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Key Concepts

  • Clinical features of viral hepatitis
  • Liver function tests
  • Diagnosis of viral hepatitis
  • Treatment of HCV infection

Case

Martin, a 34 year mathematician has been feeling tired and unwell over the last few weeks. He has recently returned from overseas after trekking in the Himalaya's, Nepal. He decides to visit his doctor, as he has noticed his urine is very dark, he feels nauseated and cannot bring himself to eat. He has also noticed right sided abdominal discomfort. Martin has a history of intravenous drug use. On examination he appears a little jaundice, has yellow sclerae and is tender in the upper right quadrant of his abdomen. The doctor requests liver function tests.

Question 1

What liver function tests are normally performed?

AST :10-40 IU/l (these are the normal values) ALT: 5-30IU/l ALP:25-115 Bilirubin (direct): 0-0.3mg/dl TOTAL Bilirubin (indirect): 0.3-1.9mg/dl

Question 2

The results of the liver function tests were:

AST, 900 IU/L; ALT, 600 IU/L; ALP, 100 IU/L; Bilirubin, 15mg/dl

What can you conclude from these results?

They are all elevated. There is obviously something wrong with the liver – hepatitis.

Question 3

What is the most likely diagnosis and what is the differential diagnosis.

From his circumstances you would say that it is viral hepatitis. Most common are hepatitis A, B, C, D, E, CMV and EBV.

Question 4

What specimens would you collect and what tests would you request in the first instance?

You would collect a blood sample. In the blood you would look for antibodies, antigens and viral DNA/RNA. You would order an EIA for the antigens or antibodies. You may also order a PCR for virus genome, but this is more expensive.


Question 5

Ask your tutor for the results and interpret them, (see Table 1, Appendix)

Note that the following are not all the tests available but they are the ones commonly ordered. Note that after getting these results, follow-up tests are often ordered)

  • HBV:
    • HbsAg (-) (surface antibodies) This is first thing to appear in the blood for hep B.
    • Anti-HBs (+) (he is positive for this but not the others because he was probably vaccinated and this uses only the surface antigens)
    • Anti-HBc IgM (-)(first antibody to show up and says acute)
    • Anti-HBc IgG (-) (appears later and indicates chronic or previous infection)
    • HbeAg (-) (core antibodies) (only shows up in actively replicating viruses)
  • HCV: EIA (Ag or Ab), RNA (PCR): Antibodies (+) (most common for HCV is antibodies) (since it is positive, he likely has HCV)
  • HEV: IgM (-) (because HEV doesn't turn chronic. Same for HAV)
  • HAV: IgM (-)
  • CMV:IgG (+), IgM (-) (positive IgG but negative IgM indicates previous infection that has cleared)
  • EBV:IgG (+), IgM (-) (IgG Avidity=94%) (avidity is how well it binds to the antigen; it goes up over time) (this indicates that he had EBV in the past)

Question 6

What other tests would you request based on these test results? (see Table 2, Appendix) You would do a test for HCV RNA using PCR.

You can do two types of PCR:

  • You can just test for presence of RNA
  • You can do quantitative PCR, which uses a dye to measure the viral load by measuring how much RNA there is in the sample. The higher the viral load the harder it is to treat the pt. It also tells us the state of the pt – acute infection tends to have a higher viral load than chronic.

Question 7

How would you manage this case?

You would tell the pt to reduce alcohol intake and advise them about risky behavior (e.g. injecting drug user). You would also vaccinate against Hep A and Hep B because of their high risk behavior.

Question 8

What are the treatment options, considerations and duration?

Interferon (IFN); ribavirin (antiviral). The exact mechanism of these two agents is not exactly known. The accepted is that ribavirin is likely to be a nucleotide analogue (i.e. they act like a nucleotide and stop the virus from making more of its genome.

These treatments have a lot of side effects. Their effectiveness also depends on the viral genotype (there are 6 different genotypes for Hep C with further variation with subtypes A, B, etc). Different genotypes respond differently to different genotypes. The most common genotype (genotype 1) is less likely to be cleared by these treatments. So if a pt has Hep C the next thing you want to know is what genotype it is. Genotype 1 accounts for about 50% of cases and is the most common worldwide.

Genotype 3 is the second most common (about 30% of cases), in Australia.

A lot of pts clear the virus themselves.

So you would need to weigh up the different factors before deciding on treatment.

Genotype 2/3 is treated for 24 weeks whereas genotype 1 is treated for about 48 weeks.

Factors that affect treatment include age, whether there is fibrosis, viral load etc. People less than 40 years old are more likely to be more responsive. Same for people with a lower viral load and/or no fibrosis. Females are also more likely to be responsive than males.

Appendices

Table 1. Interpretation of HBV diagnostic tests

HMBVirusTut1.png

Table 2. Interpretation of hepatitis C virus RNA testing in anti-HCV-positive patients

ALT Concentration HCV RNA Result Interpretation
Normal Positive Patient is infected, with undetectable liver disease
Normal Negative
  • False-positive anti-HCV: Spontaneous viral clearance
  • False negative HCV RNA: Dormant infection with no or minimal liver disease
Elevated Positive Infected with active liver disease
Elevated Negative
  • False-positive: Spontaneous viral clearance
  • False negative HCV RNA


N.B.

Negative HCV RNA by PCR assays indicate viral clearance from serum, but give no information about the state of HCV in the liver or in other privileged niches (e.g., lymphocytes). Thus, given the current state of knowledge complete viral clearance cannot be ascertained with certainty. Therefore, patients who are anti-HCV-positive who have spontaneously developed negative HCV RNA by PCR should continue to be monitored at intervals for the presence of liver disease.

Figure 1

HMBVirusTut2.png

Results

HBV

HBV surface antigen (HBsAg) negative
Anti-HBs positive
Anti-HB core IgM negative
Anti-HB core (IgM and IgG) negative
HBeAg – a marker of active infection negative

Other

EIA for HEV IgM negative
EIA for HAV IgM negative
EIA for HCV antibodies positive (large window period, if negative consider PCR assay)
CMV IgG positive, IgM negative
EBV IgG positive, IgM negative, avidity 94%