The clinical spectrum of acute hepatitis may range from mild symptoms and signs (Table 34.2) associated with recent onset of liver enzyme abnormalities to fulminant hepatic failure. Most symptoms and signs are non-specific (Table 34.2) though there are some manifestations associated with specific conditions, and if present, are helpful in differential diagnosis (Table 34.3).

TABLE 34.2 Non-specific symptoms and signs of acute hepatitis

• Malaise

• Flu-like symptoms

• Weight Loss

TABLE 34.3 Diagnostically helpful associations of acute hepatitis

Infectious mononucleosis Lymphadenopathy Pharyngitis Splenomegaly Thrombocytopenia Haemolytic anaemia	Hepatitis C Cryoglobulinaemia
	Metabolic disturbance Hyperthyroidism Kayser-Fleischer rings
Hepatitis B Polyarteritis nodosum	Drugs Desquamating dermatitis Eosinophilia

DIFFERENTIAL DIAGNOSES

A diagnostic algorithm is suggested for assessing a patient presenting with acute hepatitis (Figure 34.1). There may be obvious clues at the outset such as pregnancy, history of paracetamol overdose or recent drug use. Serology for common causes of viral hepatitis and paracetamol level should be requested as initial investigations. Failing to identify an obvious cause, other less common causes would need to be considered and liver biopsy may be necessary.

FIGURE 34.1 An algorithm for diagnostic investigations for acute hepatitis.

ANA = antinuclear antibody; BSL = blood sugar level; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; SMA = anti-smooth muscle antibody; TFT = thyroid function tests; US = ultrasound.

Acute viral hepatitis

The most common cause of acute hepatitis found on audits of consecutive presentations to the emergency department is hepatitis B, followed by hepatitis A and C (Table 34.4). History of travel, family contacts, immunocompetency, blood transfusions, intravenous (IV) drug usage, sexual practice, tattoos, body piercing, birthplace and prior vaccination can provide useful information for differential diagnosis.

TABLE 34.4 Prevalence of acute viral hepatitis

Western countries
Acute hepatitis B	30%–60%
Hepatitis A	25%–50%
Acute hepatitis C	15%–20%
EBV hepatitis	2%–10%
Hepatitis G	1%
CMV hepatitis	1%

Asian countries
Acute hepatitis B	5%–13%
Acute exacerbation of chronic hepatitis B	15%–40%
Acute hepatitis C	21%
Acute hepatitis C in hepatitis B carriers	12%
Hepatitis A	3%–4%
Hepatitis E	2%–70%^*
Hepatitis A, D, E in hepatitis B carriers	20%
Non A–E hepatitis	16%
Superimposed non A–E hepatitis in hepatitis B carriers	15%

CMV = cytomegalovirus; EBV = Epstein-Barr virus.

* There is significant geographical variability with the higher proportion of hepatitis E virus accounting for presentation of acute hepatitis reported in India.

The geographic differences in the prevalence of acute viral hepatitis also need to be borne in mind in differential diagnosis. In Western countries, most cases of hepatitis B and C are acquired as an adult through sexual transmission or drug use. Hepatitis E is unusual in Western countries but common in the Indian subcontinent (Table 34.4). On the other hand, in Asian countries, notably Taiwan, almost half the cases are represented by hepatitis B carriers presenting either with an exacerbation of hepatitis B infection or with superimposed non-B hepatotropic viral infections (Table 34.4).

The incubation interval ranging from 2 to 7 weeks for hepatitis A and E, up to 26 weeks for hepatitis B and C, is often helpful in assessing for potential source of contacts. Serological testing is generally adequate in confirming the aetiology of acute viral hepatitis. Histology is rarely required and often unhelpful for distinguishing one condition from another.

Epstein-Barr virus hepatitis

Epstein-Barr virus (EBV) infection is transmitted via oral contact. While infection is typically subclinical, it can manifest the clinical syndrome of infectious mononucleosis in a small subset of patients, with fever, exudative pharyngitis, lymphadenopathy, hepatosplenomegaly and atypical lymphocytosis. The illness is more likely to develop in a younger patient as most individuals over the age of 40 have had past contact with EBV and therefore immune to subsequent re-infection. In older patients, the diagnosis may not be immediately apparent as they are less likely than younger patients to have lymphadenopathy and pharyngitis.

Of patients with EBV infection, 80%–90% have mild hepatic parenchymal injury with most expected to resolve spontaneously. Rarely, it could manifest as cholestatic hepatitis, progress to chronic hepatitis or fulminant hepatic failure. Most cases of fatality are associated with immunodeficiency. Hence, depending on the age of the patient, testing for human immunodeficiency virus (HIV) status, X-linked lymphoproliferative disease and complement deficiency should be considered in those presenting with fulminant hepatitis.

Laboratory investigations

Atypical lymphocytes	Not pathognomonic
Atypical lymphocytes	May be found in toxoplasmosis, rubella, roseola and CMV
Lymphocytosis	Usually 12–18 × 10⁹/L
Heterophile antibody	Detectable within 1 week of symptoms Sensitivity 70%–92% and specificity 96%–100%
EBV IgM	Directed at the viral capsid antigen, early antigen and anti-EBV nuclear antigen

Cytomegalovirus infection

Clinical manifestations of cytomegalovirus (CMV) infection are similar to EBV but cervical lymphadenopathy is more frequent in EBV than CMV. It may occur as a result of primary infection or reactivation of a latent viral infection. The infection is transmitted by direct contact. CMV infection is rarely symptomatic in previously healthy adults. It is the most prevalent cause of acute hepatitis in young infants. In such cases, a subgroup may develop massive hepatocellular necrosis, giant cell hepatitis, cholestasis, cirrhosis or hepatic failure associated with poor prognosis and increased mortality.

Laboratory Investigations

Atypical lymphocytosis	Not pathognomonic
CMV IgM	False positive may be associated with pregnancy, rheumatoid arthritis, Sjögren’s syndrome and antinuclear antibody (ANA)-positive patients

Hepatitis A

Hepatitis A virus (HAV) infection is transmitted via the faecal–oral route. It is the most common cause of viral hepatitis, accounting for a quarter of acute hepatitis in some regions. Seroprevalence varies, ranging from 13% in Sweden, 60% in Australia, to 100% in highly endemic areas such as Africa, Asia and South America. HAV is notable for its relative resistance to degradation, which permits transmission within the population leading to a high attack rate of 70%–90% and secondary attack rate of 15%–20%.

Hepatitis A infection is often self-limiting. Fulminant hepatitis is rare. Infrequently, it may develop a cholestasis variant, relapse after recovery or lead to autoimmune diseases.

Laboratory investigations

HAV IgM	Confirms acute HAV infection Peak during the acute phase of infection
HAV IgM	Undetectable after 3–4 months although 25% may have IgM persistence up to 6 months or more
HAV IgG	Indicates previous exposure and immunity to hepatitis A
HAV IgG	Rising HAV IgG levels is indicative of recent exposure
HAV RNA	Not clinically useful as the virus is usually undetectable at the time of clinical manifestation

Hepatitis B

This infection is discussed in more detail in Chapter 36. Acute infection in immunocompetent adults is often self-limiting. Fulminant hepatitis is rare but associated with a poor prognosis. Individuals at risk of chronicity include those who acquired hepatitis perinatally or those with HIV coinfection. Acute hepatitis B infection may be associated with a number of extrahepatic manifestations including polyarteritis nodosa, vasculitisinduced neuropathy, renal disease, rash, arthritis and Raynaud’s phenomenon.

Laboratory investigations

Hepatitis B surface antigen	Marker of hepatitis B infection
Hepatitis B surface antibody	Detection in the presence of hepatitis B core IgG indicates resolution of hepatitis B infection and immunity
Hepatitis B surface antibody	Detection in the absence of hepatitis B core IgG indicates immunity from past vaccination
Hepatitis B core IgM	Detectable with the onset of symptoms during acute infection for up to 6 months
Hepatitis B core IgM	Not able to distinguish between acute infection and a flare as it may also reappear in chronic carriers during a severe flare
Hepatitis B core IgG	Often persists for a lifetime and therefore the best marker of exposure to hepatitis B
Hepatitis B e antigen	Marker of viral replication of wild type hepatitis B
HBV DNA	Marker of viral replication
HBV DNA	Threshold of detection varies with different assays, being the most sensitive with Taqman fluorescent-probe real time PCR at 10 copies/mL

Hepatitis D

The hepatitis D virus (HDV) is transmitted most efficiently among hepatitis B-infected patients through injection. It is therefore most prevalent among injecting drug users coinfected with hepatitis B, from 31% in Ireland to 91% in Taiwan. Perinatal transmission of hepatitis D is rare and vertical transmission of the virus has not been reported. Infection is most prevalent in Italy, Eastern Europe, Central America, Western Asia and some Pacific Islands.

Coinfection of hepatitis D and B is often self-limiting, characterised by a biphasic increase in alanine aminotransferase (ALT), and associated with higher risk of severe or fulminant hepatitis than hepatitis B infection alone. Acute superinfection of hepatitis D in established hepatitis B-infected patients may lead to a flare, which results in clearance of both infections. Chronic superinfection of hepatitis D is thought to hasten disease progression in a subgroup of hepatitis B-infected patients.

Laboratory investigations

HDV IgM	Associated with detectable hepatitis B core IgM in coinfected patients and the absence of hepatitis B core IgM in superinfection
HDV antigen	Often transiently detectable in low titres during late incubation phase and therefore of little clinical utility
HDV RNA	Not routinely available

Hepatitis E

The hepatitis E virus (HEV) is transmitted via the faecal–oral route. Epidemics of hepatitis E infection occur with ingestion of faecally contaminated water supply. Hepatitis E is the most common cause of enterically transmitted hepatitis being endemic in subcontinental India, Asia, Southeast Pacific, the Middle East, Africa and Central America. Most sporadic cases in non-endemic areas occur primarily in travellers returning from endemic countries. The incidence of infection through household contact is low (0.7%–2.2%). Clinical presentation is usually seen among individuals 15–40 years of age. Most cases are self-limited infections, which resolve in 6 weeks, but fatality can be associated with fulminant hepatitis, of which pregnant women are at higher risk.

Laboratory investigations

HEV IgM	Enzyme immunoassay directed at the structural regions ORF2 and ORF3
HEV IgM	Sensitivity 80%–100%
HEV antigen	Usually undetectable by the time ALT levels peak
HEV antigen	Can be detected in liver tissue and stool
HEV RNA	Not routinely available