SCD (HbSS) was made in this black girl at the age of 3 years. Her clinical course was mild with hospitalization only once or twice per year for bronchopulmonary infections or pain crises affecting the abdomen and limbs. At the age of 5 1/2 years, she presented with fever, abdominal pain and cholestatic jaundice. Her serum aspartate and alanine aminotransferases were elevated but the serum γ-glutamyl transpeptidase level was normal. Because of anemia, she received blood tranfusion. Levels of aminotransferases remained twice the upper normal limit. Total serum bilirubin concentration remained at approximately 70 μmol/L with direct bilirubin levels ranging between 10 and 15 μmol/L. Serologies for hepatitis A, B and C and human immunodeficiency virus were negative. Serum ferritin concentration was 144 ng/mL (N < 250). At the age of 7 years, serological markers for autoimmune hepatitis were evaluated and antinuclear and anti-smooth muscle antibodies were positive at a titer of 1:640. She also was found to have perinuclear anti-neutrophil cytoplasmic antibodies at titer of 1:80. She was therefore referred to our center for percutaneous liver biopsy. On physical examination, mild jaundice, and firm hepatomegaly were noted without splenomegaly. Biochemical data on admission are shown on Table 1. Ultrasonography of the abdomen showed heterogeneous liver and no dilated bile ducts. Liver biopsy revealed signs of chronic active hepatitis with cirrhosis associated with dilated sinusoids lined by lymphocytes and hyperplastic Kupffer cells. Perisinusoidal fibrosis was present. Perl staining for iron content was negative. No histologic signs of cholangiopathy were noted. Treatment with prednisone (1 mg/kg body weight per day), azathioprine (1.5 mg/kg body weight per day) and ursodeoxycholic acid (600 mg/m2 per day) normalized liver function tests within 1 month. One month later, she presented again with increased serum transaminases because of poor therapeutic compliance. Biochemical control was easily achieved once therapy was resumed, but vasoocclusive crises occurred during the next 2 months. Partial blood exchange transfusions were began 4 months after initiation of immunosupressive therapy and pursued every 6 weeks for 16 months. One year after initiation of therapy, the child presented with cholestatic jaundice. Total and direct serum bilirubin concentrations were 116 and 42 μmol/L, respectively, and other concentrations were as follows: aspartate aminotransferase, 158 IU/L (N < 50); alanine aminotransferase, 189 IU/L (N < 40); and γ-glutamyl transpeptidase, 193 IU/L (N < 25). Serum perinuclear anti-neutrophil cytoplasmic antibodies titer was 1:40. Intra-hepatic bile duct dilatation was noted for the first time at ultrasonography. Percutaneous transhepatic cholangiography demonstrated bile duct abnormalities compatible with sclerosing cholangitis (Fig. 1). Six months later, laparoscopic cholecystectomy was performed because of acute calculous cholecystitis. Two months later the child underwent an endoscopic sphincterotomy performed in association with endoscopic retrograde cholangiopancreatography to remove a common bile duct stone causing acute pancreatitis and obstructive jaundice. Multiple intrahepatic stones were seen. Histological examination of liver tissue specimens obtained on this occasion showed progression of cirrhosis. Azathioprine was discontinued after the episode of acute pancreatitis.FIG. 1: Percutaneous transhepatic cholangiography showing important changes of the hepatic duct confluence and the intrahepatic bile ducts, compatible with sclerosing cholangitis. Irregularities of the common bile duct wall are also seen.During the next 2 years, she had recurrent episodes of bacterial cholangitis leading twice to septic shock despite external bile duct drainage. She is currently being evaluated for liver and bone marrow transplantation. Patient 2 A 14-year-old black girl was diagnosed with SCD (HbSS) at 1 year of age after an episode of bronchopulmonary infection. She had a severe clinical course with six to eight hospitalizations each year for vasoocclusive crises and had multiple blood transfusions. At age 3 years, hepatomegaly was noted in association with elevation of serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase activities and bilirubin concentration. At age 5 1/2 years, abdominal ultrasonography showed homogeneous liver enlargement, common bile duct dilatation and calculous cholecystitis for which she underwent a laparoscopic cholecystectomy. Histological examination of the liver showed lesions compatible with chronic active hepatitis. Serological markers for viral hepatitis B, C and human immunodeficiency virus were negative. Serum ferritin level was 109 ng/ml (N < 250) and γ-globulin level was 17 g/L. Serum autoantibodies, including antinuclear, anti-smooth muscle, liver/kidney microsomal type 1, anti liver-specific cytosolic antigen, antimitochondrial type 2 antibodies and perinuclear anti-neutrophil cytoplasmic antibodies were negative. No specific therapy was initiated. At age 8 years, a second liver biopsy was performed, because of persistently elevated liver enzyme activities, serum bilirubin and total serum γ-globulin (22.6 g/L). Histological examination revealed micronodular and/or macronodular irregular cirrhosis with mild portal and lobular lymphocytic infiltrate. Perl reaction for iron was negative. Perisinusoidal fibrosis, dramatic sinusoidal distension, Kupffer cell hyperplasia, erythrophagocytosis and scarce inflammatory infiltrates within the sinusoids were also noted. These histologic findings were attributed to intrasinusoidal sickling enhanced by possible cardiac dysfunction. The patient was started on a program of partial blood exchange transfusions every 6 weeks to achieve a fraction of hemoglobin S in the blood of 50% or less. After 2-years of regular partial exchange transfusions with no change in liver function tests, she was referred to our unit for evaluation. On admission she was jaundiced, with firm hepatomegaly and no splenomegaly. Laboratory studies are shown in Table 1. Antinuclear antibody titers were high. On ultrasound, the liver appeared normal in size with increased and slightly irregular echogenicity of the parenchyma and nodular margins. A percutaneous liver biopsy showed progression of cirrhosis and inflammatory lesions compatible with autoimmune hepatitis. The patient was treated with prednisone (1.3 mg/kg/d) and liver function tests normalized within 1 month. One vasoocclusive crisis after the start of steroid therapy prompted us to decrease the steroid dose relatively rapidly (to 0.5 mg/kg/d) in 3 months and subsequent initiation of azathioprine therapy (1.5 mg/kg/day). Relapse related to poor compliance occurred 5 months after start of therapy, but remission was easily achieved with a slight increase in steroid dosage. After 3 years, she remained in remission while on prednisone (0.14 mg/kg every other day) and azathioprine (1.2 mg/kg/d) with no evidence of cardiac functional anomalies or portal hypertension. No cholangiography has been performed but there has been no clinical indication of sclerosing cholangitis.TABLE 1: Clinical and biochemical data at diagnosis of autoimmune hepatitisPatient 3 The diagnosis of SCD (HbSS) was made in a 3-year-old black girl who presented with swelling of the extremities. She had an episode of acute hemolytic anemia and received her first blood transfusion at age 4 years. Her clinical course was uneventful for the next 2 years. Hemoglobin levels remained above 7.5 g/dL. Hyperproteinemia ranging between 86 and 105 g/L was noted. The total γ-globulin level was elevated (66 g/L). Parasitic diseases were excluded but she did not undergo further investigations. At age 6 years she presented with fever, abdominal pain and pneumonia. A second blood transfusion was required because of significant anemia. Abnormal liver function tests were noted on this occasion and she was admitted for further investigation 2 months later. Jaundice and mild hepatomegaly, but no splenomegaly were noted. Results of liver function tests are shown in Table 1. Total-γ-globulin level was 62 g/L. Serology for hepatitis A, B and C was negative. Serum antinuclear, anti-smooth muscle antibodies and perinuclear anti-neutrophil cytoplasmic antibodies titers were positive (Table 1). Abdominal ultrasonography showed a heterogeneous liver of micronodular aspect. Because of prolonged prothrombin time, no liver biopsy was performed. Because evaluation suggested autoimmune hepatitis type 1 with cirrhosis, the child was started on prednisone and azathioprine therapy (both at 1 mg/kg/d), and ursodeoxycholic acid (600 mg/m2 per day). Remission with normal prothrombin time occurred within 3 months of therapy, allowing a progressive decrease in steroid dosage. She did not experience any vasoocclusive crises but presented 6 months later with osteomyelitis that was successfully treated with antibiotics. At 12-month follow-up, her autoimmune hepatitis relapsed, probably because of poor therapeutic compliance. Steroids were increased to 1 mg/kg/day. At last follow-up 2 months later, liver function tests were normal and there was no evidence of portal hypertension or signs of sclerosing cholangitis. DISCUSSION These cases underline the difficulty in making a diagnosis of autoimmune hepatitis in the context of diseases with potential to affect the liver such as SCD. Autoimmune hepatitis, a chronic inflammatory condition, occurs predominantly in females and is characterized by increased levels of serum bilirubin and/or aminotransferase activities, and elevated levels of gamma-globulin G together with circulating autoantibodies. According to the type of autoantibodies, autoimmune hepatitis is classified into two types: type 1 with positive antinuclear antibodies or smooth muscle antibodies and type 2 with positive liver/kidney microsome type 1 antibodies or anticytosol type 1 antibodies. Autoimmune hepatitis type 1 occurs mainly in older children (median age, 10 1/2 years) and is often associated with autoimmune cholangiopathy, inflammatory bowel disease or sclerosing cholangitis (8,9). A scoring system recently has been proposed by the international autoimmune hepatitis group to facilitate the diagnosis of autoimmune hepatitis. The score is calculated on the presence of features including: female sex; alkaline phosphatase/aspartate aminotransferase or alanine aminotransferase ratio less than 1.5; serum gammaglobulins or immunoglobulin G levels twice the upper normal limit; positive antinuclear or smooth muscle or liver/kidney microsome type 1 antibodies titers (>1:80); negative hepatitis viral markers; absence of hepatotoxic drug history or alcohol intake; characteristic liver histology; presence of other associated immune diseases; seropositivity for other defined autoantibodies; human leukocyte antigen DR3 or DR4 for North European caucasoid and Japanese populations. According to these criteria, scores of 10 to 15 and >15 before treatment indicate “probable” “definite” autoimmune hepatitis, respectively. When response to therapy is included, the corresponding values are 12 to 17 and >17 (10). As shown in Table 1, the scores of the children reported here excluding the parameter of alcohol intake were greater than 15 and thus satisfied the pretreatment criteria for “definite” autoimmune hepatitis type 1. All responded to standard immunosuppressive therapy. In case 2, although serum autoantibodies were initially not found at the time of the first liver biopsy, she already satisfied these international criteria for the diagnosis of “probable” autoimmune hepatitis, mainly because of the association of hypergammaglobulinemia with characteristic liver histology and should had started immunosupression therapy. The finding of increased γ-globulin levels associated with increased transaminases activity should raised the possibility of autoimmune hepatitis, although patients with SCD present frequently with hypergammaglobulinemia possibly related to infections (11). Conversely, some patients with autoimmune hepatitis may lack hypergammaglobulinemia (8). The occurrence of autoimmune hepatitis type 1 in SCD patients has been previously reported, in one 28-year-old woman and in two 11-year-old children (one boy, one girl) (6,7). Autoimmune sclerosing cholangitis has also been previously reported in one 13-year-old girl with SCD associated with ulcerative colitis (6). In patient 1, the finding of bile duct damage associated with significant titers of perinuclear anti-neutrophil cytoplasmic antibodies may suggest an autoimmune process because these antibodies are typically associated with autoimmune sclerosing cholangitis rather than autoimmune hepatitis (12). However, ischemic damage of the intrahepatic bile ducts resulting from recurrent vasoocclusive crises or acute anemia, as suggested by Hillaire et al. (13), cannot be excluded. Extrahepatic and intrahepatic lithiasis were not seen before or at the time of diagnosis of sclerosing cholangitis and possibly developed subsequently. Whether a pathophysiological link exists between SCD and autoimmune hepatitis remains to be determined. Among 163 children followed for autoimmune hepatitis at our center, 19 children (11.5%) are of West African or French West Indies origin, of whom three reported here have SCD (HbSS). Therefore, the prevalence of SCD (HbSS) in our series of black children with autoimmune hepatitis (3 of 19, 15.8%) appears much higher than that reported in the overall French population from African origin (1 of 1250) (14). All patients with SCD and autoimmune hepatitis reported had type 1 autoimmune hepatitis. Other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune hemolytic anemia have also been reported in patients with sickle cell anemia (15-19). In a series dealing mostly with adults, it was suggested that management of autoimmune hepatitis in patients not of European Caucasoid or Japanese extraction may require more aggressive treatment (20). However, among the SCD children reported here, remission of autoimmune hepatitis was easily achieved with relatively low dose steroids. Steroids have been reported to possibly trigger vasooclusive crises, as occurred in cases 1 and 2 (7,16). Indication for partial blood exchange transfusions may be discussed at initiation of therapy and maintained until steroid dosage is decreased to approximately ≤0.5 mg/kg body weight per day, as performed in case 1 (21). Hydroxyurea therapy, which enhances the synthesis of hemoglobin F, could be beneficial in preventing vasoocclusive crises (22). Avoidance of steroids and the use of cyclosporin A, at least initially to induce remission of autoimmune hepatitis, could be another therapeutic option in SCD patients (23). In conclusion, SCD patients, especially females who present with increased liver enzyme activities, cholestatic jaundice and hypergammaglobulinemia, should be evaluated for autoimmune hepatitis or autoimmune sclerosing cholangitis as part of a full diagnostic workup. The cases reported here emphasize the importance of examining liver histology to establish the diagnosis of autoimmune hepatitis. Magnetic resonance cholangiography, less invasive than percutaneous cholangiography or endoscopic retrograde cholangiopancreatography, should be performed at presentation or follow-up to look for possible bile duct damage. Early diagnosis and treatment might prevent rapid progression to cirrhosis and liver failure in these patients, whose underlying disease of unpredictable prognosis may severely affect their hepatobiliary system. The best therapeutic management, steroids versus cyclosporine, and the indication for partial blood exchange transfusions or hydroxyurea therapy remains to be determined to avoid the occurrence of vasoocclusive crises and possible ischemic damage of bile ducts.