Definition (Pediatr Rev 2011;32:333)
• Multiple etiologies w/ liver inflammation and hepatocyte death w/ ↑ serum AST/ALT
• Etiology, evaluation, and treatment varies per age groups and risk factors/exposures
Etiology (Pediatr Rev 2011;32:333; Pediatr Rev 2001;22:219)
• Neonatal: Usually p/w cholestasis; DB >20% TSB (Clin Liver Dis 2006;10:27)
• 25% 2/2 biliary atresia, 25% bile acid synthetic defect, Alagille, etc.
• 30% metabolic diseases of which 10% are alpha-1-antitrypsin deficiency
• Hereditary hemochromatosis, galactosemia, tyrosinemia, hereditary fructose intolerance, mitochondrial diseases
• 5% congenital infections (TORCH infections)
• 15% idiopathic neonatal hepatitis
• Older infants, children, and young adults (Pediatr Rev 2001;22:219)
• Viral hepatitis is most common; accounts of 70–80% liver failure in children
• Hepatitis A (HAV), HBV, HCV, HDV, HEV, EBV, CMV, HSV, VZV
• Biliary tract obstruction/disease (see later discussion)
• Cholelithiasis (sickle cell), cholecystitis, sclerosing cholangitis (IBD)
• Metabolic liver disease: Alpha-1-antitrypsin deficiency, Wilson dz, CF
• Autoimmune liver disease: Generally progresses to cirrhosis; types 1 and 2
• Hepatotoxins: Acetaminophen and EtOH most common but many others
• Antiepileptics (carbamazepine, phenytoin, valproic acid)
• Antibiotics (sulfonamides, INH, azoles)
• Other drugs of abuse (ecstasy, PCP, cocaine)
• Over-the-counters and herbals (NSAIDs, amanita mushroom)
• Vascular disease: Budd–Chiari syndrome, ischemia, veno-occlusive disease
• Infiltrative disease: Steatohepatitis (NASH), sarcoidosis, TB
Selected Clinical Manifestations, Evaluation, and Treatment
• Presentation can vary from asymptomatic to fulminant hepatic failure
• Sx may include, abdominal pain (particularly RUQ), hepatomegaly, nausea and vomiting, fever, acholic stools, jaundice, encephalopathy, tremor (asterixis)
• Hepatitis A: RNA virus, acute and self-limited infection w/ fever, jaundice, fatigue, N/V and diarrhea; at risk for fulminant hepatic failure if underlying liver disease
• Most common cause of acute viral hepatitis
• Symptomatic in ∼30% <6 yo (rarely w/ jaundice), 70% symptomatic in older pts
• Transmission is fecal–oral, blood-borne, and vertical transmission rare; travel hx
• Check serology for IgM (lasts 4–6 mo after acute infection) and IgG
• Treatment is supportive; 2 dose vaccination for prevention
• Pt <1 yo and likely future exposure; give immunoglobulin (Pediatrics 1996;98:1207)
• Hepatitis B: DNA virus, acute or chronic, or just abn labs (Clin Liver Dis 2006;10:133)
• Asymptomatic, anicteric seroconversion is the norm if young, more sx if older
• Vertical transmission patients usually w/ nml ALT for yrs, mild histopath Δ’s
• Risk of chronic HBV inverse to the age of infection. 90% w/ vertical transmission, 25–50% btw ages 1–5, and only 5–10% in older (Clin Liver Dis 2006;10:133)
• 25% of infants/older children w/ HBV develop cirrhosis or HBV-related HCC
• HBeAg+, HBeAB negative usually w/ high HBV viral load, inc infectivity
• Endemic regions (Asia, Africa, S. America); vertical transmission most common
• Mother HBsAg and HBeAg+, vertical inf rate 70–90%; HBeAg neg 5–20%
• Transmission through infected body fluids, percutaneous, or permucosal
• If mom HBsAg+/unknown, give HBV vac and HBIG w/i 12 hr at diff sites
• No risk associated w/ breast-feeding
• Check HBsAg, HBeAg, anti-HBsAb, anti-HBcAb, anti-HBeAB, HBV viral load
• Management of chronic HBV in children (Pediatrics 2009;124:e1007)
• Prove chronicity (HBsAg+ >6 mo)
• In addition to above obtain baseline ALT, CBC, AFP, liver U/S, and FHx of liver dz
• HBeAg+, Anti-HBe–, ALT nml, HBV DNA >20,000 IU/mL = immune tolerant
• Follow ALT and AFP q6–12 mo and HBeAg/Anti-HBe q12mo; if ALT elevated (above nml or >40 IU/L) or AFP >10 ng/mL – refer to hepatologist
• HBeAg−, Anti-HBe +/−, ALT nml, HBV DNA <2,000 IU/mL = inactive carrier
• Follow ALT and AFP q6–12mo and HBeAg/Anti-HBe and HBV q12mo; if ALT-elevated or AFP >10 ng/mL, or if HBV >2,000 IU/mL – Refer
• ALT elevated, AFP >10 ng/mL, HBeAg− with HBV >2,000 IU/mL &.or +FHx liver dz or HCC then immediate referral to hepatologist
• Immunize all household contacts, immunize/check immune status of pt for HAV
• Immunize for hepatitis A, check yearly AFP and liver U/S
• Hepatology will follow q1–2yr liver U/S, obtain liver bx and consider treatment if patient >2 yo and ALT >1.5–2× nml for >3 mo, active HBV replication (+HBeAg or HBV DNA >4 log) w/o seroconversion and bx w/ evidence chronic hepatitis
• No treatment of proven efficacy in the pediatric population
• INF-alpha w/ seroconversion in 20–58% (used in children for last 10 yr)
• Lamivudine w/ seroconversion in 23–35% (N Engl J Med 2002;346:1706)
• Requires 1 yr of therapy and can develop resistance, well-tolerated
• Rx options in lamivudine-refractory pts include entecavir, adefovir
• Chronic HBV infection as infant confers a 15–25% chance early death 2/2 liver dz
• Hepatitis C: RNA virus; acute disease mild, insidious, often asymptomatic
• <20% w/ jaundice but 50–60% w/ persistent infection (less than in adults)
• Transmission is primarily from exposure to infected blood
• Now vertical xfr >> transfusion as risk; since 1992 (universal blood screening)
• Vertical risk ∼5–6%; inc w/ HIV coinfection (∼20%) (Clin Liver Dis 2006;10:133)
• No inc risk of xfr w/ breast-feeding unless w/ bleeding or cracked nipples, in which case advisable to hold breast-feeds (Adv Exp Med Biol 2004;554:211)
• Usually asymptomatic in 1st 20 yr, w/ mild inflam, necrosis, and fibrosis on bx
• Risk of cirrhosis and HCC in adulthood exists; but low (∼5%)
• Check HCV RNA viral load and genotype if RNA is positive; best prognosis for genotypes 2 and 3 as best response to therapy, though type 1 is most common
• Treatment: Few contraindications to INF, higher frequency of response, less relapse, shorter duration of disease, but natural history of disease unclear
• FDA approved rx include INF-alfa-2b w/ ribavirin (age 3–17) w/ 49% SVR (Hepatology 2002;36:1280) & PEG-INF-alfa-2b w/ ribavirin w/ 48% SVR (Hepatology 2005;41:1013). New agents under study (telaprevir & boceprevir)
• Consider for genotypes 2 and 3, also if bx w/ significant injury or fibrosis
• Genotype 1 w/ minimal inflammation or fibrosis can be followed
• Vaccinate all patients against hepatitis A and hepatitis B
• Need for surveillance AFP and screening U/S unknown at present
• Hepatitis D: Only can infect pts w/ HBV, at initial infection or afterwards; usually w/ acute illness and 5% risk of fulminant hepatitis; rx is supportive care
• Hepatitis E: Acute illness, developing world, severe in pregnant pts (10% mortality)
• Epstein–Barr virus (EBV): Acute hepatitis and jaundice in adolescents w/ mononucleosis; acute jaundice, pharyngitis, LAD, splenomegaly
• CMV, VZV, HSV, toxo: Usually w/ systemic presentation in immunocompromised
• Alpha-1-antitrypsin disease: (AD genetics), AAT opposes proteolytic enzymes
• Only 20% of PiZZ homozygous patients present with liver disease
• In 1st 20 yr, liver dz > respiratory (COPD/emphysema); can present w/ neonatal jaundice, or later w/ acute jaundice, chronic hepatitis, or cirrhosis
• Smoke exposure is major determinant of lung fxn; can be mistaken for asthma
• Check alpha-1-antitrypsin level (dz if <11 μmol/L) and genotype study
• Rx for significant liver disease is transplant; curative as liver makes A1AT
• Wilson disease: (AR genetics), dysregulation of copper metabolism w/ excess accumulation in liver, CNS, kidney, corneas (Pediatr Rev 2001;22:219)
• Acute hepatitis or fulminant liver dz (mod ↑ AST/ALT, low/nml AP, w/ Coombs neg hemolytic anemia, coagulopathy), to chronic hepatitis and cirrhosis
• Often w/ marked neuropsychiatric sx, motor disturbance, depression, psychosis, if present will also have Kayser–Fleischer ring (gold discoloration from copper deposit in Descemet membrane of cornea seen on slit lamp)
• Renal involvement w/ proximal tubule dysfunction, proteinuria, glucosuria, RTA
• Diagnosis by 24-hr urinary copper excretion >100 mcg (Hepatology 1992;15:609)
• Urine copper ↑ in other liver dz, check w/ penicillamine challenge test; 500 mg at start and at 12 hr of collection, level >1,600 mcg (per 24 collection) urinary copper diagnostic of Wilson (large validation study in children)
• Ceruloplasm low in disease, and can be variable, poor positive predictive value
• Autoimmune hepatitis: Chronic inflammatory disease, unknown etiology, generally resulting in cirrhosis; 2 types (Clin Liver Dis 2006;10:89)
• 40% type I (mean age 10 yr) and 80% of type II (6.5 yo) dx’d before age 18 yr
• Usually presents as acute hepatitis w/ F > M; usually evidence of chronic dz already present at dx; spider nevi, ascites, palmar erythema, splenomegaly
• AST/ALT inc, usually w/ hypergammaglobulinemia
• Type I: + anti-smooth muscle Ab and ANA+; other sx IBD, vasculitis, arthritis, ↓ plts, GN, hemolytic anemia, fibrosing alveolitis
• Type II: More rapidly progressive, +anti–liver-kidney microsome Ab and or +anti–liver-cytosol Ab; DM, thyroiditis, vitiligo, alopecia, AI enteropathy
• Rx w/ immunosuppression; generally prednisone and then Imuran complete/
sustained response in 95% patients
• Hepatotoxins: Acetaminophen OD is 1° cause of acute hepatic failure in childhood
• Treatment (except for acetaminophen OD; see ED chapter) is supportive usually w/ improvement after withdrawal of hepatotoxin. (Pediatrics 2004;113:1097)
• AST/ALT 8–20+ × nml: Acetaminophen, ASA, halothane, INH, VPA
• AST/ALT >3× nml: Augmentin, 6MP, carbamazepine, ketoconazole, minocycline, phenobarbital, PTU, sulfonamides
• AST/ALT <3× nml: Cyclosporine, erythromycin, estrogens
• Budd–Chiari: Any blockage of blood outflow from liver resulting in congestion
• Acute, subacute, chronic, or fulminant; dx w/ U/S + Doppler, CT, MRA, venogram
• Rx may involve meds (anticoag, thrombolysis), IR (stent, angioplasty, TIPS), or surgery (shunts, transplant).