Gastrointestinal

Acute viral hepatitis: hepatitis A, B, C, D, E

Clinical Overview and When to Suspect Acute Viral Hepatitis

— New jaundice, dark urine, acholic stools, RUQ discomfort, malaise, anorexia, low-grade fever, nausea

— Markedly elevated aminotransferases with ALT > AST (helps distinguish from alcoholic hepatitis where AST>ALT and rarely >500)

— Exposure clue in stem: travel to endemic area, undercooked shellfish, daycare outbreak, IVDU, new tattoo/piercing, MSM, needlestick, transfusion before 1992, hemodialysis, perinatal exposure, pregnancy in South Asia

— HAV, HEV: fecal–oral (the "vowels come from the bowels")

— HBV, HCV, HDV: parenteral/sexual/perinatal

— HEV: zoonotic via undercooked pork in developed countries; waterborne in endemic regions

— HAV 15–50 d, HEV 15–60 d, HBV 30–180 d, HCV 14–180 d, HDV requires HBV

— HAV, HEV: self-limited; no chronic state (HEV genotype 3 can chronicify in immunosuppressed)

— HBV: chronic in 5% adults, 90% perinatal

— HCV: chronic in ~75–85%

— HDV: only in HBsAg-positive patients; coinfection vs superinfection

Board pearl: A young adult with jaundice, ALT 2,400, AST 1,800, and recent shellfish ingestion → suspect HAV; order anti-HAV IgM first, not a hepatitis panel shotgun, when the exposure is classic.

Step 3 management: Most acute viral hepatitis is managed outpatient with supportive care; admit only for INR ≥1.5, encephalopathy, intractable vomiting, or bilirubin >15.

Acute viral hepatitis = acute hepatocellular injury (ALT/AST often >10× ULN, frequently >1000 U/L) caused by hepatotropic viruses A, B, C, D, E, presenting within weeks of exposure.

When to suspect on Step 3:

Transmission shortcuts:

Incubation windows (useful for stems):

Outcomes by virus:

Acute liver failure (ALF) risk: highest with HBV (especially with HDV superinfection) and HEV in pregnancy (mortality up to 20–25% in 3rd trimester).

Presentation Patterns and Key History

— Incubation: asymptomatic viral replication

— Prodromal (preicteric): 1–2 wk of flu-like malaise, anorexia, nausea, distaste for cigarettes, RUQ pain, low-grade fever; ALT rising

— Icteric: jaundice, dark urine (bilirubinuria precedes scleral icterus by days), pale stools, pruritus; symptoms paradoxically improve as bilirubin peaks

— Convalescent: weeks to months; fatigue lingers

— Children with HAV (>70% subclinical under age 6)

— Acute HCV (only ~25% jaundiced — explains why HCV is usually caught chronically)

— Acute HBV in adults often subclinical

— HBV: serum sickness–like syndrome (urticaria, arthralgias, fever) in prodrome from immune complexes; polyarteritis nodosa, membranous nephropathy

— HCV: mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, MPGN (more chronic, but tested)

— HEV: Guillain-Barré, neuralgic amyotrophy

— HAV: rare cholestatic variant with prolonged pruritus and jaundice up to 18 wk

— Travel within 6 months, especially Mexico, Central/South America, South Asia, sub-Saharan Africa

— Sexual history, number of partners, MSM, anal-oral contact

— IVDU, intranasal cocaine, tattoos/piercings outside licensed shops, incarceration

— Occupation: healthcare, daycare, food service, sewage workers

— Transfusion before 1992 (HCV) or 1972 (HBV)

— Household contact with hepatitis case

— Acetaminophen, herbal supplements, mushroom ingestion (rule out alternative)

Key distinction: Symptoms peaking as transaminases fall and bilirubin rises is typical of viral hepatitis; persistent rising AST/ALT with worsening INR suggests evolving acute liver failure — escalate.

Board pearl: "Aversion to smoking" in a 22-year-old daycare worker = HAV until proven otherwise.

Classic four-phase clinical course (most apply to HAV, symptomatic HBV, HEV):

Anicteric or asymptomatic presentations dominate in:

Extrahepatic clues by virus:

Key history elements to elicit (Step 3 stems plant these):

Physical Exam Findings and Hemodynamic Assessment

— Mild–moderate illness; scleral icterus when total bilirubin >2.5–3 mg/dL

— Jaundice best seen under natural light at sclerae and sublingual frenulum

— Excoriations from pruritus (cholestatic phase)

— Tender hepatomegaly in 60–80% — smooth, mildly enlarged liver edge

— Splenomegaly in ~15% (more with HBV/HCV)

— No ascites, no caput medusae, no palmar erythema, no spider angiomata — these point to chronic liver disease and should prompt reframing

— Usually normal vitals; tachycardia suggests dehydration from poor PO intake or impending decompensation

— Hypotension + jaundice → consider sepsis, ALF with SIRS, or alternative diagnosis (ischemic hepatitis)

— Encephalopathy: subtle (day-night reversal, impaired serial 7s) to overt (asterixis, somnolence, coma)

— Asterixis: have patient extend wrists, dorsiflex fingers x 30 sec

— Fetor hepaticus

— Worsening jaundice with shrinking liver span (ominous — massive necrosis)

— Bruising, mucosal bleeding, oozing IV sites → coagulopathy

— Urticaria/arthritis-like rash in HBV prodrome (serum sickness)

— Palpable purpura on lower extremities in HCV cryoglobulinemia

— Track marks, tattoos (epidemiologic clues)

CCS pearl: On the CCS interface, order "mental status exam" and "neurologic exam" at each visit when acute hepatitis is on the differential — catching grade I encephalopathy early triggers ICU transfer and transplant center contact, scoring management points.

Key distinction: Stigmata of chronic liver disease (gynecomastia, spider angiomata, ascites, caput) in a "first jaundice" presentation = acute-on-chronic, not acute viral hepatitis alone — change your evaluation.

General appearance:

Abdominal exam:

Hemodynamics:

Red flags for acute liver failure (ALF) — examine for these every visit:

Skin exam:

Lymphadenopathy: small posterior cervical nodes can occur; prominent adenopathy should prompt EBV/CMV workup.

Diagnostic Workup — Initial Labs

— AST, ALT — typically 500–5,000; ALT > AST

— Total and direct bilirubin — direct predominant in hepatocellular pattern

— Alkaline phosphatase — mildly elevated; markedly high suggests cholestatic variant or alternative

— GGT — supports hepatic origin of ALP

— Albumin, total protein

— PT/INR — single most important prognostic lab; INR ≥1.5 with any encephalopathy = ALF

— CBC (atypical lymphocytes suggest viral; thrombocytopenia → chronic disease)

— BMP — assess hydration, renal function

— Glucose — hypoglycemia is an ominous ALF sign

— Lipase — viral hepatitis can cause pancreatitis (HAV, HEV)

— Acetaminophen level — always send in new acute liver injury, regardless of history

— Pregnancy test in reproductive-age women (HEV implications)

— Anti-HAV IgM (acute HAV)

— HBsAg, anti-HBc IgM, anti-HBs (acute HBV pattern: HBsAg+, IgM anti-HBc+)

— Anti-HCV antibody + HCV RNA (anti-HCV may be negative in window; HCV RNA confirms acute infection)

— Anti-HEV IgM (especially with travel, pregnancy, pork exposure, or unexplained hepatitis)

— Anti-HDV only if HBsAg positive

— EBV VCA IgM, CMV IgM, HSV PCR (immunocompromised), HIV

— ANA, ASMA, anti-LKM, IgG (autoimmune hepatitis can mimic)

— Ceruloplasmin in <40 y with Coombs-negative hemolysis or ALF

— Iron studies; ferritin extremely high in ALF

Board pearl: Anti-HBc IgM is the marker that catches the window period of acute HBV when HBsAg has cleared but anti-HBs has not yet appeared — memorize this.

Step 3 management: If INR ≥1.5 or any altered mental status, do not wait for serology — admit and contact transplant center.

First-line panel for any suspected acute hepatitis:

Viral serology panel — order all initially when source unclear:

Adjunctive serologies when indicated:

Urinalysis: bilirubinuria precedes jaundice; useful early clue.

Diagnostic Workup — Advanced and Confirmatory Studies

— Acute HBV: HBsAg+, anti-HBc IgM+, HBeAg+, HBV DNA high, anti-HBs–

— Window period: HBsAg–, anti-HBs–, anti-HBc IgM+ (only positive marker)

— Chronic HBV: HBsAg+ >6 mo, anti-HBc IgG+, IgM–, anti-HBs–

— Resolved: HBsAg–, anti-HBc IgG+, anti-HBs+

— Vaccinated: anti-HBs+ only, anti-HBc negative

— Isolated anti-HBc: occult infection, false positive, or remote resolved — check HBV DNA

— Anti-HCV+ → reflex HCV RNA (quantitative)

— In acute HCV, RNA may be detectable before antibody seroconversion (window ~4–10 wk)

— Genotype no longer required for most pangenotypic DAA regimens but still ordered in complex cases

— Order anti-HDV total in every HBsAg-positive patient at least once (CDC 2023)

— Confirm active infection with HDV RNA

— Distinguish coinfection (anti-HBc IgM+) from superinfection (anti-HBc IgG+) — superinfection has worse prognosis

— Anti-HEV IgM (acute), HEV RNA (immunosuppressed, chronic HEV, pregnancy)

— RUQ ultrasound with Doppler for all acute hepatitis to exclude biliary obstruction, Budd-Chiari, mass, and to assess parenchyma

— CT/MRI generally not first-line; MRCP if biliary disease suspected

— Rarely needed in acute viral hepatitis

— Reserve for diagnostic uncertainty (rule out AIH, drug-induced, infiltrative), often transjugular if coagulopathic

— King's College Criteria for transplant listing

— MELD for chronic decompensation

Key distinction: HBeAg marks high infectivity and active replication; anti-HBe appears with seroconversion and lower replication — not a marker of acute vs chronic by itself.

Board pearl: Anti-HBs+ with anti-HBc+ = past infection (immune); anti-HBs+ alone = vaccinated. Tested every year.

Interpreting HBV serology — high-yield matrix:

HCV confirmation:

HDV testing:

HEV:

Imaging:

Liver biopsy:

Prognostic scores in ALF:

Risk Stratification and First-Line Management Logic

— Low risk (outpatient): tolerating PO, INR <1.5, bilirubin <15, no encephalopathy, reliable follow-up, no comorbid cirrhosis

— Moderate (admit ward): intractable vomiting/dehydration, bilirubin 15–25, INR 1.5–2 without encephalopathy, social barriers

— High (ICU/transplant center): INR ≥2, encephalopathy any grade, hypoglycemia, rising creatinine, shrinking liver, hemodynamic instability → acute liver failure

— Supportive care: hydration, antiemetics (ondansetron preferred; avoid prochlorperazine in hepatic dysfunction), nutrition, rest as tolerated

— Stop hepatotoxins: alcohol, acetaminophen >2 g/day, herbals, statins (temporarily), unnecessary meds

— Avoid sedatives that mask encephalopathy

— Pain control: acetaminophen ≤2 g/day acceptable; avoid NSAIDs (renal, bleeding risk)

— Vaccinate against the other hepatitis viruses (HAV vaccine if HBV/HCV patient is non-immune; HBV vaccine if HCV or HAV patient is non-immune)

— HAV, HEV: supportive only; no antivirals in immunocompetent

— Acute HBV: supportive in immunocompetent adults (>95% clear); antivirals (entecavir/tenofovir) if severe (INR ≥1.5, bilirubin >10, persistent symptoms >4 wk, encephalopathy) or immunocompromised

— Acute HCV: treat with DAAs — current AASLD/IDSA endorses treatment at diagnosis; do not wait for spontaneous clearance in most adults

— HDV: treat underlying HBV; consider bulevirtide where available

Step 3 management: New acute HCV diagnosis → start pangenotypic DAA (glecaprevir/pibrentasvir 8 wk or sofosbuvir/velpatasvir 12 wk) rather than observation; SVR >95% and prevents chronicity.

CCS pearl: Order "advance to regular diet as tolerated" early — there is no role for NPO or low-protein diets in acute viral hepatitis without encephalopathy.

Stratification framework on presentation:

Core management principles (all viruses):

Virus-specific first-line logic:

Contact tracing and post-exposure prophylaxis (PEP) initiated immediately — see chunk 15.

Pharmacotherapy — First-Line Regimens

— No antivirals

— Symptomatic: ondansetron 4–8 mg PO/IV q8h prn; IV fluids; cholestyramine for pruritus in cholestatic variant

— Most adults: no antivirals — observation with weekly LFTs/INR

— Indications to treat acute HBV:

– INR ≥1.5

– Total bilirubin >10 mg/dL persisting >4 wk

– Any encephalopathy

– Immunocompromised host

– Coinfection with HCV or HDV

— Regimen: tenofovir alafenamide (TAF) 25 mg daily or entecavir 0.5 mg daily (avoid entecavir in lamivudine-resistant)

– TAF preferred over TDF if osteoporosis, CKD, or in elderly

– Continue until HBsAg seroconversion + 12 wk consolidation

— Pangenotypic DAA regimens:

– Glecaprevir/pibrentasvir 300/120 mg daily × 8 wk (preferred; avoid in decompensated)

– Sofosbuvir/velpatasvir 400/100 mg daily × 12 wk (safe in decompensated cirrhosis)

— No ribavirin needed for treatment-naive without cirrhosis

— Drug interactions: glecaprevir/pibrentasvir contraindicated with atazanavir, rifampin, carbamazepine, ethinyl estradiol; sofosbuvir/velpatasvir cannot be combined with amiodarone (bradycardia)

— Check HBsAg, anti-HBc before DAAs — HBV reactivation risk; start HBV antiviral prophylaxis if HBsAg+

— Treat HBV with tenofovir/entecavir

— Bulevirtide 2 mg SC daily (entry inhibitor, EMA-approved; FDA pending) for chronic HDV

— Pegylated interferon-α 48 wk historical option

— Immunocompetent: supportive

— Immunocompromised with chronic HEV: reduce immunosuppression first; ribavirin 600 mg/day × 12 wk if persistent

Board pearl: N-acetylcysteine has shown benefit in non-acetaminophen ALF with early-grade encephalopathy — give while arranging transfer.

Key distinction: Acute HBV → usually no antiviral; acute HCV → treat immediately. Opposite intuition from chronic management for some students.

Hepatitis A:

Hepatitis B (acute):

Hepatitis C (acute):

Hepatitis D:

Hepatitis E:

Expanded Pharmacology and Adjuncts

— Antiemetics: ondansetron first-line; metoclopramide acceptable; avoid prochlorperazine, promethazine (sedation masks encephalopathy)

— Pruritus: cholestyramine 4 g BID–QID, hydroxyzine sparingly, UDCA 13–15 mg/kg/d in cholestatic HAV

— Pain: acetaminophen ≤2 g/day acceptable; avoid NSAIDs, tramadol, opioids unless essential

— Antipyretic: acetaminophen low dose preferred over NSAIDs

— Statins (resume after ALT <3× ULN)

— Methotrexate, azathioprine, valproate, isoniazid, amiodarone, nitrofurantoin

— Oral contraceptives (cholestasis risk)

— Herbal supplements (kava, comfrey, green tea extract, ma huang)

— Patients with new HCV: vaccinate against HAV and HBV if non-immune

— Patients with new HBV: vaccinate household and sexual contacts; HAV vaccine if non-immune

— HAV PEP within 2 weeks: HAV vaccine for healthy ages 1–40; immune globulin (IG) 0.1 mL/kg IM for <1 yr, >40, immunocompromised, chronic liver disease (can give both in high-risk)

— HBV PEP within 24 h ideally, ≤7 d perc, ≤14 d sexual: HBIG 0.06 mL/kg IM + HBV vaccine if exposed person unvaccinated/non-responder

— HCV: no PEP available; baseline + 3- and 6-month HCV RNA testing

— Baseline HBsAg, anti-HBc, HIV, eGFR, pregnancy test

— On-treatment ALT and HCV RNA at week 4

— SVR12: undetectable HCV RNA 12 wk post-therapy

CCS pearl: When ordering tenofovir, choose TAF for elderly or eGFR 15–60; TDF for younger patients without renal/bone risk — case-tailoring matters.

Step 3 management: Always screen for HBV before starting DAAs, rituximab, or chemotherapy — reactivation can be fatal.

Symptom-directed agents (all viruses):

Drugs to stop or hold in acute hepatitis:

Vaccination integrated with pharmacotherapy:

Post-exposure prophylaxis (PEP) pharmacology:

DAA monitoring:

Interferon: largely obsolete for HBV/HCV in 2024 except select HDV until bulevirtide widely available.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher risk of symptomatic HAV with cholestatic course, prolonged jaundice, hospitalization, mortality up to 1.8%

— More likely to need HAV IG rather than vaccine alone for PEP

— Acute HBV in elderly: lower chronicity risk but higher fulminant risk

— Polypharmacy review essential — discontinue hepatotoxins

— Atypical presentations: confusion may be only sign of early encephalopathy; check ammonia, MMSE serially

— Tenofovir TDF requires dose adjustment <50 mL/min; switch to TAF if eGFR 15–60 (no adjustment) or entecavir (adjust)

— Sofosbuvir-based DAAs safe at any eGFR including dialysis (label updated 2019)

— Glecaprevir/pibrentasvir: safe in CKD including dialysis

— Ribavirin: avoid if CrCl <50; dose-reduce and monitor Hb

— HCV-associated cryoglobulinemic MPGN: treat HCV with DAAs first; rituximab if severe

— Hemodialysis units: outbreaks of HBV and HCV historically — screen all dialysis patients quarterly

— Acute viral hepatitis on cirrhosis = acute-on-chronic liver failure (ACLF) — high mortality

— Avoid protease inhibitors (glecaprevir, voxilaprevir) in Child-Pugh B/C

— Sofosbuvir/velpatasvir ± ribavirin is the DAA of choice in decompensated cirrhosis

— Entecavir or tenofovir safe in cirrhosis; avoid interferon

— Monitor for variceal bleed, SBP, HRS during admission

— HEV genotype 3 can cause chronic hepatitis — reduce immunosuppression, then ribavirin

— HBV reactivation prophylaxis with entecavir/tenofovir during immunosuppression

Board pearl: A 70-year-old with HAV, bilirubin 18, ALT 1,200 — admit; elderly HAV is not the benign childhood disease.

Key distinction: Avoid protease-inhibitor DAAs (anything ending "-previr") in decompensated cirrhosis — they can worsen hepatic decompensation.

Elderly (≥65):

Renal impairment:

Hepatic impairment / cirrhosis:

Transplant recipients:

Special Populations — Pregnancy and Pediatrics

— HEV in 3rd trimester: fulminant hepatic failure in up to 20–25%; fetal demise common — counsel travelers to endemic regions to avoid travel; no licensed HEV vaccine in US (available in China)

— HBV in pregnancy:

– Screen all pregnant women for HBsAg at first prenatal visit (USPSTF, ACOG)

– HBsAg+ mother: check HBV DNA; if >200,000 IU/mL → tenofovir (TDF) from week 28 to 4 wk postpartum to reduce vertical transmission

– Newborn of HBsAg+ mother: HBIG + HBV vaccine within 12 hours of birth; complete series; post-vaccination serology at 9–12 mo

– Breastfeeding not contraindicated with HBV if infant vaccinated

— HCV in pregnancy:

– Universal HCV screening recommended at first prenatal visit (USPSTF 2020)

– DAAs not yet routinely recommended in pregnancy (off-label; sofosbuvir/ledipasvir studied)

— Treat postpartum; infant tested with HCV RNA at 2–6 mo or anti-HCV after 18 mo

– Breastfeeding allowed unless cracked/bleeding nipples

— HAV vaccine is inactivated — safe in pregnancy when indicated

— HAV mostly subclinical in children <6; vaccinate all at age 12–23 months (2-dose series)

— HBV universal birth dose vaccine within 24 h, then 1 and 6 months; 90% chronicity if untreated perinatal infection

— HCV vertical transmission ~6% (higher with HIV co-infection); test exposed infants

— Pediatric DAAs FDA-approved down to age 3 (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir)

— Reye syndrome historical link to aspirin during viral illness — avoid ASA in children with viral hepatitis

Step 3 management: HBsAg+ mother with HBV DNA 1.5 million IU/mL → start tenofovir at 28 wk, deliver per obstetric indications, newborn gets HBIG + vaccine in delivery room.

Board pearl: HEV + pregnancy = highest mortality of any viral hepatitis scenario, especially genotype 1 in South Asia.

Pregnancy:

Pediatrics:

Complications and Adverse Outcomes

— Defined as INR ≥1.5 + encephalopathy + no prior chronic liver disease, within 26 wk of jaundice

— Highest risk: HBV (1%), HBV+HDV superinfection (up to 20%), HEV in pregnancy

— Cerebral edema is leading early ICU cause of death; intracranial hypertension management with hypertonic saline, mannitol

— Coagulopathy: do not transfuse FFP empirically unless bleeding or pre-procedure — INR is needed for prognosis

— Hypoglycemia, lactic acidosis, AKI, sepsis, ARDS

— HBV chronicity: 90% perinatal, 30% age 1–5, <5% adult

— HCV chronicity: 75–85%

— Chronic HBV/HCV → cirrhosis (20–30% over 20–30 yr) → HCC

— Surveillance with US ± AFP every 6 months in cirrhotic patients and select non-cirrhotic HBV (Asian men >40, African >20, family history of HCC, HDV coinfection)

— HBV: polyarteritis nodosa, membranous nephropathy, serum sickness

— HCV: mixed cryoglobulinemia (palpable purpura, arthralgia, neuropathy, MPGN), porphyria cutanea tarda, lichen planus, B-cell NHL, insulin resistance

— HEV: Guillain-Barré, neuralgic amyotrophy, encephalitis, pancreatitis

— HAV: rare autoimmune hepatitis trigger

— HAV ~0.3% overall, up to 1.8% >50 yr

— HBV acute mortality ~1%, fulminant 30%

— HEV 1–3% general, 20% pregnant 3rd trimester

Board pearl: Palpable purpura + arthralgia + neuropathy + low C4 = HCV cryoglobulinemia — order cryocrit, complements, HCV RNA.

Key distinction: HBV superinfection with HDV = worst acute outcome; coinfection (simultaneous) is usually self-limited.

Acute liver failure (ALF):

Chronic infection:

Cirrhosis and HCC:

Extrahepatic complications:

Aplastic anemia, pancytopenia: rare post-viral hepatitis complication, especially seronegative variant

Cholestatic hepatitis A: prolonged jaundice, pruritus, weight loss; resolves

Relapsing hepatitis A: 10% have biphasic course over 6–9 months — still no chronicity

Mortality:

When to Escalate — ICU, Consult, Inpatient Triage

— INR <1.5

— Bilirubin <15 mg/dL and not rising rapidly

— Tolerating PO, hydrated

— No encephalopathy or coagulopathy

— Reliable follow-up within 48–72 h

— Stable social situation, access to phone

— Persistent vomiting, dehydration

— Bilirubin 15–25 or rising

— Comorbid pregnancy with HEV

— Elderly with significant symptoms

— Significant coagulopathy without encephalopathy (INR 1.5–2)

— Need for IV antiemetics, fluids, observation

— INR ≥2 or rapidly rising

— Any grade of encephalopathy

— Hypoglycemia, lactic acidosis

— Rising creatinine, oliguria

— Hemodynamic instability

— Cerebral edema concern (papilledema, posturing)

— Contact transplant center early — King's College Criteria are retrospective; do not wait

— INR >6.5, or any 3 of:

– Age <10 or >40

– Etiology: non-A non-B hepatitis, drug, halothane

– Jaundice >7 days before encephalopathy

– INR >3.5

– Bilirubin >17.5 mg/dL

— Hepatology early in any concerning case

— Infectious disease for HIV coinfection, occupational exposure, HDV

— OB for HEV in pregnancy

— Social work, public health for contact tracing, PrEP/PEP, substance use referral

CCS pearl: On CCS, transfer to ICU and "consult hepatology, consult transplant surgery" as soon as INR ≥1.5 with encephalopathy — order BMP, glucose q4h, ammonia, neurochecks q1h.

Step 3 management: Pregnancy + HEV + jaundice = admit immediately; do not discharge home regardless of vitals.

Outpatient management criteria (all of):

General ward admission:

ICU and transplant center transfer — any of:

King's College Criteria for transplant in non-acetaminophen ALF (any one):

Consultations:

Key Differentials — Other Viral and Infectious Hepatitides

— EBV: heterophile-positive mononucleosis, atypical lymphocytes, splenomegaly, mild ALT/AST elevation (usually <500); rash with amoxicillin

— CMV: similar to EBV but heterophile-negative; common in immunocompromised, post-transplant

— HSV hepatitis: rare but fulminant; pregnancy 3rd trimester, immunocompromised; anicteric, very high AST/ALT (>5,000), thrombocytopenia, fever — treat empirically with IV acyclovir if suspected

— VZV: disseminated varicella with hepatitis in immunocompromised

— Adenovirus: pediatric, transplant recipients

— Yellow fever, dengue, Lassa, Ebola: travel-related hemorrhagic fevers

— SARS-CoV-2: mild transaminitis common; severe hepatitis rare

— Leptospirosis (Weil disease): jaundice, AKI, conjunctival suffusion, calf myalgia, freshwater exposure

— Q fever (Coxiella burnetii): granulomatous hepatitis, livestock exposure, doughnut granulomas

— Brucella, syphilis (secondary), TB, rickettsia: granulomatous hepatitis

— Amebic liver abscess: travel, single right-lobe lesion, anchovy-paste aspirate

— Pyogenic abscess: fever, RUQ pain, leukocytosis, biliary source

— Ascending cholangitis: Charcot triad/Reynolds pentad — cholestatic pattern, not hepatocellular

— Heterophile + young adult + pharyngitis → EBV

— Pregnancy + fulminant hepatitis + ALT 5,000 + low platelets + no jaundice → HSV (treat now)

— Returning traveler + jaundice + AKI + conjunctival suffusion → leptospirosis (doxycycline/penicillin)

— Livestock + headache + transaminitis + endocarditis history → Q fever (doxycycline)

Key distinction: Anicteric hepatitis with ALT >5,000 in a pregnant or immunocompromised patient → think HSV hepatitis; start empiric acyclovir while awaiting PCR — mortality is high.

Board pearl: EBV/CMV hepatitis typically ALT 200–500; viral hepatitides A–E usually go much higher.

Non-hepatotropic viruses causing acute hepatitis:

Bacterial/parasitic:

Distinguishing features for the stem:

Key Differentials — Non-Infectious Causes

— Acetaminophen: massive AST/ALT (>10,000), low bilirubin early, INR rises; treat with NAC (Rumack-Matthew nomogram); always check level

— Idiosyncratic: amoxicillin-clavulanate (cholestatic), isoniazid, nitrofurantoin, statins, methotrexate, valproate, phenytoin, herbals (kava, green tea extract, OxyELITE, hydroxycut)

— Anabolic steroids: bland cholestasis

— Massive AST/ALT (>5,000), peaks then falls rapidly, LDH very high, AST:ALT close to 1

— Setting: hypotension, heart failure, sepsis, recent cardiac arrest

— Young/middle-aged women, +ANA, +ASMA, elevated IgG, other autoimmune disease

— Can present acutely; biopsy with interface hepatitis

— Treat with prednisone ± azathioprine

— AST:ALT >2:1, both usually <500, elevated GGT, macrocytosis, malnutrition, history of heavy use

— Maddrey discriminant function ≥32 → prednisolone if no infection

— Age <40, hemolytic anemia, low alkaline phosphatase, ALP:bilirubin <4, low ceruloplasmin, Kayser-Fleischer rings, neuropsychiatric signs

Board pearl: Young patient + Coombs-negative hemolytic anemia + acute liver failure + low ALP = Wilson disease; arrange transplant evaluation.

Step 3 management: In every new transaminitis, send acetaminophen level, ethanol, urine tox, HAV/HBV/HCV/HEV serology, RUQ US — workup is patterned regardless of leading suspicion.

Drug-induced liver injury (DILI):

Ischemic hepatitis ("shock liver"):

Autoimmune hepatitis (AIH):

Alcoholic hepatitis:

Wilson disease:

Budd-Chiari: ascites, RUQ pain, hepatomegaly; Doppler shows hepatic vein occlusion; hypercoagulable state

Acute fatty liver of pregnancy / HELLP: 3rd trimester, hypoglycemia, coagulopathy, hypertension/proteinuria for HELLP — deliver

Biliary obstruction: cholestatic pattern (ALP, GGT, bilirubin dominate), dilated ducts on US

Infiltrative: lymphoma, amyloidosis, sarcoid — ALP-predominant, hepatomegaly

Mushroom poisoning (Amanita): GI symptoms then hepatic necrosis — silibinin, NAC

Secondary Prevention, Discharge Plans, Long-Term Care

— HAV vaccine: 2 doses (0, 6–12 mo); routine in children 12–23 mo; adults at risk (travel, MSM, IVDU, chronic liver disease, occupational, homeless, household contact)

— HBV vaccine: birth dose + 2-3 dose series; universal adult vaccination 19–59 yr (ACIP 2022); ≥60 with risk factors

— Combined Twinrix for HAV+HBV available

— HEV vaccine (Hecolin): China only

— No vaccine for HCV or HDV (HBV vaccine prevents HDV)

— HAV: vaccine if 1–40 healthy within 2 wk; IG for <1, >40, immunocompromised, CLD

— HBV: HBIG + vaccine for unvaccinated/non-responder; vaccine alone for known responders

— HCV: monitor only (HCV RNA at baseline, 3, 6 mo); treat if seroconverts

— Acetaminophen ≤2 g/day, avoid NSAIDs, alcohol abstinence

— Acute HBV cleared: confirm anti-HBs seroconversion at 6 mo

— Acute HCV: continue DAAs, check SVR12; vaccinate against HAV/HBV

— Acute HBV chronic conversion (HBsAg >6 mo): refer hepatology, start surveillance

— Safer sex (condoms until non-infectious or partner immunized)

— Do not share razors, toothbrushes, needles, glucometers

— Cannot donate blood, organs, sperm

— IVDU: refer to medication for opioid use disorder (MOUD) — buprenorphine, methadone; syringe services

— Food safety: handwashing, no food prep while infectious for HAV (until 1 wk after jaundice)

— Chronic HBV high-risk groups and all cirrhotics → US ± AFP q6 mo

Step 3 management: Universal adult HBV vaccination 19–59 is now ACIP standard — offer at every encounter; this is heavily tested.

Board pearl: HCV cured with DAAs still needs HCC surveillance if cirrhosis present — SVR reduces but does not eliminate risk.

Vaccination — bedrock of prevention:

Post-exposure prophylaxis (PEP) summary:

Discharge medications and counseling:

Behavioral counseling:

HCC surveillance:

Follow-Up, Monitoring, Counseling

— Recheck ALT, AST, bilirubin, INR at 1–2 wk, then q2–4 wk until normal

— Most resolve by 2–6 months

— Cholestatic HAV variant: monitor longer with cholestyramine, UDCA

— Return precautions: confusion, somnolence, bruising, persistent vomiting, worsening jaundice

— LFTs and INR weekly until improving

— HBsAg at 6 months to confirm clearance (if persistent → chronic HBV, refer hepatology)

— Anti-HBs at 6–12 mo to confirm immunity

— If on antivirals: HBV DNA q3 mo, eGFR, phosphate (if TDF)

— Baseline: HCV RNA, genotype if needed, HBsAg/anti-HBc, HIV, eGFR, pregnancy, drug interaction review

— Week 4 on treatment: ALT, HCV RNA (optional), adherence

— End of treatment: ALT

— SVR12: HCV RNA 12 wk post-treatment — defines cure

— Continue HCC surveillance if cirrhosis (q6mo US ± AFP)

— Re-screen IVDU patients annually for reinfection

— ALT, HBV DNA, HBeAg/anti-HBe q3–6 mo

— HCC surveillance per AASLD risk groups

— Fibrosis assessment with elastography or APRI/FIB-4

— Alcohol abstinence during recovery and ideally lifelong if chronic HBV/HCV

— Vaccinate household and sexual contacts

— Discuss reproductive plans, vertical transmission

— Mental health support (stigma, fatigue, depression with chronic HCV)

— Substance use treatment referral

— Disability/work clearance — usually return to work when symptoms resolve and not jaundiced; food handlers per public health

CCS pearl: Schedule follow-up at 2 wk, 1 mo, 3 mo, 6 mo for acute HBV; order corresponding labs each visit — CCS rewards interval-appropriate monitoring orders.

Board pearl: SVR12 = cure for HCV; >95% durable.

Outpatient acute HAV/HEV follow-up:

Acute HBV follow-up:

Acute HCV on DAAs:

Chronic HBV monitoring (if conversion):

Counseling content:

Document reportable disease and counsel patient about confidential health department contact tracing.

Ethical, Legal, and Patient Safety Considerations

— Acute hepatitis A, B, C, D, E are reportable to local/state health departments in all US states

— Reporting triggers contact tracing, PEP delivery, outbreak control, food-source investigation (HAV)

— Reporting does not require patient consent; physician obligation supersedes privacy in this context

— DAA therapy: discuss cost, drug interactions, HBV reactivation risk, pregnancy considerations

— HBV antiviral indefinite duration in chronic disease — shared decision-making

— Liver transplant listing: complex consent, especially if encephalopathic — engage surrogate per state hierarchy; in ALF, emergent listing can proceed under emergency exception while pursuing surrogate

— HIV/HBV/HCV disclosure to partners encouraged via patient or via Department of Public Health partner services — anonymous notification available

— Most states do not allow physician to disclose to partner without consent, but duty-to-warn statutes vary — know your state

— Source patient testing requires consent in some states, exempt in others (post-exposure laws)

— Exposed worker confidentiality protected; offer PEP per CDC algorithm

— OSHA Bloodborne Pathogens Standard mandates exposure plans, free HBV vaccination

— HAV: exclude until 1 week after jaundice or per public health

— HBV: HCWs performing exposure-prone procedures with high viral loads (>1,000 IU/mL) need practice modification; consult occupational health

— HCV-positive HCW: rarely restricted; case-by-case

— Universal HCV screening (USPSTF: all adults 18–79 at least once; all pregnant women each pregnancy) without requiring disclosure of IVDU avoids stigma-driven undertesting

— Do not condition treatment on sobriety — modern guidelines treat regardless of ongoing use

— Acute viral hepatitis discharge: ensure follow-up appointment before discharge, written instructions on return precautions, medication reconciliation, vaccination plan for contacts

— Handoff to PCP and hepatology with closed-loop communication

Step 3 management: Always report acute viral hepatitis to public health — listed on Step 3 ethics items.

Mandatory reporting:

Informed consent edge cases:

Confidentiality and partner notification:

Occupational exposure (needlestick):

Food handlers, healthcare workers, daycare:

Substance use and stigma:

Transition of care:

Vaccine refusal: document, revisit, respect autonomy; in pregnancy, neonatal HBV vaccine refusal — counsel risk, document, involve social work; cannot override parental refusal except via court order in extreme circumstances.

High-Yield Associations and Rapid-Fire Facts

— Daycare outbreaks, shellfish, contaminated water, travel, MSM

— Cholestatic and relapsing variants; no chronicity

— Vaccine: 2 doses; PEP with vaccine ± IG

— Partially dsDNA, Hepadnavirus, replicates via reverse transcriptase

— Polyarteritis nodosa, membranous nephropathy

— Window period — anti-HBc IgM only marker

— Universal vaccination 19–59; perinatal: HBIG + vaccine

— Treat acute if severe; chronic with tenofovir/entecavir

— Reactivation with rituximab, chemo, anti-TNF, steroids — prophylax

— Flavivirus, no vaccine

— Cryoglobulinemia, PCT, lichen planus, MPGN, B-cell NHL

— Universal screening adults 18–79 once; pregnant women each pregnancy

— DAAs cure >95%; HBV screen before DAAs

— IVDU primary risk; baby boomers historically; transfusion pre-1992

— Defective RNA virus, requires HBsAg

— Coinfection (acute together) vs superinfection (worse, fulminant in 20%)

— Test all HBsAg+ at least once

— Bulevirtide emerging therapy

— Fecal-oral, waterborne (genotype 1/2 South Asia, Africa)

— Genotype 3/4 zoonotic — undercooked pork, deer, shellfish; can chronicify in immunosuppressed

— Pregnancy 3rd trimester: 20% mortality

— Vaccine in China only

— "Vowels from bowels" (A, E fecal-oral)

— "A, E acute; B, C, D chronic" (with HDV needing HBV)

— "eAg = e for extra infectious"

— Anti-HBs alone = vaccinated

— Anti-HBs + anti-HBc = resolved

— HBsAg + anti-HBc IgM = acute

— HBsAg + anti-HBc IgG (no IgM) = chronic

— Anti-HBc IgM alone = window

Board pearl: PAN + young man + transaminitis = test HBsAg.

Key distinction: "Hepatitis D" only exists in HBsAg-positive patients — never order alone.

HAV:

HBV:

HCV:

HDV:

HEV:

Mnemonics:

Serology one-liners:

Acute liver failure highest risk: HBV+HDV superinfection, HEV in pregnancy.

Board Question Stem Patterns

— Answer: anti-HAV IgM; supportive care; report to public health; PEP for contacts

— Answer: HBIG + initiate HBV vaccine series within 24 hours

— Answer: start tenofovir at 28 wk; newborn gets HBIG + vaccine within 12 h

— Answer: reflex HCV RNA; if positive, start DAAs after screening HBV/HIV

— Answer: entecavir or tenofovir prophylaxis to prevent reactivation

— Answer: HEV; admit, supportive care, transplant evaluation if worsens

— Answer: HCV with cryoglobulinemic vasculitis; check HCV RNA; DAAs ± rituximab

— Answer: resolved past infection — immune; no treatment

— Answer: vaccinated

— Answer: acute liver failure; admit ICU, contact transplant center, NAC, glucose, neuro checks

— Answer: chronic HBV; assess HBV DNA, ALT, HBeAg, HCC surveillance, family screening, test for HDV once

— Answer: HSV hepatitis; empiric IV acyclovir

— Answer: screen HAV, HBV, HCV, HIV, syphilis, gonorrhea/chlamydia; vaccinate HAV/HBV

— Answer: start DAA therapy rather than wait for spontaneous clearance

Step 3 management: Always pair the serologic answer with a management action (PEP, antiviral, report, vaccinate contacts) — Step 3 stems test the next step, not just diagnosis.

Board pearl: Anti-HBc IgM is the "trap" answer that distinguishes window-period acute HBV from resolved infection.

Pattern 1 — Daycare worker, jaundice, shellfish or travel:

Pattern 2 — Needlestick exposure in unvaccinated HCW from HBsAg+ source:

Pattern 3 — Pregnant woman, HBsAg+, HBV DNA 1,200,000 IU/mL at 26 weeks:

Pattern 4 — IVDU with positive anti-HCV:

Pattern 5 — HBsAg+ patient starting rituximab:

Pattern 6 — Returning traveler from India, pregnant, jaundiced, INR 2.0:

Pattern 7 — Young man with palpable purpura, neuropathy, low C4, proteinuria:

Pattern 8 — Stable serology: HBsAg–, anti-HBc+, anti-HBs+:

Pattern 9 — HBsAg–, anti-HBs+, anti-HBc–:

Pattern 10 — Acute hepatitis with INR 1.8 and confusion:

Pattern 11 — HBsAg+ for >6 months:

Pattern 12 — Anicteric pregnant woman, ALT 6,000, low platelets, fever:

Pattern 13 — MSM with proctitis and acute hepatitis:

Pattern 14 — Acute HCV diagnosed in seroconverting needlestick HCW:

One-Line Recap

Acute viral hepatitis A–E presents with hepatocellular injury (ALT > AST, often >1,000), is managed primarily with supportive care plus virus-specific antivirals for severe acute HBV and all acute HCV, with vigilant monitoring for acute liver failure (INR ≥1.5 + encephalopathy) and immediate public-health reporting, contact tracing, vaccination, and PEP.

Board pearl: "Vowels from bowels (A, E), consonants from blood (B, C, D)" — pair this with serology mastery and you will dominate every hepatitis stem on Step 3.

Diagnose: anti-HAV IgM, HBsAg + anti-HBc IgM, anti-HCV with reflex HCV RNA, anti-HEV IgM, anti-HDV if HBsAg+; always check acetaminophen level, INR, and RUQ ultrasound.

Treat: HAV/HEV supportive; acute HBV antivirals only if INR ≥1.5, bilirubin >10, encephalopathy, or immunocompromised (tenofovir or entecavir); acute HCV treat with pangenotypic DAAs (glecaprevir/pibrentasvir 8 wk or sofosbuvir/velpatasvir 12 wk); screen HBV before DAAs to prevent reactivation.

Escalate: INR ≥1.5 + any encephalopathy = acute liver failure → ICU + transplant center; King's College Criteria guide listing; HEV in 3rd-trimester pregnancy and HBV+HDV superinfection carry the highest mortality.

Prevent: universal adult HBV vaccination 19–59; HAV vaccine for at-risk and travelers; HBIG + vaccine for perinatal HBV exposure and unvaccinated needlestick; universal HCV screening once in adults 18–79 and each pregnancy; report all acute cases to public health; counsel on alcohol abstinence, safer sex, MOUD for IVDU, and HCC surveillance for chronic HBV and post-SVR cirrhotics.