Introduction
Hepatitis is a common gastrointestinal manifestation in the pediatric age group and the commonest etiology being viral, but it is important to distinguish autoimmune hepatitis (AIH) from other forms of chronic hepatitis because a high percentage of cases respond to immunosuppressive therapy. AIH is a chronic hepatic inflammatory process manifested by elevated serum aminotransaminase concentrations, the presence of serum auto-antibodies, and/or hypergammaglobinemia. AIH may be present at any age from infancy to adolescence with an incidence of 0.4 and a prevalence of 1 per 100,000 children, respectively.[1] It is more common in women than in men (female-to-male ratio of 3.6 to 1).[2] AIH has an extremely variable course, ranging from acute asymptomatic hepatitis to severe fulminant hepatic failure.[3] Some cases can present with extra-hepatic autoimmune diseases like celiac disease, thyroiditis, or systemic autoimmune disease, such as systemic lupus erythematosus (SLE), autoimmune polyendocrinopathy syndrome (APECED), immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, and lymphoprolipherative syndromes.[4] AIH is difficult to diagnose because of increasing and decreasing immunological activity. In the absence of a single diagnostic test for AIH, the International Autoimmune Hepatitis Group has devised a diagnostic system for comparative and research purposes that includes several positive and negative scores, the sum of which gives a value indicative of probable or definite AIH.[5,6] This case series highlights common clinical, biochemical, and immunological variation which will help physicians in the early diagnosis of AIH and prevent progression of disease and reduce morbidity and mortality.
Case Presentations
Case 1
A 4-year-old female child presented with complaints of yellowish skin and sclera discoloration, high-colored urine, and poor appetite since 2 months and a history of jaundice 6 months back, lasted for 15 days and subsided on its own. On admission, the child was conscious, oriented vitals were stable. Icterus was present. Abdominal examination revealed a liver of 4 cm with a span of 11 cm, firm in consistency, with round borders and a smooth surface. Spleen was firm 2 cm with no evidence of free fluid. Liver function tests showed derangement as summarized in Table 1. Abdominal ultrasonography revealed hepatomegaly with liver parenchymal disease and splenomeglay. Color doppler ultrasound imaging showed normal venous flow. There was no collateral circulation or hepatic vein thrombosis. A liver biopsy showed portal widening with inflammation around portal and interlobular area. Hepatocyte shows ballooning with intra hepatic cholestasis. Features suggestive of Hepatitis with Cirrhosis, grade 8 Ishak-modified Histology activity index. Hence the child was started on Immunosuppression with oral Prednisolone 2mg/kg/day. On follow-up after one month, the bilirubin level decreased to less than twice the upper limit of normal. Prednisolone was tapered by 5 mg over 2–4 months until a maintenance dose of 0.1–0.3 mg/kg/24 hr was achieved. But the child was lost to follow-up for one year and stopped medications on her own. The child was presented with a relapse, total bilirubin of 7.8 mg/dl, direct component of 5.2 mg/dl, SGOT 1106, SGPT 846. Liver biopsy was done to see disease activity. It revealed hepatitis with activity. Started on oral prednisolone with 2 mg/kg/day then was tapered by 5 mg over 2–4 months until a maintenance dose of 0.1–0.3 mg/kg/24 hr is achieved. The child has been asymptomatic for the last six months and has no signs of steroid toxicity.
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Table 1: Comparison of cases
Case 2
A 6-year-old girl presented with complaints of fever, mild to moderate grade, with jaundice since 30 days and abdominal distension since 10 days. On examination, the child had a glasgow coma scale (GCS) of 9/15 (E2V2M5), hemodynamically stable. Pallor, icterus, and bilateral pedal edema without signs of liver cell failure were there. An abdominal examination revealed generalized distension with visible veins. The liver was 3 cm with a span of 11 cm, firm in consistency with round borders and a smooth surface. The spleen was firm 2 cm, fluid thrill was present. Blood investigation revealed deranged liver function test as summarized in Table 1. The child required intubation for three days due to poor sensorium and received broad spectrum antibiotics with Gram-negative coverage, high bowel washes, head elevation, and diuretics. Intensive monitoring for hypoglycemia, electrolyte imbalances, and raised intracranial pressure was done. Coagulopathy was treated with fresh frozen plasma. Ultrasonography (USG) abdomen showed a coarse heterogenous liver with splenomegaly and gross ascites suggestive chronic liver disease. Histopathology of liver biopsy was suggestive of Hepatitis with activity consistent with Autoimmune Hepatitis stage 1, grade 8 (Ishak-modified Histology Activity Index grading). Hence the child was started on oral Predisolone 2mg/kg/day. The bilirubin level started decreasing; the child was discharged after 18 days. On follow-up, after one month, bilirubin levels decreased to less than twice the upper limit of normal. Tapered prednisolone by 5 mg over 2–4 months until maintenance dose of 0.1–0.3 mg/kg/24 hr is achieved. The child is under regular follow-up and has no relapse or steroid toxicity.
Case 3
A 10-year-old girl presented with an acute complaint of jaundice for 14 days. On examination, the child was conscious and oriented vitals were stable. Icterus was present. Abdominal examination revealed a liver of 5 cm with a span of 11 cm firm in consistency, round borders. All investigations summarized in Table 1. The histopathology report for a liver biopsy featured symptoms of chronic hepatitis with cholestasis with fibrosis, modified fibrosis grade 3/6 and modified HAI. After ruling out other causes, on the basis of liver biopsy and high IgG levels, we started on immunosuppression with oral steroids. Prednisolone started at 2 mg/kg/day and was tapered by 5 mg over 2–4 months until a maintenance dose of 0.1–0.3 mg/kg/24 hr was achieved. The child was lost to follow-up due to the coronavirus disease 2019 pandemic and presented with replase, now again started on oral prednisolone.
Case 4
An 8-year-old boy presented with complaints of jaundice for 21 days, and fever and abdominal distension for seven days. On examination, the child was conscious, oriented vitals were stable. Icterus was present without signs of liver cell failure. Abdominal examination revealed mild distension; a liver was 3 cm with a span of 9 cm. firm in consistency, round borders. The spleen was not palpable. Blood investigation revealed deranged liver function tests as summarized in Table 1. Liver biopsy was planned for confirmation of diagnosis and to see disease activity, but the biopsy couldn’t be performed due to coagulopathy, which was not correctable by fresh frozen plasma. The child started on oral prednisolone as anti-LKM 1 was positive with high IgG levels. The child had an adequate response to treatment with no relapse.
Discussion
AIH is characterized by inflammatory liver histology, circulating non-organ-specific auto-antibodies, and increased levels of immunoglobulin (Ig) G in the absence of a known etiology. There is a female predominance. AIH may be associated with other autoimmune conditions like SLE or overlap syndrome with primary biliary cirrhosis and primary sclerosing cholangitis (PBC and PSC).[7–9] None of our cases had other autoimmune conditions. AIH is grouped into types I and II. Auto-antibodies associated with type I AIH are antinuclear antibody (ANA) and smooth muscle antibody (SMA). In type II AIH, auto-antibodies are anti-liver/kidney microsome 1 (LKM1) and anti-liver cytosol 1 (LC1). Auto-antibodies are a hallmark of AIH, but most are not disease specific.[10] All cases showed high serum IgG levels but only two cases had anti-LKM antibody positivity and one had ANA positivity. A lack of positive autoantibody is seen in certain cases of AIH, and they are known as seronegative AIH. Liver biopsy plays an important role in establishing a diagnosis in case of seronegative AIH and also helps in describing the severity of the disease. In our cases, remission was defined as an improvement in aminotransferase and bilirubin levels, and relapse was defined as an increase in serum aminotransferase levels after remission had been achieved. All cases have responded to oral steroids (prednisolone 2 mg/kg/day), 2 of them had relapsed due to stoppage of steroid abruptly. None of them required other immunosuppressive drugs or developed steroid toxicity. For one patient, a liver biopsy was repeated, which helped to know the activity of the disease. All of them are achieving normal growth and development on treatment. When AIH doesn’t respond to drug treatments or in cases of advanced liver disease, a liver transplant may be an option.
Conclusion
Physicians play a significant role in the primary diagnosis of the disease. It is therefore necessary to completely inform the physician about the initial presentation and laboratory findings of AIH in order to prevent progression of the disease. The diagnosis of AIH is based on a combination of clinical, biochemical, immunological, and histological features and the exclusion of other known causes of liver disease (e.g., hepatitis B, hepatitis C, Wilson’s disease, non-alcoholic steatohepatitis, and drug-induced liver disease). A liver biopsy is needed to confirm the diagnosis and to evaluate the severity of liver damage. AIH can lead to scarring of the liver (cirrhosis) and eventually to liver failure; however, the progression of AIH can be controlled with drugs that suppress the immune system. Appropriate management can prolong survival, improve quality of life, and avoid liver transplantation.[11] Steroids and azathioprine have been proposed as first-line treatment of patients but recent reviews have underlined that this combination seems to be far from ideal.[12] Drugs effective in refractory cases include cyclosporine and mycophenolate mofetil.[13] There remains controversy over the role for protocol liver biopsies to detect recurrent disease and the best immunosuppressive strategies to prevent and treat recurrence.[14]
Learning points
- (1) AIH has an extremely variable course ranging from acute asymptomatic hepatitis to severe fulminant hepatic failure, but it is important to distinguish AIH from other forms of hepatitis because a high percentage of cases respond to immunosuppressive therapy.
- (2) Hypergammaglobulinemia is the most consistent finding for AIH, as our all cases showed high serum Ig G levels.
- (3) Auto-antibodies may not positive is every case of AIH, typical liver histopathology findings and correlation with liver function tests will help to diagnose.
- (4) Relapse of the disease is common. The optimal duration of immunosuppressive treatment for AIH is not known, but long-term treatment is required.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient’s parent consent.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors thank the Dean, Topiwala National Medical college and BYL Nair Charitable Hospital, Mumbai for giving opportunity to publish this manuscript.
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