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Chronic Hepatitis, Pediatric


Basics


Description


  • Chronic hepatitis is a continuous inflammation of the liver that can lead to cirrhosis.
  • Features include inflammation not caused by acute self-limiting infection or past drug exposure, with raised transaminases and histologic evidence of hepatitis.

Epidemiology


Depends on the cause of the underlying disease  
  • Nonalcoholic steatohepatitis (NASH) is a leading cause of elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT).
  • Hepatitis B: common in immigrant children from Asia and Eastern Europe
  • Hepatitis C: common in those who had blood transfusions and blood products before screening became available, history of IV drug abuse
  • Wilson disease presents mainly in older children (>2 years of age) and adults.
  • Autoimmune liver disease is more common in females and patients >6 months of age.
  • Autoimmune hepatitis (AIH) may be associated with other autoimmune conditions such as diabetes, ulcerative colitis, autoimmune thyroiditis, and celiac disease.
  • Cystic fibrosis and α1 antitrypsin deficiency

Pathophysiology


Pathology has been traditionally classified by evidence of chronic persistent hepatitis, chronic aggressive hepatitis, and chronic lobular hepatitis. All are associated with damaged hepatocytes as well as inflammatory cellular infiltration accompanied by liver regeneration.  
  • Chronic persistent hepatitis
    • Minimal portal tract fibrosis
    • Slightly widened portal tracts
    • Limiting plate is intact and inflammation does not extend beyond this.
    • No bridging fibrosis between portal tracts
  • Chronic aggressive hepatitis
    • Perilobular hepatitis, with inflammatory cells extending from portal tracts into parenchyma with fibrosis
    • Piecemeal necrosis: necrotic hepatocytes surrounded by lymphocytes and fibroblasts
    • In advanced disease, fibrosis bridges the portal tracts (bridging fibrosis).
    • Cirrhosis occurs when there is loss of architecture owing to fibrosis.
  • Chronic lobular hepatitis
    • Liver architecture is preserved with scattered changes of acute hepatitis with hepatocyte necrosis in the lobules (perivenular regions).
    • Associated with hepatitis B and non-A, non-B hepatitis

Etiology


  • Autoimmune liver disease
  • Viral hepatitis
  • Obesity (NASH)
  • Progressive familial intrahepatic cholestasis (PFIC) syndromes
  • Congenital hepatic fibrosis
  • Cystic fibrosis
  • Metabolic disease
    • Mitochondrial disease
    • Lysosomal storage disorders
    • Peroxisomal disease
    • Lipid storage disease
    • Glycogen storage disease
    • Wilson disease and others
  • Drug hepatotoxicity
    • Methotrexate
    • Isoniazid
    • Thioguanine
    • 6-Mercaptopurine
    • Valproate
  • Liver disease associated with other chronic diseases
    • Cardiac disease
    • Autosomal recessive polycystic kidney disease
    • Diabetes mellitus
    • Langerhans cell histiocytosis
    • Immunodeficiency
    • Total parenteral nutrition cholestasis

Diagnosis


History


  • Preceding clinical signs and symptoms for at least 6 months and complete medical history
    • History of blood transfusions
    • Surgery
    • Medications
    • Foreign travel
    • Social circumstances that predispose to liver diseases
  • Symptoms of chronic illness can be nonspecific:
    • Poor growth
    • Intermittent jaundice
    • Abdominal pain
    • Bleeding
    • Malabsorption
    • Fever
    • Amenorrhea
    • Poor school achievement
    • Itching
  • Variceal bleeding may be a presenting symptom in patients with portal hypertension.
  • A history of jaundice in infancy, family history of liver disease or autoimmune liver disease, blood transfusions, IV drug use, or multiple sexual partners can suggest an etiology of hepatitis.

Physical Exam


Stigmata of chronic liver disease are as follows:  
  • Spider nevi, palmar erythema
  • Dilated veins on abdomen/cutaneous shunts
  • Palmar erythema
  • Cyanosis (hepatopulmonary syndrome)
  • Clubbing
  • Jaundice
  • Pruritus/scratch marks (due to accumulation of bile salts in the epidermis)
  • Hypercholesterolemic xanthomas
  • Enlarged liver or small, shrunken liver
  • Splenomegaly
  • Ascites
  • Rickets
  • Mental changes
  • Fetor associated with high ammonia
  • Poor weight gain/FTT, weight loss

Diagnostic Tests & Interpretation


Lab
  • General liver testing: albumin, creatinine, γ-glutamyl transferase, AST, ALT, bilirubin, PT/INR, CBC, ammonia level
  • Other testing as indicated by the specific clinical presentation
    • Viral serologies: hepatitis B, hepatitis C, hepatitis D
    • Autoantibodies: type 1: smooth muscle (also called antiactin), antinuclear, antisoluble liver antigen; type 2: liver kidney microsomal, primary sclerosing cholangitis: pericytoplasmic antineutrophil (p-ANCA)
    • Immunoglobulins: IgG elevated in autoimmune liver disease
    • Fasting glucose, insulin levels, CRP, lipid profile (suspected NASH)
    • α1 Antitrypsin level and phenotype
    • Serum ceruloplasmin, serum copper, 24-hour urine copper (+/- penicillamine challenge), quantitative liver copper (Wilson disease)
    • Cholesterol, triglycerides elevated in cholestatic syndromes, glycogen storage, Alagille syndrome, certain lysosomal disease, steatohepatitis
    • Metabolic workup as indicated
    • CPK level to rule out muscle source of elevated ALT/AST
    • Urinary succinylacetone: tyrosinemia
    • Urinary bile acids: bile acid synthetic defects
    • Sweat test and cystic fibrosis genotyping
    • Alpha fetoprotein (AFP) level
    • Fibrosis markers (FibroSURE; FibroTest; ActiTest) are not validated for children but may be useful in older patients.

Diagnostic Procedures/Other
  • Ultrasound with Doppler flow studies: should focus on liver and spleen and may detect steatosis
  • Other testing as indicated by specific clinical presentation
    • MRI can demonstrate percentage steatosis.
    • FibroScan can measure liver stiffness/fibrosis.
    • Liver biopsy
    • Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic retrograde cholangiopancreatography (MRCP) may be useful if primary sclerosing cholangitis is suspected.
    • Colonoscopy: sclerosing cholangitis, inflammatory bowel disease
    • Bone marrow aspirate to exclude Niemann-Pick type C or other storage disorders
    • Enzyme analysis to evaluate for lysosomal storage disease, glycogen storage disease
    • Angiography: congenital or acquired venous or arterial malformations, assessment of portosystemic shunt
    • Cardiac catheterization to assess pulmonary hypertension and cardiac status
    • Macroaggregated albumin scan to assess hepatopulmonary syndrome and hepatic encephalopathy
    • Muscle biopsy to assay respiratory chain enzymes in mitochondrial disorders
    • Genotyping: Wilson disease, cystic fibrosis, and others

Differential Diagnosis


Nonhepatic etiologies of lab or physical exam abnormalities  
  • Hepatomegaly: elevated right-sided cardiac pressures, such as patients with Fontan operations, right-sided heart failure; respiratory diseases with lung hyperexpansion
  • Splenomegaly
    • Blood malignancies
    • Storage diseases
    • Hematologic disease with hemolysis
    • Infection
    • Vascular
  • Jaundice: often confused with hypercarotenemia
  • Elevated transaminases: consider nonhepatic sources such as skeletal muscles in myopathies; with jaundice, consider hypopituitarism in infancy
  • Alkaline phosphatase: may be elevated in growing children and in rickets; may not indicate biliary obstruction
  • γ-Glutamyl transferase
    • Produced in renal tubules, pancreatic and biliary ducts
    • Often elevated in patients on antiepileptic drugs and in alcoholics
  • Abnormal coagulation: anticoagulant medications, bacterial overgrowth with malabsorption, inherited disorders of coagulation, sepsis

Treatment


General Measures


The management of patients is dictated by the underlying diagnosis.  
  • General management
    • Maintaining growth and development is paramount.
    • Fat-soluble vitamins (A, D, E, K) given orally are poorly absorbed in cholestasis, and levels must be monitored.
    • Anthropometric parameters must be recorded, including skinfold thickness.
    • Body mass index
    • Preference for medium-chain triglyceride (MCT)-rich formulas can reduce fat malabsorption.
    • Branched-chain amino acids may be useful in patients with hepatic encephalopathy.
    • Ursodeoxycholic acid: choleretic
    • Encourage bolus feedings; minimizing continuous feeding and total parenteral nutrition may reduce gallbladder sludge.
    • Proactive involvement of clinical psychologist and play therapist can help alleviate problems such as depression and fear.
    • Aggressive weight management in patients with obesity/hypermetabolic syndrome with steatohepatitis; curbing passive activities such as television, computer games
    • Chronic debilitating pruritus: indication for liver transplantation after failure of medical therapy. Treatment for pruritus includes the following:
      • Actigall (ursodeoxycholic acid)
      • Rifampicin
      • Ondansetron
      • Antihistamines
      • Naltrexone
      • Zoloft
      • Cholestyramine
      • Ultraviolet light
    • Monitoring portal hypertension: Assessment of portal flow on ultrasound and spleen size may provide some indication of disease progression.
    • Treatment of recurrent cholangitis may decelerate the progression of liver disease.
    • Aggressive treatment for spontaneous bacterial peritonitis in patients with ascites
    • Early referral to a liver transplant center
    • Complete immunization schedule including hepatitis A, hepatitis B, and annual flu shots.
  • Specific management depends on the underlying liver disease.

Ongoing Care


Follow-up Recommendations


Patient Monitoring
  • Look for hepatocellular carcinoma developing in patients with chronic liver disease.
  • Obtaining an ultrasound scan of liver and AFP every 6 months is considered a reasonable schedule.
  • Advise patients with splenomegaly to wear a spleen guard and avoid activities (e.g., contact sports) that can cause splenic rupture.

Prognosis


Some cases of chronic hepatitis are associated with diseases that are treatable. Others are progressive and not amenable to treatment. A subset of patients will progress to end-stage liver disease and require liver transplantation.  

Additional Reading


  • Mieli-Vergani  G, Vergani  D. Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis.  2009;29(3):297-306.  [View Abstract]
  • Murray  KF, Shah  U, Mohan  N, et al. Chronic hepatitis. J Pediatr Gastroenterol Nutr.  2008;47(2):225-233.  [View Abstract]
  • Nel  E, Sokol  R, Comparcola  D, et al. Viral hepatitis in children. J Pediatr Gastroenterol Nutr.  2012;55(5):500-505.  [View Abstract]

Codes


ICD09


  • 571.40 Chronic hepatitis, unspecified
  • 571.41 Chronic persistent hepatitis
  • 070.9 Unspecified viral hepatitis without mention of hepatic coma
  • 571.42 Autoimmune hepatitis
  • 571.49 Other chronic hepatitis

ICD10


  • K73.9 Chronic hepatitis, unspecified
  • K73.0 Chronic persistent hepatitis, not elsewhere classified
  • B18.9 Chronic viral hepatitis, unspecified
  • K75.4 Autoimmune hepatitis
  • K73.2 Chronic active hepatitis, not elsewhere classified
  • K73.1 Chronic lobular hepatitis, not elsewhere classified

SNOMED


  • 76783007 Chronic hepatitis (disorder)
  • 41889008 Chronic persistent hepatitis (disorder)
  • 10295004 chronic viral hepatitis (disorder)
  • 408335007 Autoimmune hepatitis (disorder)
  • 57339008 Chronic lobular hepatitis (disorder)

FAQ


  • Q: What are the risks of providing very young patients with a liver transplant?
  • A: Lifetime risks of immunosuppression and rejection. Although transplant in the very young is more difficult, with the increased use of split liver techniques and improved use of immunosuppressives, outcomes of orthotopic liver transplantation in infants have improved.
  • Q: Why should we be aggressive with vitamin supplementation?
  • A: Chronic hepatitis is associated with significant malabsorption of vitamins A, D, E, and K. Vitamins D and E deficiencies in particular can cause rickets and neuropathy.
  • Q: How can I optimally administer oral supplements of vitamins in the very young?
  • 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: The accumulation of bile salts causes pruritus.
  • Q: What stigmata of chronic liver disease can be seen in children?
  • A: Spider nevi, liver palms (palmar erythema), splenomegaly, cutaneous shunts, and clubbing are very common.
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