Overview Table

Overview of the 5 Viral Hepatitides

Feature	Hep A (HAV)	Hep B (HBV)	Hep C (HCV)	Hep D (HDV)	Hep E (HEV)
Virus type	RNA	DNA	RNA	RNA	RNA
Transmission	Faeco-oral (e.g. contaminated water, shellfish, MSM)	Parenteral (e.g. blood to blood, sexual, vertical transmission)	Parenteral (e.g. blood to blood, vertical transmission)	Requires Hep B infection (co-infection / superinfection)	Faeco-oral (e.g. contaminated water, pork, shellfish)
Clinical presentation	Acute hepatitis (self-limiting)	Chronic hepatitis	Chronic hepatitis	Acute hepatitis (co-infection) or worsening of pre-existing chronic liver disease (superinfection)	Acute hepatitis (usually self-limiting but severe in pregnancy)
Cancer risk	None	Hepatocellular carcinoma		Hepatocellular carcinoma (via HBV)	None
Treatment	Supportive care only	Antivirals (non-curative) (e.g. Tenofovir, Entecavir)	Direct-acting antivirals (curative) (e.g. sofosbuvir, glecaprevir)	Treat underlying hep B	Supportive care (ribavirin in severe cases)
Vaccine Available	Yes		No

Hepatitis A

Aetiology

Hepatitis A virus is a non-enveloped, single-stranded RNA virus.

 

Hepatitis A is primarily transmitted via the faecal-oral route

• Consumption of contaminated water
• Consumption of contaminated food (esp. raw or undercooked shellfish, fruits, and vegetables from endemic regions)
• Sexual contact involving oral-anal exposure (GBMSM is a major risk factor)

 

Risk factors for acquiring hepatitis A:

• Poor personal hygiene (esp. after using the toilet)
  • <5 y/o are key spreaders of hepatitis A (as they often have asymptomatic or mild infections and they have poor hygiene and toileting habits)
  • Therefore, people who work in childcare / nursey settings are at increased risk
• GBMSM
• Travel to endemic areas / poor sanitation areas
• Close contact with Hepatitis A patients
• People who use drugs (both injection/non-injection drugs)
• Homelessness (due to poor sanitation and crowding)
• Not vaccinated

Clinical Features

Incubation period: 15-50 days (average 28 days)

 

Hepatitis A typically causes acute viral hepatitis

Prodromal phase (~1 week)	Abrupt onset of: Fever Malaise Anorexia Nausea and vomiting Abdominal discomfort (often RUQ)
Icteric phase (2-4 weeks)	RUQ tenderness Hepatomegaly Cholestasis features Jaundice Pale stools and dark urine Pruritus Resolution of prodromal systemic symptoms (patients tend to feel better once jaundice develops)

Prognosis

Hepatitis A is typically self-limiting, with most cases resolving completely within 2 months

• Rarely, severe fulminant hepatitis A can occur (most likely in those with pre-existing liver disease and older age)

 

Hepatitis A does NOT cause chronic hepatitis

Investigation and Diagnosis

Serology (primary diagnostic marker)	+ve Anti-HAV IgM is the definitive serological marker for acute hepatitis A   +ve Anti-HAV IgG alone represents past infection or vaccination IgG is often +ve in acute hepatitis A as well, but is NOT required for diagnosis
LFTs	Acute hepatitis gives a hepatocellular injury pattern on LFTs: ↑ AST and ALT Often >1,000 IU/L AST:ALT ratio <1 ALT:LDH ratio >1.5 Normal / mildly raised ALP and GGT ↑ Bilirubin (during the icteric phase)
Imaging	Imaging has a limited role in the diagnosis of hepatitis A: Ultrasound or other imaging modalities are not routinely required, but may be used to exclude other causes of liver disease or complications if clinically indicated

Management

Management of Patient

Hepatitis A is generally self-limiting and only requires supportive care

• Advise the patient to maintain adequate hydration and nutrition
• Avoid alcohol and hepatotoxic drugs during illness
• Exclusion from work / school / nursery until 7 days after onset of jaundice (or 7 days after symptom onset, if there is no jaundice)

Management of Close Contacts

General Advice

Provide advice on good hygiene:

• In particular, careful hand washing after using the toilet (cornerstone of preventing ongoing transmission)
• Contacts whose personal hygiene is likely to be inadequate (e.g. young children, those with severe learning disabilities) should be supervised to ensure
  that they wash their hands properly after defecation
• Those caring for non-toilet-trained children should wash their hands immediately after nappy changing or toileting

 

Provide advice for those at risk of sexual transmission (e.g. GBMSM)

• Wash hands, buttocks, groin, and penis thoroughly after sex
• Use barrier protection (condoms, dental dams, gloves) for any sexual activities including oral-anal contact
• Change condoms between anal and oral sex to prevent faeco-oral transmission

Post-Exposure Prophylaxis (PEP)

The following patients do NOT need PEP (vaccine / immunoglobulin):

• Patients who are immune
  • Previous hepatitis A infection
  • Complete course of hepatitis A vaccine in the past 10 years (2 monovalent doses or equivalent)
  • 1 dose of monovalent vaccine within the past 12 months
• Healthy <12 m/o (if not attending childcare and if all those involved in nappy changing are immunised)

 

If patients do not fall under the above exclusion criteria for PEP, they would require PEP:

Hepatitis A vaccine (single dose)	Household members Sexual contacts Childcare-related contacts (person involved in nappy changing / toileting)
Hepatitis A vaccine + human immunoglobulin	≥60 y/o Patients with chronic liver disease / with pre-existing chronic hepatitis B or C Immunosuppression

Prevention – Hepatitis A Vaccination

Hepatitis A is an inactivated vaccine, available as a monovalent (Hep A only) vaccine or in combination with Hep B or typhoid.

• A completed course of hepatitis A vaccine (2 / 3 doses, depending on the vaccine) is effective at preventing hepatitis A infection in up to 95% of recipients

 

Indications for hepatitis A vaccination:

• People who are travelling to or going to reside in endemic areas
• Chronic liver disease
• Haemophilia
• GBMSM
• People who inject drugs
• People who are at occupational risks

References

Hepatitis B

Aetiology

Hepatitis B is an enveloped, double-stranded DNA virus

• Although it is a DNA virus, it behaves like a retrovirus during replication (via an RNA intermediate using reverse transcriptase)

 

Hepatitis B is primarily transmitted via the parenteral route

• Blood-to-blood
  • Recipient of blood transfusions / blood-derived products before 1972 (there was no routine donor screening for HBsAg before 1972 in the UK) or in countries that do not perform screening
  • IVDU (sharing or using contaminated equipment)
  • Needle stick or other sharps injuries (esp. in healthcare workers)
  • Tattooing and body piercing (using non-sterile equipment)
• Sexual transmission (via semen / vaginal fluids contacting mucosa microtears)
• Vertical transmission (baby is exposed to maternal blood and genital secretions during labour)

Clinical Features

Incubation period: 40-160 days (average 12 weeks)

 

Course of hepatitis B infection

• Most adults who acquire hepatitis B develop an acute, self-limiting hepatitis
• However, in some cases, the infection fails to clear (persists for >6 months) and becomes chronic hepatitis B

Acute Hepatitis B

Children rarely develop acute symptomatic hepatitis B infection.

 

1/3 of adults are symptomatic during the acute stage of infection (non-specific symptoms):

• Flu-like illness
• Nausea / vomiting
• Arthralgia
• Abdominal pain (esp. RUQ)
• Jaundice

 

Acute hepatitis B is usually mild and self-limiting, there is a very rare risk (<1%) of progression into severe/fulminant hepatitis.

Chronic Hepatitis B

Definition of chronic hepatitis B: virus persisting for >6 months (objectively defined as +ve HbsAg persisting >6 months)

 

The younger the patient when infected, the higher the risk of developing chronic hepatitis B: ^[Ref]

• Risk is highest in infants (>90%)
• Risk is 20-50% in children (1-5 y/o)
• Risk is lowest in adults (<5%)

 

Chronic hepatitis B is usually asymptomatic or presents with non-specific symptoms (e.g. fatigue)

• Chronic hepatitis B often remains undiagnosed until complications develop (see below)
• However, the person remains infectious (as the virus persists in the body)

Complications

Complications of chronic hepatitis B and C are somewhat similar, therefore are presented together: ^[Ref1][Ref2]

	Chronic hepatitis B	Chronic hepatitis C
Hepatic complication	Cirrhosis HCC HCC can arise in the absence of cirrhosis in hepatitis B (as hep B has direct oncogenic effect due to viral integration into host genome) HCC in hepatitis C almost always arises in the context of cirrhosis or advanced fibrosis
Extra-hepatic complication / association	Polyarteritis nodosa Membranous nephropathy Lichen planus	3 most common comorbidities: Depression Diabetes CKD Other: Mixed cryoglobulinaemia Membranoproliferative glomerulonephritis Lichen planus Porphyria cutanea tarda

Investigation and Diagnosis

Work-Up

HBsAg  is the standard initial screening test for hepatitis B (as it detects both acute and chronic infection – see interpretation section below for more information)

 

If HBsAg is +ve, perform the following tests / investigations:

• Liver biochemistry (LFTs, serum albumin, total bilirubin, total globulins, FBC, prothrombin time)
• Full hepatitis B serology (anti-HBc IgM, HBeAg / anti-HBe)
• HBV DNA level (viral load) – used to monitor disease activity and response
• Testing for other viral hepatitides (hepatitis A, C, D) (testing for hepatitis D is important as it requires hepatitis B infection for its life cycle)
• HIV antibodies
• Testing for hepatocellular carcinoma (hepatic ultrasound + AFP testing)
  • Ongoing testing: 6-monthly hepatic ultrasound + AFP (in those with significant fibrosis / cirrhosis)
• Testing for cirrhosis
  • Initial test: transient elastography (e.g. FibroScan)
  • Liver biopsy should only be considered in selected patients if the transient elastography score is <11 kPa

LFTs

Acute hepatitis B gives a hepatocellular injury pattern on LFTs (similar to other causes of acute viral hepatitis):

• ↑ AST and ALT
  • Often >1,000 IU/L
  • AST:ALT ratio <1
  • ALT:LDH ratio >1.5
• Normal / mildly raised ALP and GGT
• ↑ Bilirubin (during the icteric phase)

 

However, LFTs are typically normal in chronic hepatitis B

• An isolated mildly elevated AST/ALT level may be seen

Serology Interpretation

Diagnosis of hepatitis B is made by serological testing for specific hepatitis B antigens and antibodies

Key interpretations:

	HBsAg	Anti-HBs	Anti-HBc IgM	Anti-HBc IgG
Acute infection	+ve	-ve	+ve	+ve
Chronic infection	+ve	-ve	-ve	+ve
Natural resolution	-ve	+ve	-ve	+ve
HBV vaccination	-ve	+ve	-ve	-ve

Interpretation of some additional parameters:

• HBeAg and anti-HBe status:
  • +ve HBeAg: indicates high viral load, higher infectivity and poor prognosis
  • +ve Anti-HBe: indicates falling viral replication, lower infectivity, and better prognosis

 

• Active vs inactive carrier state (applicable to chronic hepatitis B)
  • High HBV DNA (> 2,000 IU/mL) and/or ↑ ALT = active carrier
  • Low HBV DNA (< 2,000 IU/mL) + normal ALT = inactive carrier

Management

Hepatitis B is a notifiable disease in the UK.

Note that antiviral therapy is NOT routinely given to all patients with hepatitis B, it is reserved for patients with evidence of viral replication and/or hepatic inflammation and/or cirrhosis (see indications section for more details)

Antiviral Indications

Indications to offer anti-viral therapy:

• Cirrhosis + detectable HBV DNA (regardless of other parameters)
• ≥30 y/o + HBV DNA > 2,000 IU/mL (high viral load) + abnormal ALT 
• <30 y/o + HBV DNA > 2,000 IU/mL (high viral load) + abnormal ALT + severe liver disease (high transient elastography score [>6 kPa] or an abnormal liver biopsy [fibrosis/necroinflammation])
• HBV DNA > 20,000 IU/mL (high viral load) + abnormal ALT (regardless of age and extent of liver disease)

Choice of Antiviral Therapy

Antiviral therapy should only be initiated by an appropriate qualified healthcare professional with relevant expertise (i.e. not routinely in primary care)

 

Treatment choice depends on liver disease stage:

Compensated liver disease	1st line: peginterferon alpha-2a injection (48-week fixed course) 2nd line: NRTIs (tenofovir / entecavir)
Decompensated liver disease	Offer NRTIs Entecavir Tenofovir Avoid peginterferon alpha-2a in decompensated liver disease

Treatment Goal

Duration of therapy depends on the antiviral and patient characteristics: ^[Ref1][Ref2]

• Peginterferon alpha-2a is given for a finite duration of 48weeks
• NRTIs  (tenofovir, entecavir) are often given lifelong (as viral relapse is common)

 

Treatment goals: ^[Ref1][Ref2]

• Suppress HBV DNA replication
• Normalise ALT
• Achieve HBeAg seroconversion in HBeAg +ve patients (i.e. loss of HBeAg and development of anti-HBe)
• Ideally, loss of HBsAg (functional cure)

Ongoing Monitoring

Patients who are NOT taking antivirals	Monitor disease: ALT levels +/- HBV DNA levels
Patients who are taking antivirals	Monitor disease: Liver biochemistry (LFT, bilirubin, albumin) HBV DNA levels Quantitative HBsAg levels HBeAg status Monitor drug side effects: FBC Renal function Thyroid function (+ weight and height in children) – only for peginterferon alfa-2a

Hepatitis B in Pregnancy

Maternal Management

If the patient has HBV DNA >10⁷ IU/mL, antiviral therapy is indicated:

• Give tenofovir in 3rd trimester and continue until 4-12 weeks after birth (unless the mother meets the criteria for long-term treatment)

Neonatal Management

Neonates have the highest risk of developing chronic hepatitis B (>90%)

• Hepatitis B virus can be transmitted from the infected mother to the baby (vertical transmission)

 

Management of babies born to women with hepatitis B infection:

• Immediate management (after birth):
  • Monovalent hepatitis B vaccine ASAP (within 24 hours) – ALL babies
  • HBIG ideally simultaneously with vaccine – ALL babies, unless mother is HBeAg -ve and anti-HBe +ve (indicative of seroconversion)

 

• Ongoing management (selective neonatal immunisation programmes)
  • Give extra monovalent hepatitis B vaccine at 4 weeks
  • 6 in 1 vaccine (DTaP/IPV/Hib/HepB) to be normally given in 8, 12, 16 weeks and 18 months

 

• HBsAg testing between 12-18 months (to identify those who develop chronic hepatitis B despite vaccination)

Hepatitis B Immunisation

The hepatitis B vaccine is an inactivated vaccine that exists in 3 main forms:

• Monovalent (Hep B)
• Bivalent (Hep A / Hep B)
• Part of 6 in 1 (DTap/IPV/Hib/HepB)

Hepatitis B Pre-Exposure Prophylaxis

Hepatitis B immunisation should be offered to:

• Infants (part of routine childhood immunisation programme) (6 in 1 vaccine at 8, 12, 16 weeks and 18 months old)
• IVDU (including those who are likely to progress – e.g. those who smoke heroin and/or cocaine)
• People who change sexual partners frequently
• GBMSM
• Close contacts (sexual and household) of a person with hepatitis B
• People receiving regular blood or blood products and their carers (e.g. haemophilia, thalassaemia)
• Recipients of solid organ transplants
• Chronic renal failure (CKD 4 or 5, renal replacement therapy, renal transplantation programmes)
• Chronic liver disease (these patients should receive Hep A and B vaccine)
• People resident in prisons and places of detention
• Occupational risk (healthcare workers, laboratory staff)

Hepatitis B Post-Exposure Prophylaxis (PEP)

Significant Exposure Definition

• Percutaneous exposure
  • Needle stick / other contaminated sharp object injury
  • A bite which causes bleeding or visible skin puncture
• Mucocutaneous exposure to blood
  • Non-intact skin
  • Mucosal membrane
  • Conjunctiva (eye)
• Unprotected sexual intercourse

 

Percutaneous exposure to contaminated blood carries the highest risk

Management Algorithm

The following information assumes that the patient had significant exposure:

Source status	Patient immunisation status	Action
Unknown source / HBsAg +ve source	Fully vaccinated	→ Booster dose of Hep B vaccine (if last dose is ≥1 year ago)
	Unvaccinated	→ Accelerated course of Hep B vaccine +/- HBIG with 1st dose
	Known non-responders to Hep B vaccine	→ HBIG + Hep B vaccine
HBsAg -ve source	Fully vaccinated	→ No extra action
	Unvaccinated	→ Consider a course of Hep B vaccine
	Known non-responders to Hep B vaccine	→ Consider booster dose of Hep B vaccine

Assessing Response to Vaccination

Hep B vaccines are highly effective (~90% of adults respond adequately)

• Risk factors for poor response: >40 y/o, obesity, smoking, chronic renal sufficiency

 

Testing for immunity post vaccination (by measuring anti-HBs) is NOT routinely recommended

• The exception is healthcare and laboratory workers → measure anti-HBs titres 1-2 months after completion of the course
• See table for actions following testing for anti-HBs response to vaccine

Anti-HBs titre	Action
>100 mIU/mL (responder, high-titre)	No further action
10-100 mIU/mL (responder, lower titre)	Give 1 additional dose of vaccine with no further action
<10 mIU/mL (non-responders)	Perform the following: Test for current infection (HBsAg and anti-HBc) Repeat full course of the vaccine Re-test anti-HBs titre 1-2 months after completion of the repeat course   If still <10 mIU/mL after repeat course (= non-responder). If the patient is exposed to the virus, they will likely require HBIG for protection (see PEP section)

References

Hepatitis C

Aetiology

Hepatitis C is an enveloped, single-stranded RNA virus

• There are 6 genotypes, the majority of infections in England are from genotypes 1 and 3

 

Hepatitis C is primarily transmitted via the parenteral route

• Blood-to-blood
  • Recipient of blood transfusions before 1991 and blood products before 1986 (in England) (there was no routine donor screening before these years), or in countries that do not perform screening
  • IVDU (sharing or using contaminated equipment)
  • Needle stick or other sharps injuries (esp. in healthcare workers)
  • Tattooing and body piercing (using non-sterile equipment)
• Sexual transmission (via semen / vaginal fluids contacting mucosa microtears)
  • Risk is much higher in those with HIV co-infection, MSM, anal sex, oral-anal sex, presence of STIs
• Vertical transmission (baby is exposed to maternal blood and genital secretions during labour)
  • Risk is higher if the mother has HIV co-infection

Clinical Features

Course of hepatitis C infection

• Most adults who acquire hepatitis C develop an acute, self-limiting hepatitis
• ~80% patients with acute infection progress to chronic hepatitis C

Acute Hepatitis C

60% patients are asymptomatic, if symptomatic (non-specific):

• Flu-like illness
• Nausea / vomiting
• Arthralgia
• Abdominal pain (esp. RUQ)
• Jaundice

Chronic Hepatitis C

Chronic hepatitis C is usually asymptomatic or presents with non-specific symptoms (e.g. fatigue)

• Chronic hepatitis C often remains undiagnosed until complications develop (see below)
• However, the person remains infectious (as the virus persists in the body)

 

Patients co-infected with HIV-1 have a poorer prognosis than those with HCV infection alone.

Complications

Complications of chronic hepatitis C and B are somewhat similar, therefore are presented together: ^[Ref1][Ref2]

	Chronic hepatitis C	Chronic hepatitis B
Hepatic complication	Cirrhosis HCC HCC arise in the absence of cirrhosis in hepatitis B (as hep B has direct oncogenic effect due to viral integration into host genome) HCC in hepatitis C almost always arise in the context of cirrhosis or advanced fibrosis
Extra-hepatic complication / association	3 most common comorbidities: Depression Diabetes CKD Other: Mixed cryoglobulinaemia Membranoproliferative glomerulonephritis Lichen planus Porphyria cutanea tarda	Polyarteritis nodosa Membranous nephropathy Lichen planus

Investigation and Diagnosis

Work-Up

• Initial screening test: anti-HCV antibody
• If anti-HCV antibody +ve → test for HCV RNA to demonstrate the presence of the virus

Baseline investigations for confirmed hepatitis C:

• HIV testing
• Hepatitis A status (HAV-IgM) and hepatitis B status (HBsAg or anti-HBc)
• Liver biochemistry (LFTs, serum albumin, total bilirubin, total globulins, FBC, prothrombin time)
• U&E
• HbA1c (diabetes is a possible extrahepatic manifestation of hepatitis C infection)
• Ferritin level
• TFTs

 LFTs

Acute hepatitis C gives a hepatocellular inury pattern on LFTs:

• ↑ AST and ALT
  • Often >1,000 IU/L
  • AST:ALT ratio <1
  • ALT:LDH ratio >1.5
• Normal / mildly raised ALP and GGT
• ↑ Bilirubin (during the icteric phase)

However, LFTs are typically normal in chronic hepatitis C

• A mildly elevated AST/ALT level may be seen

Management

Hepatitis C is a notifiable disease in the UK.

All patients with chronic hepatitis C should be considered for antiviral therapy

• Antiviral therapy should always be initiated by a specialist
• Patients with spontaneous resolution (loss of HCV RNA within the first 6 months) do NOT need antiviral therapy
• Acute hepatitis C infection does NOT need antiviral therapy

 

1st line antiviral therapy: direct-acting antivirals (DAAs)

• Genotype testing was traditionally used to guide therapy, but with the availability of modern pangenotypic DAA combinations, genotype is often not required for regimen selection in the UK
• DAAs are always given in combination, as a once daily oral tablet for 8 or 12 weeks (>90% effective, and most effective when given before onset of cirrhosis)
  • DAA monotherapy does not reliably cover all genotypes and allows rapid resistance
  • Combination therapy targets multiple steps in the viral life cycle, preventing resistance and achieving a cure
• The treatment goal is sustained virological response (which equates to ‘cure’)

Hepatitis C Immunisation

References

Hepatitis D

Aetiology

Hepatitis D is a defective, enveloped, single-stranded RNA virus ^[Ref]

• Hepatitis D cannot replicate or infect on its own, it requires the HBsAg from hepatitis B virus to form its viral envelope (thus ‘defective’)
• Therefore, HDV infection only occurs in those with hepatitis B infection (either as co-infection or superinfection)

Clinical Features

The clinical presentation of hepatitis D infection depends on the type of infection: ^[Ref]

• HDV-HBV co-infection → acute hepatitis syndrome (just like acute hepatitis B infection, but the risk of acute liver failure is higher than HBV monoinfection)
• HDV superinfection in a person with chronic HBV → rapid worsening of pre-existing chronic liver disease (including rapid progression to cirrhosis)

Diagnosis

Hepatitis D status should be routinely checked for in those with hepatitis B ^[Ref]

• Anti-HDV antibodies indicate exposure
• HDV RNA is used to confirm active infection

 

Just like hepatitis B, hepatitis D is primarily transmitted via the parenteral route

Management

NICE guidelines recommend treating HDV-HBV co-infection with peginterferon alfa-2a

Hepatitis E

Aetiology

Hepatitis E is a non-enveloped single-stranded RNA virus

 

Similar to hepatitis A, hepatitis E is primarily transmitted via the faecal-oral route ^[Ref]

• Consumption of contaminated water
• Consumption of raw / undercooked meat from infected animals (notably pigs, wild boar, deer)
  • Including direct contact with these animals
• Consumption of contaminated shellfish

Clinical Features

Mostly asymptomatic infection or self-limiting acute hepatitis.

 

Importantly, hepatitis E in pregnant women (esp. 3rd trimester) is more likely to cause fulminant hepatic failure (high maternal mortality) ^[Ref]

Investigation and Diagnosis

Test for: ^[Ref]

• HEV IgM antibodies
• HEV RNA

Management

Supportive care is the mainstay of management of acute hepatitis E (even in pregnant women) ^[Ref]

• Ribavirin (an antiviral) can be used in chronic hepatitis E (rare and almost exclusively in immunocompromised patients)
• Ribavirin is contraindicated in pregnancy, and there is NO established antiviral therapy for hepatitis E in pregnancy