Viral Hepatitis

Hepatitis refers to inflammation of the liver and can be due to a number of causes.  Viruses cause around half of all cases of hepatitis.

Background

• Viral hepatitis is most commonly caused by Hepatitis A, B and C viruses
  • Other causes include Hepatitis D (associated with HBV) and E
    • Rarely cytomegalovirus, Epstein Barr virus, Adenovirus, HSV (very rare)

At risk patients

• Those from highly prevalent areas; injecting drug users; sex workers (take a sexual history); those who have been sexually assaulted, sustained a needlestick injury or are HIV positive
• At risk patients should be offered the first dose of HBV vaccine also
  • Injecting drug users and close contacts
  • Those with multiple sexual partners and sex workers
  • Those travelling to areas of high prevalence
  • Household contacts of those with HBV
  • Those receiving regular blood products
  • Those with occupational risk
  • Prison inmates and staff
  • Infants born to women with chronic HBV

Presentation

Different forms of acute hepatitis can be difficult to distinguish from each other by history/examination/LFTs alone.

• In all cases, the incubation phase of viral infection (varies between viruses) has no clinical features
  • In some cases, even in later stages of disease, patients may be asymptomatic (however, should have abnormalities of liver function)
    • up to 50% in HBV
• If any, symptoms can be vague.  Prodromal illness occurs in 10% in HBV; most patients with HAV
  • Fever (often mild), arthralgia and/or rash may appear around 2 weeks before any signs of jaundice, and may resolve when jaundice appears
  • Nausea and anorexia
• Symptoms/signs of acute disease- icteric phase
  • Nonspecific malaise (can be severe)
    • Often will put the patient off smoking/drinking
  • Jaundice
    • Pruritus
  • Pain/tenderness in the right upper quadrant
  • Hepatomegaly (85%)
  • Fulminant hepatitis is rare (<1%)
• Symptoms of chronic liver disease may develop with chronic infection or after an acute attack of fulminant hepatitis
  • Liver stigmata- spider naevi, finger clubbing, jaundice, hepatomegaly
  • In advanced cirrhosis- easy bruising, oedema/ascites, liver flap, encephalopathy (confusion), progressive weight loss, muscle wasting/weakness, jaundice

Generic Investigations (all viral hepatitis)

• LFTs-
  • In acute disease- ALT and AST are usually >1000 (ALT > AST typically)
  • In chronic disease- ALT and AST are only mildly elevated (<100IU/l)

Hepatitis A

Background

• Non-enveloped single-stranded RNA virus or heparnavirus (a picovirus)
• One of the more common causes of acute hepatitis worldwide- relatively rare in UK and incidence declining in the developed world (doesn’t cause chronic disease)
• Transmission
  • Faecal-oral route- can be shed in the faeces for 14-21 days before and 8 days after the onset/disappearance of jaundice
  • Travellers are at particular risk, as well as those at risk of blood borne disease (see HBV below)
• It has an incubation period of around 28-30 days during which the patient is usually asymptomatic
• Those with pre-existing liver disease (e.g. chronic HBV/HCV infection), and patients over the age of 50

Presentation

• Symptoms are quite classical of acute viral hepatitis
  • Incubation period of 2-6 weeks
  • prodromal illness (mild flu-like illness) of variable length (2 days to >2 weeks)
    • liver may be tender at this point but is rarely enlarged or painful at rest
  • Icteric phase
    • Jaundice occurs in 75-80% of patients, as does hepatomegaly
      • in 40% of patients with jaundice, pruritus is also a symptom
      • splenomegaly (15%) and lymphadenopathy (5%) can also occur
      • symptoms of prodromal illness typically resolve at this stage but patients may report fatigue lasting a few weeks
    • Abdominal pain is seen in 40%
    • Rash may develop (lower limbs; vasculitic)
  • Complete recovery may take several months but hepatitis A is a self-limiting disease that should resolve itself.
    • Last symptoms to resolve are usually anorexia, malaise and weakness (even after resolution of liver function)

Investigations specific for Hep A- serology

• IgM antibody to HAV is positive with onset of symptoms (around 4-weeks post-exposure)
  • Sensitive and specific (i.e. if not positive- diagnosis unlikely and vice versa)
  • It remains positive for 3-6 months after acute disease and can remain elevated in relapsing disease
• IgG antibody to HAV appears soon after IgM and remains present for years (indicates past infection)

Management

• Mainly supportive (fluids if necessary; antiemetics; rest)
  • If there is systemic upset, admission may be suitable
  • monitor liver function and clotting at least once a week (twice if jaundice)
• Avoid alcohol

Complications

• Relapse (15%)- 4-15 weeks after
• Cholestasis – may cause severe pruritus, diarrhoea, weight loss/malabsorption (full recovery is common)
• Fulminant liver failure- may present irritable, insomnia, confused, severe vomiting; high mortality

Hepatitis B

Background

• Hep B is an enveloped DNA virus consisting of core antigen surrounded by surface antigen.  It replicates via reverse transcription.
  • There are 8 different genotypes (vary in geographical distribution and response to treatments)
• It is transmitted by
  • blood-blood contact (needle sharing- illicit drug use; occupational hazard in medicine; blood transfusions- not in UK but elsewhere; tattoos/piercing using non-sterile equipment)
  • sexual transmission
  • mother-baby (less common with immunisation programmes)
  • NB NOT transmitted by sharing of toiletries/household products
• Acute Hep B disease is notifiable; Chronic disease is not
• HBV has an incubation period of around 60-90 days

When to Investigate

• HBV screening should be offered to at risk individuals
  • Routinely offered to pregnant women (antenatal screen)
  • The HBV vaccine should also be considered for such patients
• Patients with a raised ALT/AST >1000IU/l

Presentations

• Up to 50% of patients with acute HBV remain asymptomatic
• less than half of adults (30%) and only 10% of children present with jaundice
• Can present as a serum sickness-like prodromal illness in 10%
• Symptoms/signs are often less well-defined than HBA
• Extrahepatic manifestations of acute/chronic HBV may help aid the diagnosis
  • Thought to be due to circulating immune complexes
  • Polyarteritis nodosa (fever, rash, hypertension, eosinophilia, abdo pain, renal disease, polyarthritis)
  • Papular acrodermatitis (rare but characteristic rash affecting children- flat erythematous papular eruptions affecting face and extremities)
  • Membranous glomerulonephritis (rare presenting with proteinuria and nephrotic syndrome)

HBV Serology

• HBV surface antigen (HBsAg) is first to rise (during incubation period- undetectable in 10% of patients by the time the test is performed)
  • Usually the first test done
• HBV e-antigen (HBeAg) and HBV-DNA are detectable around the same time/shortly after
  • Disappearance of HBeAg/HBV-DNA and development of anti-HBe predicts resolution of acute disease
    • HBeAg is correlated roughly with infectivity
  • Persistence indicates possible progression to chronic disease
• IgM anti HBc is the first antibody to arise after infection- indicates infection within last 6 months
  • It appears within 1 month of HBsAg and 1-2 weeks before a rise in ALT
  • Distinguishes acute disease from exacerbations of chronic disease (replaced by IgG anti HBc which persists for life and indicates previous disease)
• Anti-HBs without anti-HBc is a marker of immunisation

Management

• Acute disease
  • Management of acute disease is usually supportive
    • Fluid resuscitation where appropriate; antiemetics
    • Antivirals are not usually recommended
• Chronic disease
  • HBeAg positive or negative with compensated liver disease
    • Offer 48-week course of PEG-interferon alfa-2a
      • tenofovir disoproxil is second line (or if pregnant in 3rd trimester)
• Prophylactic treatment during immunosuppressive therapy
  • HBsAb positive patients with a HBV-DNA >2000 IU/ml should be offered tenofovir/entecavir before starting immunosuppression treatment
• Monitoring chronic disease in those not suitable for treatment
  • Monitor ALT every 24 weeks in those HBeAg positive disease with active viral replication (HBV-DNA >2000IU/ml) (and previous ALT <30IU/ml in males or <19IU/ml in females)
  • Monitor ALT every 12 weeks if ALT rises
  • Monitor ALT every 48 weeks in HBeAg negative disease

Complications

• Hepatitis B can be chronic (HBsAg present for >6 months).  This may be inactive disease (carrier state) or may progress to fibrosis, cirrhosis (20% of chronic HBV infections) and carcinoma.  Progression is thought to correlate with levels of HBV DNA levels in the blood.
  • Chronic Hep B occurs in 90% of babies born with HBV, between 10-20% of children affected in later childhood and around 5% infected as adults

Hepatitis C

Background

• Enveloped RNA virus of Flaviviridae family
  • there are 6 major genotypes
    • type 1 and 3 are most common in the UK and is also most resistant to treatment
    • type 2 makes up the majority of remaining cases
    • types 4-6 are uncommon
    • NB patients can be infected with multiple types
• The majority of HCV is transmitted via blood-blood contact
  • IV drug users; blood products; occupational risk; endemic areas etc
  • It is rarely transmitted sexually (most cases of sexual transmission have been men with HIV having sex with men)
  • Vertical transmission is also seen
• Chronic disease is common (75%) in patients with HCV; the remainder clear the virus successfully
• There is no immunisation for HCV

Presentation 

• Like HBV, symptoms are uncommon and, if present, are rarely specific or severe
  • Flu-like prodromal illness (nausea, vomiting, mild fever)
  • Pain in the upper right quadrant
  • Jaundice is rare (20%)
  • Malaise and arthralgia can occur in chronic disease

Who to screen?

• Abnormal LFTs (as before) or unexplained jaundice
• At risk individuals- particularly IV drug users (past or present); those who have received organ donations (particularly prior to 1992)/people donating organs; children born to women found to have HCV; health care workers who perform invasive/exposure-prone procedures or who have had a needlestick injury; people on dialysis; sexual partners of those infected; people with HIV/HBV etc

How to screen?

• HCV antibody (take sample in unpreserved (clotted) blood sample tube)
  • If positive- patient has or has had HCV
    • Investigate HCV RNA levels if positive
      • If positive, patient has active (usually chronic) HCV infection
  • If negative, consider repeating the test (within a window of 3-6 months post-exposure)
    • Confirmation of NOT having chronic Hep C
      • negative HepC Ab test and have not been exposed in the last 6 months
      • 2 negative HepC Ab tests, 6 months apart
      • If positive Ab test, but 2 negative RNA tests 6 months apart (past infection cleared)

Management

• Genotyping and viral load are important investigations prior to treatment
• Drug treatment should be offered to all patients with active chronic Hep C
  • Combination of weekly PEG-interferon alfa and daily ribovarin
    • for types 1, 4, 5 and 6- take for 48 weeks (sustained viral response of 40-50%)
    • for types 2 and 3- take for 24 weeks (better response at 75-80%)
    • NB stop treatment after 12 weeks if viral load has not reduced 100-fold

Complications/Prognosis

• Unfortunately, most patients with active chronic HCV will develop cirrhosis over 20-40 years
  • 5% of these will develop a life-threatening event e.g. liver failure or carcinoma)
    • Regular monitoring of alfa-fetoprotein for hepatocellular carcinoma should be offered in these patients
• Alcohol, age, smoking, co-infection etc can all increase the rate of disease progression

Adverse side effects of treatment

• Flu-like symptoms
  • can be managed conservatively with rest/paracetamol/ibuprofen etc
• Anaemia
  • Common and should be monitored regularly
  • The use of erythropoeitin may be considered
• Worsening mental health disorders
  • May require specialist intervention/management
• Skin reactions- particularly dermatitis
• Hypothyroidism
• Alopecia
• Insomnia
• Weight loss

Hepatitis D

• Requires coinfection of HBV
• Generally considered a ‘superinfection’- causing more severe symptoms than just HBV alone
  • progression to chronic disease also more common (80% cf 15-20%)
• Can be diagnosed with serology for HDV-antibody
• Treatment is limited (antiviral treatment is relatively ineffective)

Hepatitis E

• Similar presentation and progression as HAV infection
  • faecal oral route of transmission
    • contaminated water is the most common source
    • indian subcontinent is the most commonly affected region
• Treatment is as for HAV