Viral Hepatitis

Chapter 1 – Viral Hepatitis

v History

() Some Px ~ asymp’ or mild’ symp’. Classic present’ has 4 phases:

Viral Replication:  asymptom’, & lab studies (+) serologic & enzyme markers of hepatitis.

Prodromal: anorexia, nausea, emesis, alter’ gustat’, arthalg’, malaise, fatig’, urticar’, & pruritus, & (some) aversion to cigaret’ smoke.

Icteric: ~ note dark urine, then pale stool; predomin’ GI sympt’ & malaise, Px ~ (+) icteric ~ (+) R.hypochondriac pain + hepatomega’.

Convalescent: Sympt’ and icterus resolve, liver enzymes’ level returns to normal

o  Hepatitis A Virus (HAV)

§ Incubation period: 2-7 weeks (± 28 days)

§ (Most common) Fatig’, nausea, emesis, fever, hepatomega’, jaundice, dark urine, anorexia, & rash.

§ Usu’ mild, self-limited, & confers lifelong immunity against HAV.

§ No chronic infec’.

o  HBV

§ Incubation period: 30-180 days (± 75 days).

§ Long term infec’ --(15-30% cases)à chronic liver ill’ + cirrhosis.

§ Prodromal (Preicteric) Phase: characteris: gradual onset of anorexia, malaise, & fatig’.

(+) Hepatitis, ↑ed level of liver’s enzymes, ~ + R.hypochondriac pain.

~ (+) fever, arthrit’, arthralg’, urticaral rash.

§ As progresses to icteric phase: liver’s more tender, & (+) jaundice, darken’ of urine, paler stool. Other sympt’: nausea, emesis, & pruritus.

Then, clinical course ~ high’ variab’:

(Some) Rapid sympt’ improvement,

(Some) Prolong’ ill w/ slow resolution,

(Some) Relapsing hepatitis.

(< Some) Rapidly into Fulminant Hepatic Failure (FHF) over days to weeks.

o  HCV

§ Incubation period: 15-150 days (sympt’ onset @ 5-12 weeks post-exposu’).

§ Acute infec’ sympt’ ~ appear similar to HBV’s.

§ (Up to 80% cases) Asympt’ & w/o icterus.

o  HDV

§ Incubation period: ± 35 days.

§ Chronic HBV carrier superinfected by HDV tends to (+) more severe acute hepatitits.

(80% cases) (+) chronic HDV infec’ ~ à fulminant acute hepatitis & severe chronic active hepatitis w/ progress’ to cirrhosis.

Long term, (70-80% cases) chronic liver ill’ + cirrhosis.

Chronic HBV + HDV infec’

§ If + HBV infec’ simultan’ –(oft’)à acute, self-limit’ infec’.

< 5% cases (+) chronic HDV infec’, instead.

o  HEV

§ Incubation period: 2-9 weeks (± 45 days). No report of chronic ill’.

§ Usu’ causes acute & self-limit’ infec’. Case Fatality Rate @ Pregn’ ♀: 15-20%

§ (10% cases) Fulminant ill’.

v Physic’ Exam’

o  (Oft’) low fever. Px w/ severe emesis & anorexia ~ (+) signs of dehydrat’ (s.as: tachy♥, dry mucous membr’, ↓ skin turgor, & delayed capill’ refill).

o  @ icteric phase: ~ (+) icterus of sclerae or mucous membr’ or discolor’ of tympanic membr’. Skin ~ jaundiced & ~ (+) macul’, papul’, or urticar’ rash.

o  Liver ~ tender, diffus’ enlarge’ w/ firm, sharp, smooth edge. If (+) palpable nodular liver or mass à suspect abscess or tumor!

v Complication

o  (General) Acute or Subacute hepatic necrosis, chronic active hepatitis, chronic hepatitis, cirrhosis, hepatic fail’, Hepatocell’ carcinoma (HCC) by HBV or HCV.

o  HBV

§ (Major, risk @ young child (90%); @ old child & adult (5-10%); @ immunocomprom’ Px) Chronic infec’ –(risks)à chronic active hepatitits à cirrhosis –(huge risk)à and then HCC (25-30 years post-initial infec’).

§ (Major) FHF, w/ coagulopathy, encephalopathy, & cerebr’ edema.

o  HCV

§ Acute infec’ --(rare)à FHF. (70-90% cases) Chronic infec’ –(5-20%)à cirrhosis (~ > 20 years post-initial infec’):

–(high risk)à HCC (after ± 30 years of chronic infec’).

–(20-25% cases)à liver fail’ & death.

§ (>60% cases) Chronic infec’ + fluctu’ or persisten’ ↑ed liver enzymes’ level.

§ Extrahepat’ complic’:

@ Essent’ mixed cryoglobulinemia: may form antiHCV IgG- or Rheumatoid Factor- (RF) immune complexes –(deposit)à small vessel damage –(complic’)à rash, vasculit’, glomerulonephrit’.

Focal lymphocytic sialadenitis, autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, some Non-Hodgkin lymphoma, and Mooren corneal ulcer

v Differ’ Diagn’

o  Liver abscess

o  Drug-induced hepatitis

o  Autoimmune hepatitis

o  Hepatocellular cancer

o  Pancreatic cancer

o  Abdominal Trauma, Blunt

o  Acute Cholangitis

o  Cholecystitis and Biliary Colic

o  Emergent Management of Pancreatitis

o  Emergent Treatment of Gastroenteritis

o  Gallstones (Cholelithiasis)

o  Intussusception

o  Pediatric Gastroenteritis in Emergency Medicine

o  Peptic Ulcer Disease

o  Small-Bowel Obstruction

v Workup

o  Suspected viral hepatitis @ nonicteric Px à do urine bilirubin test, or (alternative) liver enzyme panel.

o  If (+) questionable or altered mental status à do: (1) bedside fingerstick glucose to evaluate for hypoglycem’, (2) (also if suspected hepatic encephalopathy) assessing serum ammonia.

o  Total bilirubin ~ ↑ed @ infectious hepatitis (sign of worse ill’ if level’s > 30mg/dL).

o  Alkaline Phosphatase (ALP)’s usu’ normal (~ ↑ to ≤ 2x normal level) à if ↑ to > 2x normal level, consider abscess or biliary obstruction.

o  If (+) prolonged Prothrombin Time, sign of liver’s synth’s dysfunct’.

o  Look for renal dysfunct’ signs via assessing BUN & creatinine à if (+) renal dysfunct, sign of fulminant liver ill’.

o  No specific imaging needed for diagn’ of hepatitis. Do appropriate imagings (eg: USG, or CT Scan) if DDx favors gallbladd’ ill’, biliary obstruction, or liver abscess.

o  HAV

§ (+) AntiHAV IgM (standard for diagn’), disappears several months post-initial infec’.

§ (+) AntiHAV IgG, (seems to (+) lifelong immuni’ against HAV) sign of previous infec’ ≥ 2 months ago.

o  HBV

§ Acute self-limited infec’

· HBsAg (Ø indicate acute or chronic category), 1st serum marker, sign of (+) Dane particle (HBV virion) in blood.

· HBeAg, virus replicat’s sign. If virus replic slows down: (-) HbeAg &, (~ persist for years) (+) antiHBe Ab.

· HBcAg, 1st Ag to appear, as sine qua non of acute HBV infec’.

· Diagnostic: (+) antiHBc (initially IgM (standard for diagn’). Weeks later: (-) antiHBc IgM & (+) antiHBc IgG. AntiHBc (total) assay (detects both the IgM & IgG class of antiHBc).

· AntiHBc ~ (+) for life. (+) AntiHBc, sign of history of HBV infec’.

· Positive AntiHBc Total, negative HBsAg, negative antiHBs: indicate 1 of following 4:

o  False positive.

o  (Ø @ Chronic Hepatitis) Px is @ acute hepatitis window between HBsAg eliminat’ and (+) of antiHBs.

o  Px’s cleared HBV but lost antiHBs over the years.

o  (Uncommon) Px w/ active HBV replication + (+) HbeAg or (+) HBV DNA found.

· @ Px w/ cleared HBV, HBsAg usu’ (-) 4-6 months after infec’ as antiHBs becomes detectable. AntiHBs (believed to confer immunity against HBV) ~ persist for life.

§ Chronic infec’

· (+) HBsAg for > 6 months à indicate chronic HBV infec’.

· HBsAg ~ detectable for life. Px w/ (+) HBsAg = HBV carrier (inactive, or w/ chronic hepatitis)

· @ All Chronic HBV infec’: (+) AntiHBc.

· ~ or ~ Ø (+) HbeAg or HBV DNA (if positive à sign of active HBV replic’).

· HBV DNA: (-) or low @ inactive carrier, high @ chronic HBV infec’, associated w/ ↑ed infectivity.

· AntiHBs usu’ (-) @ chronic HBV infec’, if it’s (+) + (+) HBsAg à sign of unsuccess’ HBV clearan’ by antiHBs.

(Table right below) HBV’s Diagnostic Tests

Test	CHB HBeAg Positive	CHB HBeAg Negative	Inactive Carrier
HBsAg	+	+	+
Anti-HBs	-	-	-
HBeAg	+	-	-
Anti-HBe	-	+	+
Anti-HBc	+	+	+
IgM anti-HBc	-	-	-
HBV DNA	>2 × 104 IU/mL* (>105 copies/mL)	>2 × 103 IU/mL (>104 copies/mL)	< 2 × 103 IU/mL (< 104 copies/mL)
ALT level	Elevated	Elevated	Normal

§ Markers post-vaccin’ for HBV

· HBV Vaccine delivers recombinant HBsAg to Px w/o HBV-associat’ proteins & HBV DNA. (>90% recipients) (+) Anti-HBs w/o necessarily (+) HbcAg before it.

o  HCV

§  (August 2012) CDC recommends 1x blood test for HCV infec’ in baby boomers (generation born in 1945-1965) w/o ascertaining HCV risks à if (+) HCV à screen or manage HCV Px for alcohol abuse w/ referral to appropriate medical managements.

§ Liver Chemistry

· ↑ed ALT & AST, sign of liver injury, if chronic à workup to exclude chronic liver ill’.

(@ HCV Px) Ø predict therapeutic severity & severity of clinical, histologic, prognosis. Cirrhotic HCV Px ~ still (+) normal liver enzymes.

Normalization, if after acute HCV infec’: ~ sign of HCV clearan’.

Normalization, if while Px in Tx w/ IF: predict virolog’ response to Tx.

~ Sign of relapse after successful-appearing Tx.

§ Serology

· 3rd generation serolo’ assays can detect AntiHCV within 4-10 weeks of infec’.

· Recombinant HCV Antigen ELISA to detect AntiHCV IgG in sera.

This AntiHCV test is negative several months post-HCV acute infec’,

· ELISA fails to detect AntiHCV @ 2-5% HCV Px & @ immunocompromis’ Px.

· (+) AntiHCV ~ persist for life, Ø against future HCV exposure.

· (15% Px) HCV’s cleared w/o chronic hepatitis.

· (2010) FDA approved OraQuick HCV Rapid Antibody Test, can be used @ Px w/ hepatitis’ risk or sympt’ by strip-testing sample of oral fluid, whole blood, serum, or plasma.

· Recombinant Immunoblot Assays (RIBAs) use HCV Antigen fixed to a solid substrate, more specific > ELISA, being abandon’ in favor of HCV RNA test.

· 1 positive RIBA or ELISA has 1 of 3 potential interpretation:

o  True positive, (+) HCV infec’.

o  True positive, no longer viremic for HCV, w/o chronic hepatitis; can’t distinguish resolved infec’ from active infec’.

o  False positive (eg: frequently @ ELISA of Px w/ hypergammaglobulinem’, or autoimmune hepatitis).

§ HCV RNA

· Via PCR assay (qualitative PCR, most specific to find HCV infec’ before Px has AntiHCV) & branched DNA assay. Can confirm active HCV infec’.

· Aids in confirma’ of early HCV infec’ (pre- (+) AntiHCV or ↑ ALT level), seronegative HCV infec’, perinatal transmiss’ HCV infec’, also @ falsepositive cases.

· Aids in assessi’ HCV genotype & viral load, predicting response & guiding duration and dose in IF therapy,

§ Liver biopsy

· To aid diagn’ confirma’, (most reliable, usu’ @ beginning, to aid guiding aggresivity of antiviral Tx) ill’ severity assessm’, & to exclude diseases that ~ affect antiviral Tx.

· Advanced liver fibrosis (stage 3-4) ~ need screening for (complic’) HCC.

· If (+) unsuspected cirrhosis à don’t let Px (+) large esophageal varices. Author’s opini’: stage 3 is ‘cirrhosis if Ø proven otherwise’.

· If (+) signific’ liver fibrosis (stage 2-4)à ~ (+) antivital Tx aiming for better long-term outcome.

· If (+) advanced stage (stage 4) à Px may seek experiment’ therapy if HCV infec’ Ø responds to Tx.

· If (+) minimal fibrosis (stage 1) (Antiviral Tx’s risks ~ outweigh benefit (eg: @ Px w/ stage 1 liver fibrosis + major depression)) à Px ~ choose (+) or Ø antiviral Tx (@ author’s practice: (pre Px choose) advise Px that only virologic eradication can ensure no extraliver complic’ will (+), & to return for repeat liver biopsy in 3-4 years to exclude progress’ of liver ill’).

· Limitation:

o  0,1% complication risk (eg: bleed’).

o  ~ (+) sampling error.

o  ~ (+) histolo’ assessment’s interobserver variability

o  Can’t predict progress’ of chronic hepatitis C.

§ Other test @ estimating fibrosis @ chronic hepatitis C.

· Liver stiff’ can be estimated via Fibroscan (95% true positive, but less accurate @ mild fibrosis).

· Liver fibrosis can also be estimated via:

o  FIBRO SPECT-II, use measurem’ of hyaluronic acid, TIMP-1 and α-2 macroglobulin.

o  HepaScore, use measurem’ of hyaluronic acid, α-2 macroglobulin, GGT, total bilirubin, age, & gender.

o  HCV FIBROSURE measures α-2 macroglobulin, haptoglobin, GGT, bilirubin, ALT, & Apolipoprotein A1.

() (General) can exclude 1 or 4 liver fibrosis but less accurate @ disting’ moderate fibrosis. ~ Useful @ identifyi’ Px w/ low risk for advanced ill’ (eg: asymp’ ♀ w/ positive HCV RNA, persistent normal liver chemistry values, w/o alcohol abuse history or HIV infec’) or @ longitudinal follow-up of Px w/ mild ill’ on biopsy who chose to Ø antiviral Tx.

o  HDV

§ HDV’s serodiagn’ via IgM AntiHDV & IgG AntiHDV, or serum HDV RNA.

§ (Needn’t as routine @ suspected hepatitis) IgM AntiHBc to disting’ coinfec’ (positive result) from superinfec’ (negative result).

o  HEV

§ HEV’s serodiagn’ via IgM AntiHEV & IgG AntiHEV, or (@ serum or stool) HEV RNA.

o  Histolo’ Find’

§ HBV

Inactive carrier’s no or minimal histolo’ abnormal’ on liver biopsy sample.

Chronic Hepatitis B:

· Inflammato’ infiltrat’ w/ MN WBC in it ~ limited w/in portal area, or disrupt portal plate’s limits into liver lobule (interface hepatitis).

· ~ (+) Periportal fibrosis or bridging necrosis (inter-portal tracts).

(Figure right below) Ground glass cells (granular, homogenic, eosinophil’ stain’ of cytoplasm due to (+) HBsAg. Sanded nuclei, sign of HBsAg overload.

§ HCV

· (Table right below) Batts & Ludwig (1995) histolo’ HCV liver biopsy scoring.

Grade (fibrosis)	Portal Inflammation	Interface Hepatitis	Lobular Necrosis
1 - Minimal (portal)	Mild	Scant	None
2 – Mild (periportal)	Mild	Mild	Scant
3 – Moderate (septal)	Moderate	Moderate	Spotty
4 – Severe (cirrhosis)	Marked	Marked	Confluent

· (Common @ Chronic Hepatitis C) Inflammato’ infiltrat’ w/ MN WBC in it ~ limited w/in portal area, or disrupt portal plate’s limits into liver lobule (interface hepatitis).

· ~ (+) portal & periportal fibrosis. Other classic find’: bile duct damage, lymphoid follic’ or aggrega’, & macrovesicular steatosis.

§ HDV & HEV

· Histolo’ find’ @ HDV-HBV coinfec’ = @ HBV alone.

· (Classic, @ HEV infec’) Portal tract infiltrat’ by lymphocyt’ and PMN WBC, ballooned hepatocyt’, acidophilic body formation, & intralobul’ necrosis of hepatocyt’. (@ Severe cases) ~ (+) submassive & massive hepatic necrosis.

Reference:
1. http://emedicine.medscape.com/article/775507-clinical
2. http://emedicine.medscape.com/article/775507-differential
3. http://emedicine.medscape.com/article/775507-workup