| 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 |