Gastroenterology and Hepatology

Liver virology

Hepatitis B (HBV)

Introduction

    A mutation in the pre-core region will lead to failure to secrete HBeAg and the presence of HBeAb despite high HBV-DNA and evidence of chronic hepatitis. Usually HBeAb is a good sign, in these patients it isn't.

Aetiology

  • Hepatitis B is a highly infectious dsDNA virus
  • Infection is through Infected blood products, sharing needles, sexual intercourse, vertical transmission
  • Commonly found in Middle east, Asia, Africa
  • Mutations in HBV genome alter clinical expression

Virology

  • dsDNA + DNA polymerase.
  • Historically whole virus called Dane particle
  • Core HBcAg is not detectable in blood but can be found in the liver
  • Surface antigen HBsAg
  • e antigen HBeAg - suggests infectivity

Course

  • Chronic infection is seen in 10% of hepatitis B infections
  • Acute hepatitis is seen in 25% of those with HBV infection
  • Asymptomatic infection in 65% with formation of HBsAb

Acute Infection

  • Incubation period 2-6 months
  • 70 percent of patients with acute hepatitis B are subclinical
  • Jaundice, malaise, rash, small joint polyarthritis, distaste to cigarettes
  • Elevated ALT and AST
  • HBsAg +ve, IgM Anti -Hbc, No IgG Anti -Hbc, Possibly HBeAg and HBV-DNA

Supportive management

  • Recovery suggested by HBsAg negative and antibodies to HBsAg
  • Mortality < 1% with Fulminant liver failure
  • Serology for those recovered - Anti-HBsAg, IgG Anti-HBcAg, Possibly Anti-HBe Chronic Infection 10% (ALT > 6 months)
  • Chronicity less common with age. Vertically infected infants particularly at risk
  • HBsAg +ve, IgG Anti-Hbc, Possibly HBeAg, Possibly Anti-HBe, HBV-DNA positive
  • HBeAg and HBV-DNA denotes highly infectious and risks of cirrhosis and hepatocellular carcinoma
  • Treat those at risk of cirrhosis and malignancy

High risk

  • HBsAg surface antigen persists
  • HBeAg e antigen detectable unless mutant virus
  • HBV-DNA detectable
  • HBsAg seen as Ground glass appearance on H&E staining of hepatocyte

Prevention

  • Avoidance of needle sharing, prostitutes, unprotected sex particularly homosexual
  • Immunisation of high risk e.g. health care workers, addicts, dialysis patients
  • Active and passive immunisation to non immune needlestick injuries and babies of HBsAG positive mothers

Management

  • Pegylated Alpha-2b interferon 100 mcg once weekly s/c for 4 months. Flu like illness malaise, headaches. Disappearance of HBeAg in 40%. Less useful in those HBeAg negative. Useful in those with elevated ALT and AST. Not used in decompensated liver failure. Not for those with normal ALT or AST
  • Lamivudine 100 mg od 1 year : Inhibits DNA polymerase and reduces HBV-DNA, More useful in those who acquired Hepatitis B perinatally or in childhood. Used in those with decompensated disease, Used in those HBeAg negative
  • Adefovir dipivoxil 10 mg/day 1 year : Used to treat mutants which themselves cause a hepatitis
  • Liver transplantation is becoming more possible with the use of antivirals. In the past the new liver was reinfected with Hepatitis B.

    Hepatitis C

    Introduction

    • Viral infection causing a chronic viral hepatitis
    • May lead to cirrhosis and hepatocellular carcinoma

    Aetiology

    • Hepatitis C infection is due to a RNA flavivirus.
    • There are 6 genotypes with similar disease
    • Genotype 1 commoner in Europe is harder to treat
    • RNA virus - 6 genotypes (Genotype 1 responds least to treatment)
    • 80% go on to have chronic infection with abnormal LFT's
    • 30% get cirrhosis and 5% go on to develop Hepatocellular carcinoma

    Pathophysiology of Hepatitis C infection

    • Th1 response ? gamma interferon and interleukin 2 clears the virus
    • Th2 response ? interleukins 4,5,6,10,13 leads to chronic infection

    Virus from

    • Blood transfusion pre screening
    • Blood products pre screening
    • IV drug use
    • Maternal (vertical transmission)
    • Sex (uncommon)
    • Needlestick injuries in healthcare workers

    Clinical

    • Acute infection is very rare.
    • Chronic infection 80% ( inflammation after 6 months) - The infection is only symptomatic in 20% of carriers - acute infection may cause jaundice, fatigue, dark urine, abdominal pain, loss of appetite, nausea. Chronic infection presents with malaise and fatigue. Many however are picked up with screening for the virus after finding deranged LFTs

    Investigations

    • Hepatitis C RNA is first detectable marker measured with PCR.
    • There is usually a mild raised transaminases of 50-200. Types 2 and 3 do best.
    • Liver transaminases do not give a good guide to the degree of liver damage so biopsy is preferred in some cases.

    Cirrhosis is more common in these groups

    • Male sex
    • Alcohol
    • HIV
    • Older than 40 at time of infection
    • Hepatitis B
    • Immunosuppression Hepatitis C is associated with Sporadic Porphyria cutanea tarda
    • Arthritis
    • Glomerulonephritis
    • Diabetes
    • Sicca syndrome
    • Non Hodgkin's lymphoma
    • Lichen planus
    • Cryoglobulinaemia
    • Mooren's corneal ulcer
    • Idiopathic lung fibrosis

    Management

    • Pegylated alpha interferon + oral ribavirin. Treatment clears virus in about 50% - identified by a normal serum ALT and undetectable HCV RNA by the end of treatment
    • Ribavirin causes haemolytic anaemia in many patients and ribavirin is teratogenic. Ribavirin may cause haemolytic anaemia. Interferon can cause flu like symptoms and depression.
    • Liver transplantation may be carried out when advanced liver disease occurs with ascites but the new liver can be reinfected and cirrhosis can develop in the new liver.
    • There is no vaccine for HCV. Those more at risk to have progression of disease are males/immunosuppressed and with heavy alcohol intake. High risk groups are IV drug abusers and haemophiliacs. Also those at high risks of sexually acquired infections.
    • Chronic Hepatitis C infection related liver failure is the commonest cause for liver transplantation in the US
    • The response to treatment is assessed by using PCR to measure Hepatitis C virus RNA levels (it is an RNA virus). Successful treatment can be shown by a fall in ALT and evidence of reduced hepatic inflammation and fibrosis.
    • 50% respond to treatment within 6 months (a normal serum ALT and undetectable HCV RNA by the end of treatment) Genotype 1b responds poorly to treatment.
    • Indications for treatment with Pegylated alpha interferon is given s/c weekly and oral ribavirin.
      • Raised ALT
      • HCV-RNA present
      • inflammation on liver biopsy
    • There are 6 Genotypes and genotypes 2 and 3 do best with treatment and Genotype 1 does worst.

    PEG stands for polyethylene glycol - a water soluble polymer attached to the molecule and makes it longer acting. The aim is to prevent fibrosis and eradicate the HCV. There is a reduction in incidence of HCC

    Genotypes 1a and 1b are the most common in the US but also the least likely to respond to treatment

      Hepatitis B/D

      Introduction

      • Cause of hepatitis dependent on presence of HBV
      • Complications are as for HBV - cirrhosis and liver failure
      • Prevention of Hepatitis B effectively prevents hepatitis D
      • IV drug users

      Aetiology

      • is an RNA defective virus dependent on the presence of HBV.
      • An incomplete RNA virus within a shell of HBsAg
      • Can only replicate with Hepatitis B

      Clinical

      • Suspect in a flare up of Hepatitis B Investigations
      • IgM anti-D in blood
      • Serology can measure HDV Ag as well as HDV RNA by PCR

      Management

      • Treatment is supportive
      • Interferon may be used but effectiveness unknown

        Hepatocellular carcinoma (HCC)

        Introduction

        • Common worldwide liver tumour
        • Usually on a background of cirrhosis

        Risks

        • Risk of malignancy higher in Cirrhotic males (eg Males with PBC > Females with PBC) Risks of HCC higher with
        • Chronic Hepatitis B infection (not necessarily cirrhosis) - Elevated serum HBV DNA level is a strong prognostic indicator as well as HBeAg, serum ALT, and liver cirrhosis. There is a risk of 0.4% per year even without cirrhosis.
        • Chronic Hepatitis C related cirrhosis
        • Cirrhosis of any cause
        • Hereditary Haemochromatosis - up to 30% with cirrhosis develop HCC
        • Alpha-1 antitrypsin deficiency
        • Non alcoholic Steatohepatitis (NASH)
        • Dietary exposure to aflatoxin B1 from the fungi Aspergillus flavus and Aspergillus parasiticus
        • Androgenic steroids
        • COCP

        Clinical

        • Weight loss and cachexia and general deterioration in known cirrhotic
        • Ascites and abdominal pain Investigations
        • Elevated alpha-fetoprotein (AFP) in 70% of patients with HCC
        • Ultrasound is most commonly used as a screening test for HCC in high-risk patients e.g. HCV, HBV, HH, Alcohol, Males with PBC, Alpha-1 antitrypsin deficiency
        • Biopsy in selected cases

        Management

        • Tumours less than 3 cm may be resected, ablated or transplanted
        • Transarterial Embolisation is used
        • Chemotherapy has a limited use
        • Survival of less than 18 months