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THE INVESTIGATION OF HEPATITIS

Initial laboratory investigations

LFT =AST, ALT, GGT, AP, LDH, 
bilirubin, albumin, protein (total)
Urinalysis
FBC
PT 


Cannot distinguish different types of viral 
hepatitis by clinical features or routine laboratory tests. Because of different clinical outcomes and treatment options available, it is imperative that the correct aetiological diagnosis be made using various serological assays and specific laboratory measurements.

Acute

 

Causes

Specific laboratory tests

Hepatitis A virus infection 

Hepatitis A serology 

Hepatitis B virus infection

Hepatitis B serology, especially hepatitis B core IgM

Hepatitis C virus infection

Hepatitis C serology and hepatitis C PCR, 
if hepatitis C antibody is not detectable

Hepatitis D virus infection

Hepatitis B surface antigen - if positive, then test specifically for Hepatitis D antibodies

Hepatitis E virus infection 

Hepatitis E antibodies

Hepatitis G virus infection 

Hepatitis G PCR

Infectious mononucleosis 

" Paul-Bunnell" test Specific EBV serology

Cytomegalovirus infection

CMV serology
Virus detection by culture or PCR
in urine, buffy coat may rarely be required

Leptospirosis 

Leptospira serology. For culture, consult pathologist

Q fever
Alcoholic hepatitis 

Q fever (Coxiella burnettii) serology Diagnosis is based on clinical assessment. Blood ethanol levels are helpful in detecting recent alcohol ingestion. In chronic alcoholism, macrocytosis, thrombocytopenia, prolonged PT, elevated GGT, urate or triglycerides may be found. The most reliable indicator of chronic excessive alcohol ingestion is carbohydrate-deficient transferrin (CDT).
An AST/ALT ratio of >1 suggests liver disease is due to alcohol.  Protein electrophoresis may assist in establishing chronicity.  Liver biopsy, if hepatomegaly is present. 

Drugs e.g. paracetamol flucloxacillin 
amoxicillin/clavulanate anabolic steroids 
isoniazid anticonvulsants esp. valproate
NSAID halothane 

Requires a detailed drug history 

Hepatic ischaemia 

Liver biopsy

Chronic

AST, ALT, ALP, GGT, total protein, albumin (LFT).  Elevated serum immunoglobulins (IgG, IgA) and beta-gamma bridging on protein electrophoresis support the diagnosis of chronic hepatitis. Serum immunoglobulins (G, A, M) or protein electrophoresis are also useful to distinguish the various causes of chronic hepatitis. A markedly raised IgM supports the diagnosis of primary biliary cirrhosis. The severity (grade) and degree of fibrosis (stage) are determined on liver biopsy. 

 

Causes

Specific laboratory tests

Hepatitis B virus infection 

Hepatitis B serology - a positive test for hepatitis B surface antibody and core antibody indicates the presence of immunity to hepatitis B, and another cause for the elevated amino-transferase levels should be sought. A positive test for hepatitis B surface antigen and core antibody indicates the presence of infection
Tests to determine whether there is viral replication, including serologic tests for hepatitis B e antigen, hepatitis B e antibody, and hepatitis B virus DNA , should be undertaken. 
In patients with positive tests for hepatitis B virus DNA and hepatitis B e antigen, liver biopsy and treatment should be considered. 

Hepatitis D virus infection 

Hepatitis B surface antigen - if positive, then test specifically for Hepatitis D antibodies

Hepatitis C virus infection 

Hepatitis C serology - if positive, the result will confirm with the hepatitis C PCR assay.
Hepatitis C viral load is necessary if therapy is indicated - baseline and follow-up levels.
Hepatitis C genotyping may be necessary. Liver biopsy may be indicated. 
Alpha fetoprotein monitoring for detection of hepatocellular carcinoma. 

Hepatitis G virus infection 

Hepatitis G PCR

Autoimmune hepatitis

Smooth muscle, mitochondrial, and liver/kidney microsomal antibodies. ANF. 
Serum protein electrophoresis
A liver biopsy is essential to confirm the diagnosis.

Alcoholic hepatitis 

Liver function tests
Carbohydrate deficient transferrin (CDT) - the most reliable indicator of chronic excessive alcohol ingestion 
Protein electrophoresis may assist in establishing chronicity.  Liver biopsy , if indicated.


The diagnosis is supported by the finding of a ratio of AST:ALT of at least 2:1. The degree of elevation of aminotransfer-ase levels may also be helpful in identifying alcohol abuse. It is rare for the AST level to be more than eight times the normal value in patients with alcohol abuse, and it is even less common for the ALT level to be more than five times the normal value in such patients. In fact, the ALT level may be normal, even in patients with severe alcoholic liver disease.
Measurement of GGT may also be helpful in diagnosing alcohol abuse. A GGT level that is twice the normal level in patients with an AST:ALT ratio of at least 2:1 strongly suggests the diagnosis of alcohol abuse. However, the lack of specificity of the GGT level precludes its use as a single test to diagnose alcohol abuse.

In chronic alcoholism, macrocytosis, thrombocytopenia, prolonged PT, elevated GGT, urate or triglycerides may be found. 

Nonalcoholic steatohepatitis 

No history of alcohol abuse. Presence of risk factors e.g. obesity, TPN, drugs such as amiodarone and methotrexate, dyslipidaemia. 2 - 3 fold elevation of AST and ALT with ALT activity higher than AST.
Liver biospsy

Medication 

  • nonsteroidal antinflammatory drugs
  • antibiotics 
  • antiepileptic drugs
  • antituberculosis drugs. 

A careful history-taking and meticulous review of laboratory data are critical for identifying a medication as the cause of elevated aminotransferase levels

The easiest way to determine whether a
medication is responsible for the elevation is to stop treatment and see whether the test results return to normal.

Haemochromatosis 

Iron studies
Liver biopsy


Hereditary hemochromatosis is a common 
genetic disorder. Cost-effective screening starts with the measurement of serum iron and total iron-binding capacity. A transferrin saturation value (obtained by dividing the serum iron level by the total iron-binding capacity) of more than 45 percent is suggestive of hemochromatosis. Measurement of serum ferritin provides less specific information, because it is an acute-phase reactant. 
If screening tests suggest the presence of iron overload, a liver biopsy should be performed to assess hepatic iron levels and the severity of liver damage. A hepatic iron index (the hepatic iron level in micromoles per gram of dry weight divided by the patient's age) of more than 1.9 is consistent with the presence of homozygous hereditary hemochromatosis.

Genetic testing is now available to identify the mutation in the hemochromatosis (HFE) gene that causes the majority of cases.

A liver biopsy is not necessary for patients with hereditary hemochromatosis who are younger than 40 years of age and who have normal liver function.

Wilson's disease

Serum copper, caeruloplasmin 24 hour urine copper levels Liver biopsy, to confirm the diagnosis.

Wilson's disease, a genetic disorder of 
biliary copper excretion, may cause elevated aminotransferase levels in patients with no other symptoms of the disease. The clinical onset is usually between the ages of 5 and 25 years, but the diagnosis should be considered in patients up to the age of 40 years. 
The initial screening test for Wilson's disease is measurement of serum ceruloplasmin. The levels will be reduced in approximately 85 percent of affected patients. Patients should also be examined by an ophthalmologist for Kayser-Fleischer rings. 

If the ceruloplasmin level is normal and Kayser-Fleischer rings are absent, but the physician still suspects that Wilson's disease may be present, the next test is a 24-hour urine collection for a quantitative assessment of copper excretion. Excretion of more than 100 ug of copper per day is suggestive of Wilson's disease. The diagnosis is usually confirmed by liver biopsy to measure hepatic copper levels.
Patients with Wilson's disease have hepatic copper levels of more than 250 ug per gram of liver, dry weight. 

Primary biliary cirrhosis

Mitochondrial antibodies

Granulomatous 

Diagnosis requires liver biopsy. 

Causes

Specific laboratory tests

Idiopathic 

 

Sarcoidosis

Angiotensin converting enzyme 
(ACE/SACE)
Liver biopsy, to confirm the diagnosis.

Drugs e.g. allopurinol 

Requires a detailed drug history

Infection e.g. Q fever. brucellosis

Q fever ( Coxiella burnettii ) serology Brucella antibodies Blood cultures - alert the laboratory Liver biopsy for histology and bacterial culture

Tuberculosis 

Tuberculin skin test (Mantoux) may be helpful in assessing the risk of active infection, but a negative test may be present in active disease e.g. miliary tuberculosis. Liver biopsy for histology and mycobacterial culture

Hodgkin�s disease

Liver biopsy for histology

 

REFERENCES

  1. Viral hepatitis. S Afr Med J 1994; 84 (8): 523 - 583
  2. Krawitt EL. Autoimmune hepatitis. NEJM 1996; 334: 897 - 903
  3. Lee WM. Hepatitis B virus infection. NEJM 1997; 337: 1733 - 1745
  4. Walsh K Alexander GJ. Update on chronic viral hepatitis. Postgrad Med J 2001; 77 (910): 498 - 5005
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