Acute Viral Hepatitis

Hepatitis

Definition – any inflammation of the liver, caused by several things:

toxic – pharmacologic or chemical agents (halothane, isoniazid, alcohol)

inherited (metabolic disease) – Wilson’s disease (copper), galactosemia, alpha-1-antitrypsin deficiency

viral – rubella, infectious mononucleosis, CMV, or hepatitis viruses (primarily or exclusively infect the liver), herpes simplex, etc.

Acute vs. Chronic – acute is self-limiting, usually disappear within six months without long-term sequelae

Severity Levels – subclinical, anicteric (no jaundice), icteric (jaundice), fulminant (necrosis – need transplant; 50% fatal)

symptoms usually nonspecific viral symptoms, jaundice, anorexia, nausea, diarrhea, malaise, fatigue

Forms of Infectious Hepatitis - originally only two – short (A) or long (B) incubation – some in neither category (non-A non-B)

now known to be at least seven forms (A-E, G, and TTV) – very different – only common feature is that they infect liver
A and E are transmitted fecal-oral (enteral) and only exist in acute forms
the rest can be chronic, and are transmitted through blood or body fluids (parenteral; B sexually and maternally)

Hepatitis Type B – Most Common Type Worldwide, 30% of U.S. cases

70-150 day incubation – most cases are acute (1% fulminant, 30% icteric, rest anicteric or asymptomatic)

Chronic Infection Possible – 5% in adult transmission, 90% in infant; 200 million worldwide, 1 million in U.S.

20-40% in some places (subsaharan Africa, SE Asia, China), reservoir perpetuates itself (pass during childbirth)
associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HPC) – almost always fatal

could be caused by oncogenic insertion into host DNA, mutated cellular genes, or accellerated liver regeneration

Parenteral Transmission – carrier has more than 10 trillion particles per ml of serum, so needlestick can infect

most common worldwide is maternal-neonate transmission (rare in US)
in U.S. 50% sexual – 67% of gay male population carriers for hepB (break mucosal surface more easily)
20% drug use, (needlesticks, share razors) – getting less common due to preventative measures

Hepadnavirus – "Hepatitis DNA virus" (it is the only DNA hepatitis virus) – discovered in late 1960s

lipid coated dsDNA virus ((-) strand longer than (+) strand) – has a nick in (-) strand for DNA replication

replicative viral particle is 42 nm in diameter with 27 nm core Þ called Dane particle

important proteins:

surface protein: HBsAg (S antigen) – also pre-S region that binds albumin

virus makes ten times as much as is needed, so excess of empty S antigen in serum during infection

core protein: HBcAg (C antigen) which is hydrolyzed to HBeAg (E antigen, also in core)

antibodies to these are present only if virus is replicating

DNA polymerase, X gene (primer for DNA synthesis), protein kinase (phosphorylate major core polypeptide)

Life cycle – binds albumin and liver albumin receptor, internalized into hepatocytes, uncoated, DNA released

(-)DNA transcribed to: (1) viral (+)RNA (makes C antigen in nucleus and S antigen in cytosol) and (2) pregenomic (+)RNA
pregenomic (+)RNA reverse-transcribed to (-)DNA then degraded; partial (+)DNA synthesized, packaged
virus released by budding through cell membrane to Space of Disse
sometimes virus inserts into host genome – becomes non-replicative

Hepatitis B is NOT directly cytopathic – the cellular immune response that controls the virus also kills liver cells.

MHC Class I presents C antigen; cytotoxic T-cells recognize and kill the cell (acute hepatitis full of lymphocytes)
MHC Class I or CD8 cells may be underexpressed in individuals that get chronic hepatitis (e.g., newborns)

Serology and Humoral Immunity

serum S antigen peaks 12 weeks, disappears by 20 weeks – persists in chronic infection

IgG to S antigen appears some time after S antigen disappears – protective against reinfection

"window period" is period of time between disappearance of S antigen and appearance of IgG to S antigen

C antigen not found in serum – IgM to C antigen is found in the "window period," replaced by IgG 6-12 months later

IgM to C antigen is important diagnostically – only evidence of infection during window period

E antigen found in serum when virus is replicating, after S antigen appears

if IgM to E antigen appears, E antigen usually disappears, and infection will be asymptomatic

chronic Hep B: S antigen persists without its antibody, also IgM to C antigen and viral DNA

50% chronic cases have IgG to E antigen (asymptomatic); 50% have E antigen (cirrhosis)

Vaccine – exogenous S antigen (from recombinant DNA in yeast vector) – produce IgG response

also passive form – pooled IgG to S antigen confers transient immunity

Treatment for chronic hepatitis – alpha interferon – normalized transaminase in 40%, no S antigen in 10-20% (cure)

Hepatitis D (delta) – requires Hepatitis B for its surface protein, 5% of U.S. cases

30-90 day incubation; cannot exist without Hepatits B

Parenteral transmission – sexual in endemic areas (Mediterranean/Middle East/South America/Africa), blood in U.S.

Deltavirus – defective ssRNA(-) virus, 35-37 nm, encapsulated by S antigen of Hepatitis B

direct cytopathic effect – makes hepatitis B much more virulent and persistent
predisposes to fulminant liver failure, but does not predispose to chronic form of hepatitis B

delta antigen – unique to Hep D

IgM against it (not protective) appears concurrently with IgM against C antigen of HepB

Prevention – includes screening of blood, safe sex, and vaccination against Hepatitis B

Hepatitis A – Always Acute – Most Common Type in U.S. – 50% of U.S. Cases

15-50 day incubation (average 30) – can cause fulminance, but most recover 2-4 weeks (20% brief reoccurance)
primarily occur in children (usually asymptomatic); less common in adults but serious – 75% icteric if beyond age 14

in U.S., 10-20% have antibodies by age 20, 50% by age 50; higher in underdeveloped countries
epidemics occasionally occur in U.S.

Enteral Transmission – fecal/oral among households or foodstuffs (e.g. Mexican strawberry epidemic)

accompanies outbreaks of war (250,000 killed during WWII, more than casualties) – "jaundiced epidemic hepatitis"
sometimes acquired parenterally (transfusion, inoculation, gay sex)
1-2 weeks before onset of symptoms; shedding of virus in stool via biliary system of liver

transaminases rise to quite high values (>1000 I.U./L) five days before clinical manifestation

can stop epidemics with strict hygiene, but no virus in stool by time jaundice appears

Picornavirus – 27 nm in diameter, 8000 nucleotide (+)ssRNA, one serotype

IgM against hepatitis A antigen useful for diagnosis – persists 6-12 months, replaced by IgG (protective)

no direct cytotoxicity – immune response kills cells

Vaccine – passive (IgG) and active (Hepatitis A antigen) both work well

active vaccine only given to high-risk people (travelers, homosexual males, drug users, chronic liver disease)
chronic hepatitis C always vaccinated, since hepatitis A superinfection nearly always leads to fulminant liver failure

Hepatitis C – Most Common Chronic Hepatitis – But Only 16% of Acute U.S. Cases

15-180 day incubation (average 50), acute infection is asymptomatic 75% of the time
chronic infection occurs in 85% of those acutely infected – 20% get cirrhosis, 1-5% get hepatocellular carcinoma

four million chronically infected in U.S., mostly 30-50 years old; 100 million worldwide
Hepatitis C is the leading cause of chronic liver disease in the U.S. – number one cause of liver transplantation
reinfection almost invariable after transplantation, possibly due to immunosuppression

Parenteral Transmission – usually IV drug use or transfusion; very rarely sexual or perinatal

at one time 7-10% of transfused individuals got hepatitis C – now 1/300,000 since screening procedures used
cause of 90% of post-transfusion hepatitis in the developed world; 30% of drug addicts and hemophiliacs have Hep C
more likely to get disease if older (>50), alcohol, immunosuppressed
very preventable – incidence dropped 90% since 1970s (200,000 to 20,000 per year)

Flavivirus – 30-50 nm diameter, 9000 (+)ssRNA virus, 9000 nucleotides, lipid envelope, completely sequenced

RNAs appear in serum 14 days after exposure
frequently mutates – 6 different genotypes and more than 50 subtypes

Type 1 most virulent and most likely to cause cirrhosis

transaminases rise 45-50 days, but not by much (to 300-500) – they fluctuate from normal to tenfold too high

Prevention – screen organ/tissue donors, high risk behavior modification, blood and body fluid precautions

vaccine non successful, since virus mutates so rapidly – IgG not protective, so reinfection possible

Treatment – alpha interferon very effective in resolving chronic infection in 30% of cases

alpha interferon + ribavirin – even more effective – 50% clear RNA from serum (perhaps eliminate infection)

Hepatitis E – Always Acute, but Uncommon – <1% of U.S. Cases

10-60 day incubation (average 40 days) – course follows Hepatitis A
sporadic epidemics – 10-50% in underdeveloped countries have antibodies

almost all U.S. cases from travellers or immigrants; no U.S. outbreaks

always acute, but does NOT cause cirrhosis – 10% mortality in pregnant women

Enteral Transmission – fecal/oral transmission, often waterborne

transaminase increase 40 days after exposure
2-5% of Americans that do not travel have antibodies – perhaps swine virus

Calicivirus – 27-34 nm, nonenveloped, 7600 nucleotide (+)ssRNA

IgM – weeks or months; IgG long lasting, but does not confer immunity (hence no vaccine)

Hepatitis G – Recently Discovered – Accounts for 10-30% of non-A-E

15-150 day incubation – often coinfected with B or C
virtually all patients asymptomatic with no long-term sequelae – some fulminance, possibly due to coinfected B or C

Parenteral Transmission likely – virus cleared from bloodstream by antibody to envelope protein on virus (E₂)

TTV – Transfusion Transmitted Viral – Recently Discovered – 1997

40-60 day incubation – mostly asymptomatic – linear (+)ssRNA, 4 genotypes – possibly a parovirus

Parenteral Transmission strongly implied, incubation of 6-9wks

Other – Non-A-E, Non-G, Non-TTV – could be many other viruses

mild, usually self limited – could be not virus at all (side effects of alcohol, drugs, etc)
2-4% is under investigation – new agents being identified – not as important role as others