Paediatric Liver Disease

Aetiology of hepatitis 

• Infection
  • Hep A, B, C, D, E
  • EBV, CMV
  • Leptospirosis, brucellosis, Q fever, cat-scratch disease, gonorrhoea, syphilis, typhoid fever
  • Amoebic
• Drug or toxin-related (see next slide)
• Chronic hepatitis
• Autoimmune hepatitis
• Sclerosing cholangitis
• Metabolic 
  • Wilson’s disease
  • Alpha-1 antitrypsin deficiency
  • Cystic fibrosis
• Systemic illness e.g. IBD, cardiac disease, TPN

Chronic hepatitis

• In adults, defined as biochemical or histological changes persisting >6 months
• In children, this would cause delayed diagnosis and as such, any persistently abnormal serum aminotransferase levels beyond 3 months warrant aggressive evaluation
• All children with suspected chronic hepatitis of any duration warrant paediatric gastroenterology referral

Acute Hepatitis

History

• Often prodromal 1 week of malaise, nausea, vomiting, anorexia and low-grade fever followed by icteric phase
• Risk factors for viral hepatitis
  • Daycare
  • Contacts
  • Endemic community (e.g. remote Aboriginal communities)
  • Overseas travel
  • Residental facilities or schools for the disabled
  • Exposure to blood products, injecting drug use or MSM
• Always question any therapies in use e.g. paracetamol exposure
• Systems review for associated issues e.g. respiratory for CF

Examination

• Tender hepatomegaly +- splenomegaly
• Arthralgia/arthritis/rash can be seen in Hep B
• Signs of chronic liver disease
  • Clubbing
  • Spider naevi
  • Scratch marks
  • Bruising
  • Asterixis
  • Ascites
  • Prominent abdominal veins
  • Oedema

Investigations

• FBC, LFT and coags
  • Serum ALP may be raised due to bone growth in children
  • PT is best indicator of synthetic function
• If hepatitis evident:
  • Anti-HepA IgM
  • HBsAg
  • Anti-HBc IgM
  • HCV antibody
  • If all negative
    • EBV/CMV serology
    • Serum caeruloplasmin levels
    • Sweat test
    • Alpha-1 AT levels

Viral hepatitis

• HepA and E do not cause chronic hepatitis
• All can cause fulminant hepatitis

Hepatitis A

• RNA virus
• Faecal-oral
• 50% have no identified source
• 15-50 days incubation period (mean 30 days)
• Highest titres in stool 1-2 weeks prior to symptoms
• Acute self-limited illness
• Under 6yo, only 30% have symptoms and jaundice is rare
• Treatment
  • Avoid hepatotoxic agents
  • Pruritis can be treated with cholestyramine, antihistamines or local therapy
  • Admit if warning signs develop (repeated vomiting, deepening jaundice, any sign of synthetic failure

• Immunisation and post-exposure prophylaxis
  • Vaccine approaches 100% efficacy and adults and children
  • Recommended for overseas travel to endemic regions, ATSI (in remote parts of Australia), childcare workers/disability workers, intellectual disabilities, chronic lier disease
  • PEP with normal human IG indicated for household and sexual contacts within 2 weeks of exposure and for unimmunised children and employees in facilities

Hepatitis B

• DBA virus
• Shared through blood and body fluids
• Perinatal transmission is usually through delivery
• Non-sexual transmission occurs in households and young children are at highest risk
  • Likely frequent interpersonal contact of non-intact skin or mucous membranes
• Incubation 45-160 days (mean 90 days)
• Asymptomatic carrier state to fulminant fatal hepatitis
• Young children are mostly asymptomatic
• Extra-hepatic manifestations can be seen and include arthalgia/arthritis/macular rash and papular acrodermatitis (Gianotti-Crosti syndrome)
• Chronic HBV seen in 90% of perinatal infection, 25-50% of age 1-5yo and 2-6% of older children/adults
  • Chronic infection can lead to chronic hepatitis and cirrhosis +- carcinoma

• Tests
  • HBsAg in acute infection
  • Anti-HBcAg IgM arises before anti-HBsAg
  • Chronic HBV infection
    • Positive HBsAg + anti-HBcAg
  • Resolved infection
    • Anti-HBsAg and anti-HBcAg
  • Post-vaccination
    • Anti-HBsAg only
  • HBeAg and HBV viral DNA indicates ongoing viral replciation, increased disease activity and infectivity

• Management
  • F/U labs to determine resolution, carrier state and chronic liver disease
  • IFN-alpha, lamivudine and other antivirals are being used to treat chronic Hepatitis B with long-term remission and reduced complications
  • Liver transplant is an option in end-stage chronic hepatitis
• Immunisation and PEP
  • Vaccine part of immunisation schedule + recommended for healthcare workers, haemodialysis and HIV patients, patients receiving blood products, chronic liver disease
  • Recommended as PEP for unimmunised household and sexual contacts of persons with acute HBV infection, newborns of HBsAg positive mothers and after needlestick injuries that contain or might contain HBsAg
    • Newborns and needlestick injuries should also receive HepB IG for immediate protection

Hepatitis C

• ssRNA virus
• Parenteral spread
• Risk facctors
  • IVDU
  • Haemophilia patients who received untreated blood products in the past
  • Haemodialysis patients
  • High-risk sexual behaviours
  • Vertical transmission rate of 5-10% (most common cause in developed countries)
• Incubation period 2 weeks to 6 months (mean 6-7 weeks)

• Presentation
  • Acute disease tends to be mild and insidious
  • Most children asymptomatic
  • 15% of patients develop symptoms
  • Persistent HCV then occurs in the majority
  • Chronic liver disease, cirrhosis and hepatocellular carcinoma can follow
• Lab
  • Total anti-HCV antibody assays (may be negative early on)
  • HCV RNA PCR

• Management
  • Avoid hepatotoxics
  • Immunise against HepA and HepB
  • Not a contraindication to breastfeeding
  • IFN-alpha, ribavirin and other antivirals have shown good results
• No vaccine and PEP not efficacious

Hepatitis D

• RNA genome + delta protein antigen covered in HBsAg
• Only causes co-infection or superinfection in those with acute or chronic HBV infection
• HDV requires HBV as a helper virus
• Spread by parenteral, percutaneous or mucous membrane inoculation
• Rare in Australia
• Incubation period 2-8 weeks in superinfection (vs. 45-160 days in co-infection = similar to HBV)
• Converts asymptomatic or mild chronic HBV into fulminant disease
• HepB immunisation protects against HDV completely

Hepatitis E

• Enterically spread non-Hep A/non-HepB hepatitis
• High case-fatality rate in pregnant women
• Does not cause chronic infection
• Self-limited acute illness only

Drug and toxin-induced hepatitis

• Need to consider all drugs in last month
• Most commonly reported complementary medicines in Australia causing liver disease include kombucha tea, echinacea, evening primrose tea and valerian
• Can often establish diagnosis by cessation of suspicious agent and normalisation of LFT’s
• Consider paracetamol, sodium valproate, phenytoin, methotrexate, oestrogens, ceftriaxone and anabolic steroids

Chronic hepatitis

• Persistent HepB/C/D, autoimmune hepatitis, sclerosing cholangitis, Wilson’s, Alpha-1 AT deficiency, cystic ibrosis, IBD, cardiac disease, TPN, drugs and toxins
• Autoimmune hepatitis
  • AH type I: ANA positive. Females mostly, lethargy, jaundice and signs of CLD
  • AH type II: ANA negative, anti-liver-kidney microsomal antibodies positive
  • Both associated with thyroiditis, GN, haemolytic anaemia, erythema nodosum
• Sclerosing cholangitis
  • Primary SC: Associated with IBD
  • Secondary SC due to obstruction

Hepatic failure

• Definition in adults:
  • Hepatocellular dysfunction of rapid onset, and
  • Encephalopathy within 8 weeks of jaundice
• Definition in children (Paediatric ALF study group)
  • Biochemical evidence of liver injury (<8 weeks duration)
  • No history of chronic liver disease
  • Caogulopathy not corrected with Vit K
  • INR >1.5 with encephalopathy OR INR >2 if no encephalopathy
• Management is similar for those with chronic liver disease and subsequent liver failure, except specific therapy may exist

• Classification by time interval between onset of jaundice and encephalopathy has aetiological and prognostic importance
  • 7 days or less: Hyperacute (better prognosis)
  • 8-28 days: Acute
  • 5-12 weeks: Subacute

Causes

• Neonates and infants
  • Cholestasis: Biliary atresia, choledochal cyst
  • Idiopathic neonatal hepatitis
  • Cystic fibrosis
  • Endocrine: Hypopituitarism/hypothyroidism
  • Infections:
    • Viral: CMV, Herpes, EBV, parvovirus, rubella, adenovirus, enterovirus
    • Bacterial: Sepsis, UTI, TB, syphilis
    • Parasitic: Toxoplasmosis
  • Metabolic: Alpha-1 AT deficiency, and many others
  • Toxins: Paracetamol, TPN, hypervitaminosis A
  • Tumour

• Older children
  • Infection
    • Viral: Hepatitis A-D, enterovirus, varicella, EBV, adenovirus, CMV, herpes, rubella
    • Bacterial: Listeria, TB
    • Parasitic: Toxoplasmosis
    • Toxins and drugs: Paracetamol (most common cause in developed world)
    • Malignancy: Leukaemia/lymphoma, neuroblastoma, primary hepatic tumours
    • Wilson’s disease
    • Hepatic venous occlusion
    • Fatty liver: Obesity, pregnancy
    • Hepatic hypoperfusion: Cardiogenic shock, hypovolaemic shock, septic shock
  • Aspirin and Reye’s syndrome
    • Reye’s syndrome = Mitochondrial dysfunction leading to acute encephalopathy, selective hepatic dysfunction and visceral fatty infiltration
    • Preceding viral illness (classically Varicella), immune mediators and aspirin can all limits normal function of mitochondrial oxidative phoshorylation and fatty acid beta-oxidation
    • Forsyth et al. identified a dose-response relationship with aspirin
  • Zellweger’s syndrome
    • Cerebrohepatorenal syndrome
    • Autosomal recessive peroxisomal abnormality leads to abnormal bile synthesis and fatty-acid oxidation
    • Presents with multiorgan failure and failure to thrive
    • Jaundice in 50%
  • Alpha-1 AT deficiency
    • 1/4000 live births are affected by autosomal recessive disorder
    • Cholestasis in neonatal period, IUGR, FTT and hepatomegaly are classic
    • PiZZ (most associated with liver disease), PiSz, PiSS or Pi FZ and MZ (carrier)
  • Tyrosinaemia
    • Autosomal recessive deficiency of last enzyme in phenylalanine metabolism
    • Progressive liver failure and renal tubulopathy
  • Galactosaemia
    • 1/40 000 liver births
    • Autosomal recessive deficiency of galactose-1-phosphate uridyl-transferase leading to accumulation of galactose-1-phosphate in liver, brain and kidneys
  • Wilson’s disease
    • 1/30 000 live births
    • Hepatic failure, neuropsychiatric symptoms, renal tubulopathy, haemolysis, hormonal changes, Kayser-Fleischer rings (brown)
  • Alagille’s syndrome
    • Autosomal dominant intrahepatic biliary hypoplasia
    • 1/100 000 live births
  • Biliary atresia
    • Complete absence of all extra-hepatic biliary structures mostly
    • Jaundice, pale stools and dark urine
  • Mushrooms
    • Amatoxin is hepatotoxic
    • Heat-stable octapeptide
    • 6-48 hours after ingestion, abdominal pain, diarrhoea, coma, seizures and hepatic failure
    • Mortality of up to 30%
    • Cholinergic symptoms can also occur

Pathophysiology

• Hepatic encephalopathy
  • Interplay of three factors:
    • Reduction in synthesis of substances essential for normal brain function
    • Production of neurotoxins
    • Reduced elimination of neurotoxins
  • Ammonia, inflammatory cytokines, benzodiazepine-like substances and manganese all contribute to neuronal dysfunction
  • Balance of inhibitory versus excitatory neurotransmitters is altered
  • Ammonia appears to augment inhibitory neurotransmission
  • The role of sepsis, hypoglycaemia and raised ICP are also important

History

• Neonatal
  • Jaundice
    • Pale stools suggests cholestasis
    • Dysmorphic features may provide clues
    • After change in diet may suggest metabolic disorder
• Infants and older children
  • Loss of appetite, vomiting, fevers, abdominal pain, jaundice
  • Diet and travel history important
  • Risk of exposures to viruses
  • Exposure to hepatotoxins

Examination

• Hepatomegaly and jaundice
• Firm, nodular liver = cirrhosis
• Tenderness = acute hepatitis
• Splenomegaly = portal hypertension or infiltration e.g. storage disease, extramedullary haematopoiesis or malignancy
• Ascites
• Phenotypic differences may be evident
• Neurological examination for asterixis and assess stage of encephalopathy
• Cutaneous features of chronic liver disease

Hepatic encephalopathy – Stages

Investigations

• Cause and extent of dysfunction
• FBC, LFT, Glucose, Coags, renal function, VBG
• Viral serology, copper and caeruloplasmin levels, urine metabolic screen, Pi typing, lactate level, drug screening or imaging – Await paediatric hepatologist
• INR and serum bilirubin are not predictive of post-transplant survival
• Renal dysfunction requiring dialysis is associated with higher mortality
• PT <10% (INR >6) 4 days after mushroom ingestion is predictive of fatal outcome

Management

• Close monitoring
• Monitoring of: ECG, glucose, acid/base, coagulation, LFT, electrolytes
• Vascular access, NG tube
  • Lactulose reduces absorption of nitrogenous wastes
  • Neomycin and/or metronidazole given enterally reduce enteric bacterial load and nitrogenous waste production
• Supplemental glucose, potassium, albumin, coagulation factors, O2 and intravascular volume may all be required
  • 10% glucose often required to maintain normoglycaemia
• Identification of treatable cause, evolving encephalopathy and raised ICP
• Prevention of infection, gastric ulceration
• Aggressive antimicrobial management if any signs of sepsis

Contraindications to transplant

• Uncontrolled systemic infection
• Extrahepatic metastasis in liver tumours
• Irreversible neurological injury
• Multiorgan failure

Poor prognostic features
(King’s College Criteria)

• Unknown aetiology
• Toxin associated (other than paracetamol)
• Age under 10
• Age over 40
• Jaundice for >7 days prior to encephalopathy
• Serum bilirubin >300
• INR >3.5
• pH <7.3
• Serum creatinine >300
• Single factor above = 80% mortality
• Three or more factors = 95% mortality

Prognosis

• Mortality is 60% despite transplantation services
• Sepsis is the cause of death in 10%
• Mortality rate of all children undergoing liver transplant is 20-30%
• Paracetamol acute liver failure with one King’s college criteria = 55% mortality
• MELD can be used over 12yo
• Paediatric MELD (PELD) can be used under 12 yo

Last Updated on November 20, 2021 by Andrew Crofton