65. Classification and differential diagnostics of jaundice. Acute and chronic viral hepatitis

Page created on May 15, 2021. Last updated on March 15, 2024 at 22:47



Jaundice or icterus refers to the yellowish discoloration of the skin, sclerae, and mucous membranes due to deposition of bilirubin. This occurs due to an increased concentration of bilirubin in the blood (hyperbilirubinaemia). Discoloration of the sclerae occurs at lower concentrations of bilirubin than the skin.

The reference range of total bilirubin is 5 – 20 µmol/L. Scleral icterus (subicterus) occurs when the bilirubin level reaches approx 40 µmol/L, while generalised icterus occurs at approx 70 µmol/L.

We distinguish two types of hyperbilirubinaemia: unconjugated hyperbilirubinaemia, where the elevation in bilirubin is predominantly due to elevation in unconjugated bilirubin, and conjugated hyperbilirubinaemia.


There are many possible causes of hyperbilirubinaemia and jaundice, each of which can be classified according to the type and pathomechanism.

  • Prehepatic hyperbilirubinaemia
    • Due to increased bilirubin production (increased haemoglobin breakdown)
      • Haemolytic disorders (G6PD deficiency, sickle cell anaemia, etc.)
      • Dyserythropoiesis (thalassaemia, etc.)
      • Resolving (healing) haematoma or haemorrhage
    • Due to impaired hepatic uptake of bilirubin
      • Drugs
      • Heart failure
    • Impaired conjugation of bilirubin in the liver
      • Gilbert syndrome
      • Crigler-Najjar syndrome
      • Hepatitis
      • Cirrhosis
      • Wilson disease
      • Hyperthyroidism
  • Intrahepatic hyperbilirubinaemia
    • Hepatitis
    • Cirrhosis
    • Infiltrative diseases of the liver
  • Posthepatic hyperbilirubinaemia (cholestasis, obstructive jaundice)
    • Choledocholithiasis
    • Cholangitis
    • Tumour compressing the biliary tree (pancreatic head, biliary, gallbladder, liver)

Clinical features

Subicterus is usually the first sign of jaundice. If due to cholestasis, symptoms like pruritus, and fat malabsorption may occur. Other symptoms and findings of cholestasis depends on the type and etiology:

Type Color of stool Indirect bilirubin Direct bilirubin Bilirubin in urine Urinary urobilinogen Common cause
Prehepatic jaundice Dark Increased Normal Normal Increased Haemolytic conditions
Intrahepatic jaundice Pale, acholic Increased Increased Increased (dark urine) Normal or increased Cirrhosis
Posthepatic jaundice Pale, acholic Normal Increased Increased (dark urine) Absent Biliary obstruction


Further evaluation depends on the clinical and laboratory findings. AST and ALT are useful markers of hepatocellular injury, while ALP and GGT are markers of cholestasis.

If prehepatic jaundice is supected, the patient should be evaluated for haemolysis (LDH, haptoglobin, blood smear).

If intrahepatic jaundice is suspected, the patient should be evaluated for hepatitis, cirrhosis, and possible causes of them.

If posthepatic jaundice is suspected, the patient should be examined with ultrasound. If this shows signs of gallstone disease (dilated bile duct), an ERCP should be performed, which may remove the stone. If ultrasound shows signs of malignancy, a CT should be performed. ALP and GGT are also elevated in case of cholestasis.

Hepatitis A

Definition and epidemiology

Hepatitis A virus (HAV) is a picornavirus and an RNA virus.


Like hepatitis E, transmission is faecal-oral. Transmission usually occurs due to:

  • Contaminated food or water
  • Close personal contact
  • IV drug users
  • Blood exposure (rare)

For hepatitis, bowels are vowels. Those hepatitides who are vowels have faecal-oral transmission.

Clinical features

HAV causes mild and self-limiting acute hepatitis. It is usually asymptomatic in children, and generally mild if symptomatic in any age. The incubation period is approximately 30 days.

Symptoms include non-specific symptoms and jaundice. Around 30% of adults experience jaundice symptomatic, while < 5% of children do, although non-specific symptoms are more frequent.

Progression to acute liver failure is very rare and occurs mostly in those with underlying liver disease. HAV cannot cause chronic hepatitis, but cholestatic hepatitis or relapsing hepatitis can occur.

Diagnosis and evaluation

Typical laboratory features of viral hepatitis can be present in hepatitis A as well as the other viral hepatitides:

  • ESR low
  • WBC low
  • Lymphocytosis
  • AST and ALT > 8x the normal value
  • Mixed hyperbilirubinaemia
  • ALP normal

Diagnosis is based on serology. IgM anti-HAV shows acute infection while IgG anti-HAV shows immunity to HAV, either due to past infection or vaccination.


There is no specific treatment for HAV.


HAV can be prevented by vaccine. The vaccine is not part of the childhood vaccination programme, but is recommended for:

  • Travelers to intermediate and high HAV prevalence areas (tropics and subtropics)
  • Men having sex with men
  • IV drug users
  • Persons with chronic liver disease

The vaccine is also indicated as post-exposure prophylaxis if within 14 days of the exposure. If the exposed person is immunodeficient, anti-HAV immunoglobulin (passive immunization) should be given as well.

Proper food and water safety as well as hygiene is also important for prevention.

Hepatitis B

Definition and epidemiology

Hepatitis B virus is a DNA virus.

The virus consists of the so-called Dane particle and the coat and free particles. The Dane particle contains the virus core, the core antigen (HBcAg), and the e antigen (HBeAg). The coat and free particles contain the surface antigen (HBsAg).


HBV is very infective, 50 – 100 times more infective than HIV. Like hepatitis C and D, transmission usually occurs due to:

  • Parenteral
    • IV drug users
    • Health care personnel
  • Sexual (esp. men who have sex with men)
  • Perinatal

Clinical features

Hepatitis B can cause both acute and chronic hepatitis.

For acute hepatitis, about 30% of persons are asymptomatic. Symptomatic persons generally have jaundice and nonspecific symptoms like fatigue and anorexia.

Chronic hepatitis occurs more frequently in children than adults. It’s usually asymptomatic, but problematic because it can cause chronic liver disease and hepatocellular carcinoma.

Diagnosis and evaluation

Diagnosis is based on serology, including anti-HBs, anti-HBc, and anti-HBe, and detection of the two HBV antigens, HBeAg and HBsAg.

  • HBsAg – general marker of HBV infection
  • HBeAg – marker for infectiveness (indicates replicating virus)
  • HBV-DNA – marker for infectiveness (indicates replicating virus)
  • Anti-HBs – general marker of immunity
  • Anti-HBc IgM – marker of acute infection
  • Anti-HBc IgG – marker for past or chronic infection

In acute infection, HBsAg, HBeAg, and IgM anti-HBc are present. Seroconversion from HBsAg to anti-HBs indicates resolved infection.

In chronic infection, HBsAg and IgG anti-HBc are present.

In a vaccinated person, anti-HBs alone is present.


Acute hepatitis B requires no treatment.

Chronic hepatitis B is treated with pegylated interferon or nucleoside analogues like entecavir or tenofovir.


HBV can be prevented by vaccine. The vaccine is part of the childhood vaccination programme and is given right after birth (in Hungary) or at 3 months (in Norway). For those who were not vaccinated in childhood, the vaccine is recommended for those at high risk, like health care workers, and teenagers.

Passive immunization (HBIG) is used as post-exposure prophylaxis and must be given within 48 hours.

Hepatitis C

Definition and epidemiology

Hepatitis C virus a flavivirus and an RNA virus.


Like hepatitis B and D, transmission is parenteral, sexual, or perinatal. The most common route of transmission is IV drug use.

Clinical features

The incubation time is 6 – 7 weeks. Jaundice occurs in only 20%, 80% of patients are asymptomatic.

Chronic hepatitis occurs in 70% and is an important cause of cirrhosis and HCC.

Diagnosis and evaluation

Diagnosis can be made based on serology (anti-HCV) or HCV RNA by PCR. Anti-HCV appears 12 weeks after exposure, which is after the symptomatic period, so anti-HCV is used for screening of asymptomatic persons.

To diagnose HCV in symptomatic persons, HCV RNA should be measured instead.

Most patients are recognized in the chronic stage.


Both acute and chronic hepatitis C can be cured with direct-acting antivirals (DAAs), but people with acute HCV should be monitored for 12 – 16 weeks for whether they clear the infection themselves. If not, treatment is initiated.

Chronic hepatitis C is the most common cause for liver transplantation.

Hepatitis D


The hepatitis D virus is defective, as it lacks certain parts to function. Because of this, it can only cause infection when hepatitis B is also present, as the hepatitis D virus requires the hepatitis B surface antigen (HBsAg) for it to function.

Like hepatitis B and C, transmission is parenteral, sexual, or perinatal.

Clinical features

Coinfection with HBV causes more severe acute hepatitis or fulminant hepatitis, but no increased risk of chronic hepatitis.

Superinfection of a person with chronic HBV increases risk of cirrhosis and accelerates disease progression.

Diagnosis and evaluation

Diagnosis is based on serology. IgM anti-HDV indicates acute infection, while IgG anti-HDV indicates chronic infection.

Hepatitis E

Definition and epidemiology

Hepatitis E virus is a hepevirus and an RNA virus.

There are four genotypes. Types 1 and 2 are mostly found in the tropics and subtropics and cannot cause chronic hepatitis. They only infect humans.

Types 3 and 4 are found in animal reservoirs and can cause chronic hepatitis. These types are mostly present in Western countries.


Like hepatitis A, transmission is faecal-oral.

Transmission of types 1 and 2 usually occurs due to:

  • Contaminated food or water
  • Close personal contact
  • IV drug users
  • Blood exposure (rare)

Transmission of types 3 and 4 usually occurs with direct contact of or consumption of infected animals, so they’re zoonotic infections.

Clinical features

HEV causes self-limited acute hepatitis. The clinical features of HEV are similar to those of HAV, with one important exception. Subtypes 1 and 2 infection has a high mortality rate in pregnant women, around 25%.

Subtypes 3 and 4 can progress to chronic hepatitis, whereas subtypes 1 and 2 can’t. Subtype 3 has special extrahepatic manifestations, including neurological problems (neuralgic amyotrophy and GBS), glomerulonephritis, and pancreatitis.

Diagnosis and evaluation

Typical laboratory features of hepatitis can be present.

Diagnosis is based on serology. IgM anti-HEV shows acute infection while IgG anti-HEV shows immunity to HEV, either due to past infection or vaccination.


Acute hepatitis E is self-limiting and does not require treatment.

Chronic hepatitis E requires treatment. In case of an immunosuppressed patients, reducing the intensity of the immunosuppressive treatment may cure the chronic hepatitis. In other cases, a 3 month course of ribavirin is used.


There is a vaccine for hepatitis E called Hecolin, but it is not generally available. It’s only lisenced in China. Hygiene and food safety is important.

Miscellaneous hepatitis viruses

Three hepatitis viruses, TTV, SEN, and HGV, can not cause hepatitis by themselves but they can (probably) cause co-infection with hepatitis A – E.

2 thoughts on “65. Classification and differential diagnostics of jaundice. Acute and chronic viral hepatitis”

  1. “Diagnosis is based on serology. IgM anti-HEV shows acute infection while IgG anti-HEV shows immunity to HAV” Here you mean HEV.

    Also, regarding “There is no vaccine for hepatitis E.” There is a vaccine for Hepatitis E called Hecolin, although not really readily available. Nevertheless, it is recommended by WHO during outbreaks.

    Kind regards

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