Pocket Medicine

GASTROENTEROLOGY

HEPATITIS

VIRAL

Hepatitis A (ssRNA; 30–45% of acute viral hepatitis in U.S.)

•  Transmission: fecal–oral route; contaminated food, water, shellfish; daycare ctr outbreaks

•  Incubation: 2–6 wk; no chronic carrier state

•  Sx: ↓ appetite, malaise, fever, N/V, RUQ pain, ± jaundice; rarely fulminant

•  Diagnosis: acute hepatitis =  IgM anti-HAV; past exposure =  IgG anti-HAV ( IgM)

•  Treatment for acute HAV supportive. Prevention: vaccinate children & Pts w/ chronic HBV, HCV (? if cost-effective) or other chronic liver disease (2 doses at 0, 6–12 mo)

•  Postexposure ppx: age 1–40 y → vaccine; age <1 or >40 y or immunosupp → Ig

Hepatitis B (dsDNA; ~45% of acute viral hepatitis in U.S.; Lancet 2009;373:582)

•  Transmission: blood (IVDU, transfusion), sexual, perinatal

•  Incubation: 6 wk–6 mo (mean 12–14 wk)

•  Acute infxn: 70% subclinical, 30% jaundice, <1% fulminant hepatitis (up to 60% mortality)

•  Chronic infxn: <5% (adult-acquired; higher if immunosupp), >90% (perinatally acquired); ~40% chronic carriers → cirrhosis; ↑ risk of cirrhosis if HCV, HDV or HIV coinfection

•  Hepatocellular carcinoma (w/ or w/o concurrent cirrhosis); ↑ risk w/ perinatal transmission & ↑’d HBV DNA. Screen chronic carriers w/ AFP & U/S vs. MRI q6mo.

•  Extrahepatic syndromes: PAN (<1%), MPGN, arthritis, dermatitis, PMR

•  Serologic and virologic tests

HBsAg: appears before sx; used to screen blood donors; persists >6 mo = chronic HBV

HBeAg: evidence of viral replication and ↑ infectivity

IgM anti-HBc: first Ab to appear; indicates acute infection window period = HBsAg become , anti-HBs not yet , anti-HBc only clue to infection

IgG anti-HBc: indicates previous (HBsAg ) or ongoing (HBsAg ) HBV infection

anti-HBe: indicates waning viral replication, ↓ infectivity

anti-HBs: indicates resolution of acute disease & immunity (sole marker after vac)

HBV DNA: presence in serum correlates w/ active viral replication in liver

Figure 3-7 Serologic course of acute HBV infection with resolution

•  Treatment for acute HBV: supportive; hospitalize for Δ MS or ↑ INR (liver transplant ctr)

•  Treatment for chronic HBV if: (1) HBeAg  w/ DNA >20,000 IU/mL & elevated ALT; (2) HBeAg  w/ DNA >2000 IU/mL & elevated ALT or liver bx demonstrates stage ≥2 fibrosis (NEJM2008;359:1486; Hep 2009;50:661; Clin Gas Hep 2011;9:285)

•  1st line is nucleo(s/t)ide analogues: entecavir or tenofovir; well tolerated & low resistance (1% for entecavir at 5 y in Rx-naïve Pts); at 5 y HBeAg seroconversion is 30–40% & loss of HBsAg is 5–10% (Gastro 2012;142:1360; Lancet 2013;381:468)

•  PEG IFNɑ-2a: best rate of HBeAg seroconversion at 1 y (27%), low tolerability limits use

•  Goal: if HBeAg  → HBeAg , anti-HBe ; if HBeAg  or  seroconversion or Asian Pt → indefinite tx or until HBsAg clears (if ever)

•  If undergo liver transplant: HBIG + nucleo(s/t)ide analogue effective in preventing reinfection

•  HIV/HBV coinfection: Rx w/ 2 drugs active against both HBV & HIV (NEJM 2007;356:1445)

•  If inactive carrier scheduled to receive immunosuppression/chemotherapy → Rx

•  Prevention: vaccinate all infants & children and at-risk adults (3 doses 0, 1 & 6–12 mo)

•  Postexposure (risk infxn ~30%) ppx: HBIG → vaccine (if unvac or known nonresponder)

Hepatitis C (ssRNA; ~10% of acute viral hepatitis in U.S.; NEJM 2011;364:2429)

•  Transmission: blood (IVDU, transfusion) >> sexual; 20–30% w/o clear precipitant

•  Incubation: 1–5 mo; mean 6–7 wk

•  Natural hx

acute infxn: 80% subclinical; 10–20% sx hepatitis w/ jaundice; fulminant hepatitis very rare; prob of spont clearance a/w IL28B & HLA class II genotypes (Annals 2013;158:235)

chronic: up to 85% → chronic hepatitis, 20–30% of whom develop cirrhosis (after ~20 y) ↑ risk of cirrhosis in men, EtOH, HIV; HCC in 2–5% of cirrhotics/y

•  Extrahepatic syndromes: cryoglobulinemia, porphyria cutanea tarda (blistering rash in sun-exposed areas), MPGN, MGUS, IPF, NHL and DM

•  Serologic, virologic, & genetic tests

anti-HCV (ELISA):  in 6 wk, does not = recovery or immunity; can be  after recovery

HCV RNA:  w/in 2 wk, marker of active infection

HCV RIBA: used to confirm  anti-HCV ELISA in Pts w/ undetectable HCV RNA

HCV genotype (1–6): guides duration & predicts response to Rx

•  Dx: acute hepatitis =  HCV RNA, ± anti-HCV; resolved =  HCV RNA, ± anti-HCV; chronic =  HCV RNA,  anti-HCV

•  Treatment indications (Hep 2009;49:1335 & 2011;54:1433; NEJM 2013;368:1907)

Acute: if no spont. clearance at 8–12 wk, consider PEG-IFNɑ-2a/b ± RBV × 12–24 wk

Chronic: RNA , plus bx w/ either chronic hepatitis & fibrosis stage >1 or compensated liver disease (in genotype 2 or 3, may proceed to Rx w/o bx b/c high response rate)

•  Triple therapy (genotype 1): PEG-IFN ɑ-2a/b, RBV, & protease inhibitor (PI), either boceprevir (BOC) or telaprevir (TVR) (NEJM 2011;364:1195 & 2405). Rx 24–48 wk; SVR rate 30–80% based on variables such as advanced fibrosis, IL28B genotype, prior response to IFN and rapid virologic resp ( RNA at wk 4 [TVR] or wk 8 [BOC]) (Gastro 2012;142:1314)

•  Dual therapy (genotypes 2 & 3): PEG-IFNɑ-2a/b + RBV; Rx 24 wk; SVR rate ~80%

•  Goal is sustained virologic response (SVR) =  viremia 24 wk after completion of Rx

•  IFN-free regimens incl. replic. complex, polymerase, & microRNA-122 inhibs. & other direct acting antivirals under study (NEJM 2012;366:216; 2013;368:34, 45, 1685, 1867 & 1878)

•  Risks of Rx: flu-like sx, psych sx (if depressed can give SSRI), thyroid dysfxn, marrow suppression (can give EPO & G-CSF), hemolysis (RBV), sexual dysfxn; PIs w/ sig drug-drug interactions, worsen anemia, & TVR a/w rash/pruritus in 6%, DRESS/SJS in <1%

•  Contraindic.: decompensated cirrhosis, preg, severe psych illness, active substance abuse, severe cardiac/pulm disease, uncontrolled DM, seizure d/o, autoimmune disease

•  CDC rec screening for HCV in anyone born 1945–1965 (Annals 2012;156:263)

•  Vaccinate all chronic HCV patients against HBV and HAV if not immune

•  Postexposure (needlestick risk ~3%) ppx: none; if HCV RNA → , consider Rx w/in 3 mo

Hepatitis D (RNA)

•  Transmission: blood or sexual; endemic in Africa & E. Europe

•  Pathogenesis: requires HBV to cause either simultaneous or superimposed infection

•  Natural hx: in HBV ↑ severity of infxn and ↑ progression to cirrhosis and HCC in chronic carriers; clears w/ HBV

•  Serologic/virologic tests: anti-HDV; follow HDV RNA during Rx (high relapse rate)

Hepatitis E (ssRNA; NEJM 2012;367:1237; Lancet 2012;379:2477)

•  In endemic areas most common cause of acute viral hepatitis

•  Transmission: fecal–oral; travelers to central & SE Asia, Africa and Mexico, exp. to swine

•  Natural hx: acute hepatitis w/ ↑ mort. (10–20%) if pregnant; rare chronic in transplant Pts

•  Dx: IgM anti-HEV (through CDC)

•  Extrahepatic sx: arthritis, pancreatitis, neuro (GBS, inflam polyradic., meningoenceph.)

Other viruses (HGV, CMV, EBV, HSV, VZV)

AUTOIMMUNE HEPATITIS (AIH)

Classification (J Hep 2011;55:171; Hep 2010;51:1)

•  Type 1: antismooth muscle Ab (ASMA), ANA; antisoluble liver antigen (anti-SLA), a/w more severe disease and relapsing disease

•  Type 2: anti–liver/kidney microsome 1 (anti-LKM1) or liver/cytosol (LC1); kids (2–14 y)

•  Overlap syndrome: AIH + PBC or PSC; Rx-induced: minocycline, nitrofurantoin, infliximab

Diagnosis and treatment

•  70% female; 40% present acutely (occ. fulminant); 34% asx; ALT can be >1000

•  Extrahepatic syndromes: thyroiditis, arthritis, UC, Sjögren’s, Coombs’  hemolytic anemia

•  Dx: scoring system combining serologies, ↑ IgG,  viral hepatitis, & characteristic liver bx (lymphoplasmacytic infiltrate & interface hepatitis) has high Sp & mod Se (Hep 2008;48:169)

•  Rx: if LFTs 10× ULN, or if 5× ULN w/ IgG 2× ULN, or bridging/multiacinar necrosis on bx

•  Prednisone + azathioprine → 65% remission w/in 3 y; 50% relapse on withdrawal of meds at 6 mo; up to 90% by 3 y; ∴ most will require long-term Rx; consider substituting budesonide for pred in noncirrhrotics w/ Rx-naive AIH (Gastro 2010;139:1198)

•  Liver transplant for ESLD; recurs in ~30% of Pts, but generally easily treated

OTHER CAUSES OF HEPATITIS OR HEPATOTOXICITY

Alcoholic hepatitis (NEJM 2009;360:2758; Clin Liv Dis 2012;16:371)

•  Sxs: can range from asx hepatomegaly to decompensation w/ ascites, encephalopathy and death. AST & ALT usually <300–500 w/ AST:ALT > 2:1, in part b/c concomitant B6 defic (ALT can be normal); ↓ plt, ↑ iron sat, ↑’d Tbili & INR indicate severe hepatitis.

•  Rx: if discriminant fxn (= 4.6 × [PT-control] + Tb in mg/dL) >32 or encephalopathy

methylprednisolone 32 mg/d × 4 wk → 4–6 wk taper; ↓ death (NEJM 1992;326:507) contraindications: GIB, chronic HBV, severe infections such as sepsis

pentoxifylline 400 mg tid ↓ mortality due to reduction in HRS (Coch 2009;4:CD007339)

NAC + steroids ↓ 30-d but not 6-mo mortality (NEJM 2011;365:1781)

•  Lille model predicts nonresponse to corticosteroids & mortality, powered by Δ Tb from day 1 → 7; nonresponders have 6-mo survival of 25% (www.lillemodel.com; Hep 2007;45:1348)

Acetaminophen hepatotoxicity (NEJM 2008;359:285; BMJ 2011;342:d2218)

•  Normal metabolism via glucuronidation and sulfation → nontoxic metabolites

•  Overdose (usually >10 g): CYP2E1 hydroxylation → reactive electrophilic species (NAPQI) that are scavenged by glutathione until reserves exhausted → hepatotoxicity

•  CYP2E1 induced by fasting and alcohol allowing for “therapeutic misadventure” in malnourished alcoholics taking even low doses (2–6 g) of acetaminophen

•  Liver dysfunction may not be apparent for 2–6 d

•  Rx: NG lavage, activated charcoal if w/in 4 h. Consider early transfer to transplant ctr.

N-acetylcysteine: administer up to 72 h after ingestion, if time of ingestion unknown or if chronic ingestion >4 g/d

Rumack-Matthew nomogram (www.tylenolprofessional.com/assets/Nomogram.pdf) predicts risk of hepatotoxicity from serum level of acetaminophen when time of ingestion is known

Low threshold to start NAC even w/ low or undetectable serum acetaminophen levels

PO NAC (preferred): 140 mg/kg loading dose → 70 mg/kg q4h × 17 additional doses

IV NAC: 150 mg/kg over 1 h → 50 mg/kg over 4 h → 100 mg/kg over 16 h; risk of anaphylaxis; use if unable to tolerate POs, GIB, preg, fulminant hepatic failure

Ischemic hepatitis

•  “Shock liver” w/ AST & ALT >1000 + ↑↑ LDH; delayed ↑↑ Tbili

•  Seen in HoTN & CHF; often requires ↑ venous + ↓ portal/arterial pressure + hypoxia

Nonalcoholic fatty liver disease (NAFLD, a spectrum of disease; Hep 2012;55:2005)

•  Definition: fatty infiltration of liver and absence of EtOH or other cause of steatosis (TPN, rapid wt loss or Rxs such as HAART, tamoxifen, amiodarone, MTX)

NAFL = steatosis,  inflammation; NASH = steatosis + inflammation ± fibrosis on liver bx

•  NAFLD: 10–30% of U.S. pop. & over 60% in T2DM & obesity

•  NASH: 2–5% of NAFLD & risk of cirrhosis in NASH w/ fibrosis on bx is 30% at 10 y

•  Pathophys: hepatic lipotoxicity w/ oxidant stress & inflammatory response; PNPLA3 high-risk SNP confers ↑ risk of hepatic fat content, NASH, & fibrosis (Hep 2011;53:1883)

•  Clinical: 80% asx, ↑ ALT > AST, but nl ALT/AST does not exclude poss. of NASH on bx

•  Dx: based on clinical variables & imaging. Liver bx remains gold standard. NAFLD fibrosis score (www.nafldscore.com) = clinical variables to predict NASH w/ advanced fibrosis.

•  Rx: wt loss, exercise, DM/lipid control (statins; Lancet 2010;376:1916); pioglitazone + vit E ↓ steatosis & inflam, not fibrosis (NEJM 2010;362:1675). Pentoxifylline under study (Hep 2011;54:1610).