Viral Hepatitis

Introduction
· Viral hepatitis is caused by viruses that cause inflammation to the liver Spectrum of clinical manifestations · Asymptomatic/ subclinical infection = serologic evidence · Acute hepatitis: symptoms are common to all viruses · Carrier state = asymptomatic individual but harbouring replicating virus · Chronic hepatitis → liver cirrhosis Systemic viral infections · Infectious mononucleosis (EBV) · CMV · Yellow fever · Dengue fever · Rubella · Haantan virus Immunological responses · Normal → acute hepatitis · Less adequate → chronic hepatitis · Inadequate → asymptomatic · Hyper → fulminant hepatitis

 

Acute hepatitis
4 phases 1. Incubation period · Peak infectivity = last asymptomatic days of incubation period to early days of acute symptoms 2. Symptomatic pre-icteral phase · Usually precedes development of jaundice by a few days to 2 weeks · Non-specific prodromal illness : headache, myalgia, arthralgia, nausea and anorexia · Vomitting, diarrhea, RHC pain · May have dark urine and pale stools · May have physical signs: i. Liver is often tender but only minimally enlarged ii. Occasionally, mild splenomegaly and cervical lymphadenopathy (more frequent in children or EBV infx) 3. Symptomatic icteric phase · Mainly conjugated hyperbilirubinaemia · Common in actue HAV infection; absent in 50% of acute HBV infection; uncommon in acute HCV · Jaundice may be mild and the diagnosis may be suspected only after finding abnormal liver blood tests in the setting of non-specific symptoms. Symptoms rarely last longer than 3-6 weeks 4. Convalescence

 

Chronic hepatitis
· Symptomatic, biochemical or serological evidence of continuing hepatic disease > 6months with histological evidence of inflammation and necrosis Aetiology o Infective = viral hepatitis (HBV, HCV) o Drugs = chronic alcoholism, isonazid, methotrexate, methyldopa, nitrofurantoin o Autoimmune = autoimmune hepatitis (may be associate with primary biliary cirrhosis and primary sclerosing cholangitis) o Metabolic = Wilson’s disease, haemochromatosis, α1 –antitrypsin deficiency Clinical course unpredictable o Spontaneous remission o Indolent disease without progression o Rapidly progressive disease → cirrhosis Causes of death o Liver cirrhosis o Liver failure o Haematemesis o Hepatocellular carcinoma

 

Hepatitis A virus
· Epidemiology= usually found in developing world → substandard hygiene & sanitation; prevelance of seropositivity increases with age · Caused by picornavirus (ssRNA), 1 serotpe · Mode of transmission= o faecal oral route o food & water borne (e.g. eating partially cooked cockles & oysters/ contaminated food & water) o person-person (e.g. sexual oral-anal) · Incubation period = 4-6 weeks o HAV appears in faeces before clinical symptoms (usually 2-3 weeks before jaundice & 1 week after onset of jaundice) · Clinical presentation o Asymptomatic (most) = subclinical & milder than HBV infection o Acute hepatitis= usually bengn and self limiting o Worse if superimposed on chronic hepatitis o Does not cause chronic hepatitis or carrier state · Complications: Fulminant hepatitis (rare) · Serological picture: o Transient viraemia → blood borne transmission rare o IgM with acute infection → fecal shedding ends as IgM increases o IgG for long term immunity Prevention · Avoid eating contaminated food or drinks · Boiling 5 mins · Immunization o Passive immunization with Ig G § IgG collected from blood of persons who have been exposed to the hepatitis A § This method of immunization is getting obsolete because of the short supply of immune globulin and the potential risk of transmission of other infection through blood products o HAV vaccine § Inactivated virus § Given in 2 doses, with the second dose being given 6 – 12 months later. Immunity after vaccine lasts for 10 – 20 years. Protection against hepatitis A begins 4 weeks after vaccination People at risk of HAV · Persons travelling to or working in countries that have high or intermediate rates of hepatitis A · Persons who work with hepatitis A virus infected primates or with hepatitis A virus in a research laboratory should be vaccinated. · Persons with chronic liver disease eg. chronic hepatitis B carriers as these patients have been reported to have a higher mortality.

 

Hepatitis B virus
· Epidemiology: endemic in Africa and Asia; Microbiology · Belongs to the Hepadnavirus family · Has 3 well characterized antigens: o HBsAg (surface) → stimulates anti-HBs o HBcAg (core) → stimulates anti-HBc o HBeAg (core associated) → stimulates anti-HBe · Dane particle = infectious spherical HBsAg particle containing HBcAg core · HBeAg arises from the same gene as HBcAg o c gene has 2 initiation codons= precore and core region o translation intitated at precore region = HBeAg → signal peptide that facilitates secretion (can be used as surrogate marker for presence of HBcAG) o translation initiated at core region = HBcAg → no signal peptide →not secreted into serum · Nucleocapsid o circular partially ds DNA o DNA polymerase with reverse transcriptase activity o HBcAg → remains in hepatocytes for complete assembly of virions, only detected in liver biopsy samples · Incubation period = 3-4months · Pathogenesis o Cell-mediated mechanisms = destruction of hepatocytes with viral/ modified surface antigens o Humoral-mediated mechanisms = GN/ vasculitis from circulating immune complex · Mode of transmission o Vertical transmission o Sexual transmission o Parententral transmission: blood transfusion, organ transplant, needle-stick injury, IV drug abuser · Clinical presentation: o Asymptomatic disease (90%) o Acute hepatitis § Fulminant hepatitis rare o Carrier status (10-15%) o Chronic hepatitis (5%) o Liver cirrhosis (3%) o HCC (1%)
Serology 1) Acute infection with recovery · HBsAg= appears before onset of symptoms, peaks and declines rapidly, undetectable at 3-6months · HBeAg= appears just after HbsAg, indicates active replication (infectiousness) i. anti-HBe appears after disappearance of HBeAg (indicates waning infection) · anti-HBc= IgM appears just prior to the onset of infection (indicates acute infection); replaced by IgG i. does not protect against re-infection ii. serves as a surrogate marker for natural HBV infection· anti-HBs IgG= appears after acute disease is over 2) Acute infection with progression to chronic disease · Carrier state = presence of HBsAg > 6 months · Chronic replication of HBV virions = persistent HBsAg, ±HBeAg and HBV DNA · Chronic sequel: cirrhosis & HCC · High risk of becoming a carrier: i. Age at time of infection · Perinatal: 85-95% · Infants: 40-50% · Children: 30-40% · Adults: 5-10% ii. Sex – male: female 3:1 iii. Ethnicity – Chinese> Malays> Indians; related to prevalence of female carriers and periantal infx iv. Impaired immune responses – transplants, drugs Markers of past infectivity · Anti-HBs IgG · Anti-HBc IgG · Anti- HBe HBV mutants · Pre-core mutant: variant C gene fails to produce HBeAg (–ve HBeAg viraemia); still infections because of HBcAG o HBV DNA necessary to detect presence of disease activity · S mutants: mutation at ‘a’ epitope (HBsAg –ve viraemia) → vaccine not effective; low frequency in Singapore Treatment · Anti-virals: lamivudine, adefovir · Interferon-α · Vaccination

 

Hepatitis C virus
·       · Caused by Flavivirus, ssRNA · Transmission: blood-borne, sexual intercourse · Incubation period: 6-12 weeks · Clinical presentation Mainly asymptomatic Acute hepatitis = general milder than HBV; no effective immunity

·        Chronic hepatitis = hallmark of HCV infection 60-80% develop chronic hepatitis 20% go on to develop liver cirrhosis Acute infection with recovery · HCV RNA detectable for 1-3 weeks during active infection, · HCV RNA frequently persists despite neutralizing antibodies (Abs present in 50-70% of acute infection; 30-50% have anti-HCV Abs after 3-6 weeks) Chronic Infection · Persistence of HCV RNA despite neutralising Ab · Episodic elevations of HCV RNA and transminases Treatment · Ribavirin and IFNα combination therapy → partial efficacy · No vaccine available; difficult to cover agains the 6 major genotypes

Hepatitis D virus
· Defective ssRNA virus → requires HBsAg coat to infect cells · HBV serves as helper virus Clinical presentation 1. Super infection: chronic HBV carrier exposed to HDV → severe hepatitis 2. Co-infection: exposed to HBV & HDV at the same time a. HBV must become established first to provide HBsAg required for HDV virion production b. Chronic hepatitis rare c. Higher rates of fulminant hepatitis (3-4%) Serology · HDV RNA appears just before and during early acute symptomatic infection · IgM anti-HDV = recent HDV exposure · To differentiate co-infectin and super infection = correlate with HBV markers
Hepatitis E virus
· Calicivirus, ssRNA · 4 genotypes, endemic in India and the Middle East · Transmission: faecal-oral, water borne · Incubation period= 4-6 weeks Clinical presentation · Acute hepatitis o Usually self-limiting and benign o Abs are non-protective · No chronic state or chronic hepatitis · High rate of fulminant hepatitis in pregnant women (25% fatal); foetal mortality also high · No vaccines Serology · HEV RNA and HEV virions present in stool and liver before onset of symptoms · IgM anti-HEV present with rising transaminase → IgG

 

Hepatitis Screen
· HAV= o Anti- HAV IgM (acute) o Anti- HAV IgG (previous infection) · HBV= o HBsAG, HBeAG, anti-HBc, IgM (acute) o Anti-HBs IgG, anti-HBe, anti-HBc IgG (previous infection) · HCV= o Anti-HCV IgM (acute) o Anti-HCV IgG (previous infection) · CMV = anti-CMV IgM · EBV = anti EBV IgM · HSV = anti-HSV IgM, HSV PCR (if patient presents with acute liver failure)

 

HAV HBV HCV HDV HEV HGV
Agent Icosohedral capsid, ssRNA Picornavirus Enveloped dsDNA Hepadnavirus Enveloped ssRNA Flavivirus Enveloped ssRNA Unenveloped ssRNA Calicivirus ssRNA Flavivirus
Transmission Faecal-oral Parenteral, close contact, vertical Parenteral, close contact Parenteral, close contact Waterborne Parenteral
Incubation period 2 – 6 weeks 4 – 26 weeks 2 – 26 weeks 4 – 7 weeks (superinfection) 2 – 8 weeks Unknown
Carrier state None 0.1 – 1% of blood donors; 90 – 95% of those infected at birth (vertical transmission); 1 – 10% infected as adults (esp. If immune-compromised) 0.2 – 1% of blood donors; <1% are healthy carriers 1 – 10% of drug addicts, haemophiliacs Unknown / none 1 – 2% of blood donors
Chronic hepatitis None 5 – 10% of acute infections (adults); 90% in infected neonates >60%; half then progress to cirrhosis <5% if co-infection with HBV; 80% upon super infection with HBV None None
Fulminant hepatitis 0.1 – 0.4% <1% Rare 3 – 4% in co-infection 0.3 – 3% 20% in pregnant females Unknown
Hepatocellular Ca No Yes + (but most common cause in Singapore due to high prevalence from vertical transmission) Yes ++(but less common in Singapore due to lower prevalence) No increase above HBV Unknown, but unlikely Probably not
Vaccine available Yes Yes No No No No
Others Acute hepatitis (symptomatic, asymptomatic) Fulminant hepatitis almost never occurs with HCV At present, not considered pathogenic

 

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