• Autoimmune liver disease
• Chronic viral hepatitis
• Bile acid synthetic defects
• Progressive familial intrahepatic cholestasis syndromes (PFIC)
• Wilson disease
• Tyrosinemia
• Persistent biliary disease: post Kasai, choledochal cyst
• Sclerosing cholangitis
• Immunodeficiency
• Glycogen storage disease
• Cystic fibrosis
• Iron storage disorders/chronic transfusion
• Mitochondrial respiratory chain defects
• Peroxisomal defects

• More common in females

• Congenital hepatic fibrosis, Niemann-Pick type C, or other storage disorders
• Lysosomal storage disease, glycogen storage disease
• Congenital or acquired venous or arterial malformations
• Wilson disease
• Cystic fibrosis
• Byler disease (PFIC-1)
• Alagille syndrome

• Symptoms of chronic illness, poor growth, intermittent jaundice, abdominal pain, bleeding, malabsorption, fever, amenorrhea, poor school achievement, and itching
• Variceal bleeding can be a presenting syndrome in patients with portal hypertension.
• A history of jaundice in infancy, family history of liver disease or autoimmune liver disease, blood transfusions, intravenous drug abuse, or multiple sexual partners can suggest an etiology of hepatitis.
• Chronicity is often defined by the persistence of hepatitis for at least 6 months.

• Spider nevi
• Cutaneous shunts
• Palmar erythema
• Cyanosis (hepatopulmonary syndrome)
• Jaundice
• Itching
• Enlarged liver or small, shrunken liver
• Splenomegaly
• Ascites
• Rickets

• Albumin, creatinine, GGT, AST, ALT, bilirubin, PT, FBC, blood group, Coombs test
• Serum ceruloplasmin, serum copper, 24-hour urine copper (penicillamine challenge), liver copper
• Cholesterol, triglycerides
• Immunoglobulins
• Complement levels (C3, C4)
• Tissue autoantibodies
• Virology: Hep A, Hep B, Hep C, Hep D
• a₁-Antitrypsin phenotype
• Urinary succinylacetone
• Urinary bile acids
• Sweat test
• AFP

• CXR
• Ultrasound scan of abdomen, focusing on liver, spleen, and kidney
• Echocardiogram
• Liver biopsy

• PTC or ERCP (or MRCP): congenital hepatic fibrosis, sclerosing cholangitis
• Colonoscopy: sclerosing cholangitis associated with inflammatory bowel disease
• Bone marrow aspirate: exclude Niemann-Pick type C or other storage disorders
• Enzyme from white cells or cultured fibroblasts (skin biopsy): to exclude lysosomal storage disease, glycogen storage disease
• Angiography: congenital or acquired venous or arterial malformations, assessment of portosystemic shunt
• Cardiac cathetherization: to assess pulmonary hypertension and cardiac status
• Microaggregate albumin scan: to assess hepatopulmonary syndrome and hepatic encephalopathy
• Muscle biopsy: respiratory chain enzymes in mitochondrial disorders
• Genotyping: where the technology is available (e.g., Wilson disease, cystic fibrosis, Byler disease (PFIC-1), Alagille syndrome)
• Active hepatitis is diagnosed
• Patients present with fatigue, nausea, malaise, anorexia, weight loss, pruritis, arthralgia, rash, and fever, but 10% have no symptoms. Findings include jaundice, hepatomegaly, cutaneous stigmata, splenomegaly, edema, ascites, cirrhosis, GI hemorrhage, dark urine, and pale stools. Active hepatitis is commonly associated with HLA B8, DR3 haplotype; younger patients have the DR3 haplotype, while older patients have the DR4 haplotype. Patients with the DR3 haplotypes have more severe disease and frequent relapses.
• Liver biopsy can be postponed until coagulopathy improves. Patients may deteriorate rapidly if not treated aggressively, and in some cases develop fulminant liver failure. Corticosteroids are started, and the dose slowly weaned over 4 to 6 weeks to maintain normal transaminases. This can take about 6 months. Remission is induced in 70% of patients within 24 months of therapy, but relapses occur in 50% in 6 months and in 70% in 36 months. Azathioprine is used when corticosteroid doses cannot be weaned. Liver function tests, immunoglobulin levels, and autoantibody titers are monitored closely. In one report, discontinuation of treatment occurred in 20% of Type 1 active hepatitis but not in Type 2. Repeat biopsies have shown histological relapse rates to be very high—87% to 100%. Forty percent of treated patients develop cirrhosis after 10 years. Malignancies developed in 5%, with the mean time of onset 9.7 years after diagnosis. In rare instances, in which the autoimmune process cannot be controlled by steroids and azathioprine, cyclosporine or tacrolimus may be tried. ERCP is done routinely in some centers on all patients with active hepatitis, and when changes of sclerosing cholangitis are detected, patients are started on ursodeoxycholic acid. The success of liver transplantation is the same as for other causes, but the disease occasionally recurs.

• Maintaining growth and development is of paramount importance to optimize the physical and mental well-being of the patient. Fat-soluble vitamins given orally are poorly absorbed and levels must be monitored. Anthropometric parameters must be recorded, including skinfold thickness. The use of medium-chain triglycerides for fat malabsorption and branch-chain amino acids in hepatic encephalopathy are useful nutritional maneuvers.
• Proactive involvement of the clinical psychologist and play therapist can help alleviate some of the problems, such as depression and fear. Chronic debilitating pruritis is an indication for liver transplantation after failure of medical therapy, which may include antihistamines, cholestyramine, naltrexone, rifampicin, and ursodeoxycholic acid.
• Monitoring portal hypertension by assessment of portal flow on ultrasound and splenic size may provide some indication of disease progression. Airplane cabin pressures are maintained at levels lower than atmospheric, and this can predispose to variceal bleeding.
• The physician must be vigilant in monitoring for spontaneous bacterial peritonitis in patients with ascites; it carries a mortality rate between 55% and 78% and a recurrence rate of 69% after 1 year.

• Chronic viral hepatitis B and C: Hepatitis B that causes chronic active hepatitis is currently treated with alpha-interferon for at least 6 months. The success rate based on adult studies is 33% and 37% for the loss of HBeAg and HBV DNA, respectively. In patients with cirrhosis, the use of interferon is risky, because it can cause liver disease decompensation, and should be given only in centers that are familiar with and have access to liver transplantation. There may be a role for Lamivudine, an oral nucleoside analogue that inhibits viral DNA replication; it has been shown to markedly reduce HBV DNA levels in 98% of patients during therapy, but there is a high recurrence rate after the drug is discontinued. Treatment of hepatitis C with interferon in children is not established. In adults, it is licensed for use, with good response in the region of 41% improvement in ALT; 70% of patients show improved histology, but with a 50% to 70% relapse rate.
• The treatment for end-stage liver failure is liver transplantation.

• Azathioprine: 1 to 2 mg/kg/d (od)
• Cholestyramine: 240 mg/kg/d in three divided doses; avoid giving with other medications because it can bind and reduce absorption. Give other medications 1 hour before or 4 hours after cholestyramine.
• Cyclosporine: 1 to 2 mg/kg/d orally (bd)
• Interferon alpha (dose from published pediatric trials):
  • Chronic HBV: 5 to 10 µ/m² given three times a week for 6 to 12 months
  • Chronic HCV: 3 µ/m² given three times a week for 6 to 12 months
• Interferon is not licensed for use in children. Very common side effects are hematologic, infectious, autoimmune, neuropsychiatric, and systemic with myelosuppression. If platelets fall below 50,000/m³ and neutrophils below 1,500/m³, then interferon dose is lowered or temporarily discontinued.
• Lamivudine (trial basis): 25 to 100 mg/d in adult for 1 year
• Naltrexone: 25 to 50 mg/d in adults (tablets, 50 mg)
• Tacrolimus: 0.15 mg/kg/d orally (bd)
• Ursodeoxycholic acid: 10 to 20 mg/kg/d (bd)

Q: Can patients with autoimmune liver disease be transplanted? Will the disease not recur?
A: Patients who end up with end-stage liver failure should be transplanted. It is not common to see the recurrence of the original autoimmune liver disease after transplant, but it occurs.

Q: What are the risks of providing very young patients with a liver transplant?
A: There is a theoretical advantage in transplanting the very young, in that less rejection occurs and immunosuppression requirements are less. Using split liver techniques, outcomes of OLT in infants has improved.

Q: Why should we be aggressive with vitamin supplementation?
A: There is significant malabsorption of vitamins A, D, E, and K. Vitamin D and E deficiencies are the most significant with rickets and neuropathy.

Q: Oral supplements of vitamins are sometimes very difficult to administer in the very young. How can I overcome this problem?
A: It is common practice in some centers to give Vitamins D and E as an intramuscular injection on a monthly basis, with levels done in between.

Q: Why do jaundiced children scratch?
A: It is the accumulation of bile salts that causes pruritis.

Q: Are the stigmata of chronic liver disease also seen in children?
A: It is very common to find spider nevi, liver palms, splenomegaly, cutaneous shunts, and clubbing.

Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis 1995;20(4):992–1000.

Johnson PJ, McFarland IG, et al. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993;18:998–1005.

Lai, CL, Chien RN, Leung NW, et al. One year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998;339(2):61–68.

Ruiz-Moreno M, Rua MJ, Castillo I, et al. Treatment of children with chronic hepatitis C with recombinant interferon a: a pilot study. Hepatology 1992;16:882–885.

Trivedi P, Mowat AP. Chronic hepatitis. In: Suchy FJ, ed. Liver disease in children, 1st ed. St. Louis: Mosby, 1994:510–523.

Vergani GM, Vergani D. Immune mechanisms in pediatric liver disease. In: Suchy FJ, ed. Liver disease in children, 1st ed. St. Louis: Mosby, 1994:173–180.