Introduction1–5

Hepatitis is defined as inflammation of the liver due to a number of possible causes. Jaundice or icterus implies a yellow discolouration of skin, sclera and mucous membranes due to hyperbilirubinaemia which may or may not be caused by hepatitis.

In children, the presentation of hepatitis includes a diverse number of viral and non-viral causes. Viral hepatitis continues to be a major health problem in developing and developed countries and can present as an acute or chronic illness.

Aetiology

Table 7.9.1 Patterns of hepatic drug injury

Centrilobar necrosis Paracetamol
Halothane Microvesicular steatosis Valproic acid Acute hepatitis Isoniacid General hypersensitivity Sulfonamide
Phenytoin Fibrosis Methotrexate Cholestasis Chlorpromazine
Erythromycin
Oestrogens Veno-occlusive disease Cyclophosphamide Portal and hepatic vein thrombosis Oestrogens
Androgens Biliary sludge Ceftriaxone Hepatic adenoma or carcinoma Oral contraceptives
Anabolic steroids

Viral hepatitis in children can present with various manifestations, ranging from asymptomatic seroconversions especially in infants, mildly symptomatic and anicteric presentations with symptoms of a flu-like or gastroenteritis-like illness, to fulminant hepatic failure as well as chronic hepatitis leading to cirrhosis and hepatocellular carcinoma. In adults, chronic hepatitis is defined as biochemical or histological changes that persist for more than 6 months. This definition in children would inappropriately delay the diagnosis of several childhood causes of non-viral chronic hepatitis which respond to specific medical therapy. Persistence of abnormal serum aminotransferase tests beyond 3 months warrants aggressive evaluation to define the aetiology of the liver injury. A child with clinical evidence of chronic liver disease should be referred to a paediatric gastroenterologist for further evaluation without the 3 month observation period.

History

Acute symptomatic viral hepatitis classically presents with a 1-week prodromal phase with non-specific symptoms of nausea, vomiting, malaise, anorexia and low-grade fever, followed by an icteric phase with dark urine followed by jaundice and pale stools. Prodromal symptoms fade with the onset of jaundice but anorexia and malaise may persist, and localised hepatic pain or tenderness and pruritus may develop. Important historical clues indicating an infectious aetiology are attendance of child care and possible disease among peers and childcare workers, exposure to highly endemic communities in Australia (e.g. remote Aboriginal communities) or overseas, attendance of schools and residential facilities for the disabled, exposure to blood products, injection drug use and high risk sexual activity (men who have sex with men). A history of acute drug or toxin ingestion or ongoing therapeutic use of potentially hepatotoxic agents should be elicited. The history should also explore the possibility of acute or chronic presentations of metabolic and systemic illnesses associated with liver disease e.g. neurological complaints in Wilson’s disease, respiratory difficulties in cystic fibrosis, or a history of cardiac disease.

Examination

Although jaundice is the hallmark of hepatitis, many children will present anicteric. Carotenaemia, which also causes a yellow-orange tinge of the skin due to high intake of carotenoids in carrots and other vegetables, can be differentiated from jaundice by the lack of scleral involvement. In addition to jaundice, physical examination in acute hepatitis may show tender hepatomegaly and mild splenomegaly. Arthralgias or arthritis and rashes can occur with hepatitis B. Signs of chronic liver disease should be specifically looked for including clubbing, leukonychia, palmar erythema, spider naevi, bruising, scratch marks, asterixis, ascites, prominent abdominal veins, oedema and signs of fat-soluble vitamin deficiency.

Investigations

Laboratory tests for hepatitis can be expensive and many may not be clinically useful in the emergency setting. Initial studies should include a full blood count, total and fractionated serum bilirubins, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) and prothrombin time (PT). A serum alkaline phosphatase level may be difficult to interpret in growing children because levels increase with bone growth. Serum AST, ALT and GGT are indicative of hepatocellular damage rather than ‘liver function tests’. Slight elevations of AST and ALT do not always predict mild disease and both can fall with end-stage liver disease. PT is the most useful indicator of synthetic function. If the aetiology of the hepatitis is unknown, anti-hepatitis A immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), IgM anti-hepatitis B core (HBc) and anti-hepatitis C virus (HCV) antibody should be obtained. If these tests are negative, other viral causes such as EBV and CMV should be considered. If no viral cause can be identified, metabolic and systemic causes of acute and chronic hepatitis should be excluded. Wilson’s disease can be detected by measuring serum coeruloplasmin levels and 24-hour urinary copper excretion, cystic fibrosis by measuring sweat electrolytes, α-antitrypsin deficiency by measuring serum α₁-antitrypsin levels.

Viral hepatitis1–4

Over the past decades the knowledge about the viruses that cause hepatitis has increased and is still evolving. The agents identified to cause hepatitis as their primary disease manifestation include hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis D virus (HDV) and formerly non-A, non-B designated viruses, hepatitis C (parenteral transmission) and hepatitis E (enteral transmission). HBV is a DNA virus whereas the other hepatotropic agents are RNA viruses. HAV and HEV are not known to cause chronic disease whereas the others can develop chronic infection. All five viruses can cause fulminant hepatitis with acute liver failure. A child with evidence of synthetic dysfunction (prolonged prothrombin time, hypoglycaemia, hyperammonaemia, lactic acidosis) with or without positive viral serology should be urgently referred to a paediatric gastroenterologist. Patients with severe hepatitis should be transferred early before intensive care therapy is required.

There are a number of other hepatotropic viruses which play a less well defined role in the pathogenesis of acute and chronic liver disease such as hepatitis G virus and TT virus. It is virtually impossible to clinically distinguish an acute infection due to one agent from another. Diagnosis is therefore dependent on the use of serologic and nucleic acid based assays. Many other viruses can cause hepatitis as part of their clinical spectrum, such as EBV and CMV.

Drug and toxin-induced liver injury^3,15

The liver is the main site of drug metabolism and is particularly susceptible to structural and functional injury from drugs and toxins. The clinical spectrum varies from asymptomatic biochemical abnormalities to fulminant liver failure. Children may be more or less susceptible than adults to hepatotoxic reactions. For example, liver injury after halothane is rare in children and paracetamol toxicity is unusual in infants compared with adolescents, whereas most cases of fatal hepatotoxicity associated with sodium valproate use have been reported in children. Excess or prolonged therapeutic administration of paracetamol combined with reduction in caloric intake may produce hepatotoxicity in children. When considering adverse reactions to medications with liver involvement clinicians need to consider all drugs taken in the previous months including prescription medications, over the counter medications and complementary medicines. In Australia the most commonly reported alternative and complementary medicines associated with hepatotoxicity according to the Adverse Drug Reactions Advisory Council (ADRAC) are kombucha tea, echinacea, evening primrose tea and valerian.

Hepatotoxicity can be predictable or idiosyncratic. Predictable hepatotoxicity implies a high incidence in exposed persons with dose dependence. Examples are paracetamol or antimetabolites such as methotrexate. Idiosyncratic hepatotoxicity is infrequent and unpredictable. It is not dose dependent, may occur at any time during exposure to the agent and may be immunologically mediated as a result of prior sensitisation.

The pathological spectrum of drug induced liver disease varies widely and is rarely specific (see table). The laboratory features also vary widely. After exclusion of other causes of liver disease, the cessation of a temporally related offending medication with normalisation of liver function tests is usually sufficient to establish a diagnosis. Treatment is mainly supportive. N-acetylcysteine is used as a specific antidote in preventing paracetamol toxicity. The prognosis of drug or toxin induced liver injury depends on its type and severity. Injury is usually completely reversible with the withdrawal of the offending agent. The mortality of submassive hepatic necrosis with fulminant liver injury may, however, exceed 50%.

Chronic hepatitis