Gastrointestinal

Acute liver failure: workup and transplant referral

Clinical Overview and When to Suspect Acute Liver Failure

— Wilson disease, vertically acquired HBV, and autoimmune hepatitis can still qualify even if cirrhosis present, provided disease was unrecognized <26 weeks

— Jaundice + altered mental status in a previously healthy adult

— APAP overdose with rising AST/ALT into thousands

— "Shock liver" pattern: AST/ALT in 5,000–10,000s after hypotensive episode, with rapid downtrend once perfusion restored

— Subacute jaundice + asterixis without known cirrhosis

— Hyperacute (<7 days): APAP, ischemia — best spontaneous survival, severe cerebral edema risk

— Acute (7–21 days): HBV, idiosyncratic DILI

— Subacute (>21 days, up to 26 wks): autoimmune, Wilson — worst spontaneous survival despite less encephalopathy

Board pearl: The diagnostic triad is INR ≥1.5 + encephalopathy + no cirrhosis, <26 weeks. Isolated transaminitis with INR 1.3 and a clear sensorium is acute liver injury, not ALF — important because management urgency and transplant listing thresholds differ sharply. Always anchor on mental status + INR, not on the AST/ALT number.

Definition: Acute liver failure (ALF) = development of coagulopathy (INR ≥1.5) and any degree of hepatic encephalopathy (HE) in a patient without preexisting cirrhosis and with illness duration <26 weeks

Epidemiology in the US: ~2,000 cases/year; acetaminophen (APAP) toxicity is the #1 cause (~45%), followed by idiosyncratic drug-induced liver injury (DILI), viral hepatitis (HAV, HBV, HEV in travelers/pregnancy), autoimmune, ischemic ("shock liver"), Budd-Chiari, Wilson, and pregnancy-related (HELLP, AFLP)

When to suspect in the ED:

Classification by interval jaundice → encephalopathy:

Why Step 3 cares: ALF is a time-critical transfer diagnosis. The ED/admitting physician must recognize it, start N-acetylcysteine empirically if any chance of APAP, and call a transplant center early, often before encephalopathy worsens.

Presentation Patterns and Key History

— I: mild confusion, altered sleep, euphoria/anxiety

— II: lethargy, disorientation to time, asterixis, inappropriate behavior

— III: stupor but rousable, marked confusion, incoherent

— IV: coma, ± decerebrate posturing

— APAP: total dose, time course (single ingestion vs staggered/therapeutic misadventure), co-ingestants (alcohol, opioids), fasting state, intent (suicidality)

— Medications/supplements: isoniazid, phenytoin, valproate, amoxicillin-clavulanate, methotrexate, statins, herbals (kava, green tea extract, Hydroxycut, ma huang), bodybuilding supplements, MDMA/ecstasy

— Mushroom ingestion: Amanita phalloides — GI prodrome 6–24h post-ingestion, then biphasic course

— Travel/exposure: HAV (food/water), HEV (pregnancy, pork, travel to South Asia), HBV (sex, IVDU, tattoos)

— Vascular: recent hypotension/cardiac arrest, cocaine, OCP/hypercoagulability (Budd-Chiari)

— Pregnancy: third trimester → AFLP, HELLP

— Wilson clues: young patient, hemolysis, neuropsychiatric symptoms, family history

Step 3 management: In any ED patient with jaundice + confusion, draw an APAP level immediately regardless of stated history — patients underreport, co-ingest, or present late when levels are low but injury is established. Empirically start IV N-acetylcysteine if APAP is even plausible; benefit extends beyond APAP to non-APAP ALF with early-stage encephalopathy.

Prodrome: nonspecific malaise, nausea, anorexia, RUQ discomfort for 1–7 days, often mistaken for viral gastroenteritis or "the flu" — this is classic for APAP and viral hepatitis

Jaundice typically appears days after the prodrome; in hyperacute APAP ALF, encephalopathy can precede visible jaundice

Encephalopathy staging (West Haven) is the single most important history element:

Targeted history checklist:

Social/psychiatric: suicidal intent shifts disposition and transplant candidacy discussion

Physical Exam Findings and Hemodynamic Assessment

— Asterixis (grade II HE) — have patient extend arms, dorsiflex wrists

— Disorientation, somnolence, clonus, hyperreflexia, posturing in grade III–IV (signs of cerebral edema/intracranial hypertension)

— Pupillary changes, bradycardia + hypertension (Cushing reflex) = impending herniation, emergency

— Hyperdynamic circulation: warm extremities, bounding pulses, wide pulse pressure, tachycardia, low SVR — mimics distributive/septic shock

— Hypoxemia → consider hepatopulmonary syndrome, aspiration, ARDS

— Kayser-Fleischer rings (slit lamp) → Wilson

— Needle tracks → viral

— Spider angiomas/palmar erythema → suggest chronic disease (re-evaluate "acute" label)

— Check MAP — target ≥65; if low, fluid-resuscitate then add norepinephrine (first-line vasopressor in ALF)

— Avoid hypotonic fluids and overaggressive crystalloid (worsens cerebral edema); balanced crystalloids preferred

— Trend lactate — persistently elevated lactate despite resuscitation = poor prognosis and a King's College criterion for APAP-ALF

Board pearl: Asterixis + jaundice + INR ≥1.5 = ALF until proven otherwise — get hepatology and transplant on the phone before the patient progresses to grade III, because airway protection and ICP control become the dominant management issues once mental status drops. Patients with grade III/IV HE have ~55% mortality without transplant; intubate early, sedate with propofol (lowers ICP), and elevate head of bed to 30°.

General appearance: jaundice (sclerae, sublingual), fetor hepaticus, ecchymoses, scratch marks from cholestatic pruritus

Neurologic exam — the most prognostic:

Abdominal: tender hepatomegaly early; a shrinking liver on serial exam in subacute ALF is ominous (massive necrosis). Ascites suggests Budd-Chiari, AFLP, or subacute course

Cardiopulmonary:

Skin/eyes (clues to etiology):

Hemodynamic assessment in ED:

Diagnostic Workup — Initial Labs, Imaging, Biomarkers

— CBC, CMP (Na, K, Cr, glucose, AST, ALT, ALP, total/direct bilirubin, albumin)

— PT/INR, fibrinogen, type & screen

— VBG/ABG with lactate, ammonia

— APAP level (timed from ingestion if known; rerun in 4h if early), salicylate level

— Comprehensive tox screen, ethanol

— Pregnancy test in all reproductive-age women

— HAV IgM, HBsAg, anti-HBc IgM, anti-HCV + HCV RNA, HEV IgM (especially pregnant/travel), HSV PCR (immunocompromised, pregnant, fever)

— ANA, anti-smooth muscle Ab, IgG, anti-LKM for autoimmune

— Ceruloplasmin, 24h urinary copper, slit lamp if <40 yo

— Blood cultures, urinalysis, CXR — infection is common and easily missed

— AST/ALT >5,000 with low bilirubin early → APAP or ischemia (ischemia: LDH also markedly elevated, AST:ALT often >1; rapid downtrend with perfusion)

— ALT > AST, gradual rise, bilirubin climbing → viral or DILI

— Alk phos low, low uric acid, hemolytic anemia, AST:ALT >2, ALP:bilirubin <4 → Wilson disease

— AST/ALT modest (300–500) + DIC + hypoglycemia in 3rd trimester → AFLP

— RUQ ultrasound with Doppler in every ALF patient — assess hepatic/portal vein patency (rule out Budd-Chiari), parenchyma, biliary tree, ascites

— Noncontrast head CT if grade III/IV HE to rule out bleed before lumbar puncture or transplant transfer

CCS pearl: On CCS, the order set on arrival should include: CBC, CMP, INR/PT/PTT, fibrinogen, type & screen, APAP/salicylate, viral hepatitis panel, ammonia, lactate, ABG, blood cultures, urine tox, β-hCG, RUQ US with Doppler, and start IV NAC before levels return. Glucose checks q1–2h — hypoglycemia is common and lethal.

First-line ED labs (order all at presentation):

Patterns:

Imaging:

Diagnostic Workup — Advanced and Confirmatory Studies

— Wilson disease: serum ceruloplasmin <20 mg/dL, 24h urinary copper >100 µg, hepatic copper on biopsy if accessible, Coombs-negative hemolytic anemia + low alkaline phosphatase is the classic ED clue

— Autoimmune hepatitis: ANA, ASMA, anti-LKM-1, IgG (markedly elevated); liver biopsy (often transjugular due to coagulopathy) shows interface hepatitis and is needed before considering steroid trial

— HSV hepatitis: consider in immunosuppressed, pregnant, or febrile anicteric ALF with very high transaminases — HSV PCR + empiric acyclovir while awaiting result

— Budd-Chiari: Doppler US first; CT or MR venography confirms; investigate myeloproliferative neoplasm (JAK2 V617F), PNH, antiphospholipid

— AFLP: Swansea criteria; fatty infiltration on imaging; emergent delivery is treatment

— Malignant infiltration: lymphoma, breast/lung mets, melanoma — contrast-enhanced CT/MRI; biopsy if suspected

— Arterial > venous accuracy; >150 µmol/L correlates with cerebral edema risk and prompts ICP-directed therapy

— Not used to grade encephalopathy clinically — exam trumps the number

— Optic nerve sheath ultrasound, transcranial Doppler, occasionally invasive ICP monitor in grade III/IV listed for transplant (controversial due to bleeding risk; correct INR with rFVIIa or platelets before placement)

— Continuous EEG if subclinical seizures suspected

Key distinction: Don't anchor on a single AST/ALT pattern. Ischemic hepatitis and APAP toxicity both cause AST/ALT in the thousands, but ischemic injury normalizes within 7–10 days with hemodynamic support, while APAP injury peaks at 72–96h and may progress to ALF despite normalizing transaminases — bilirubin and INR are the truer guides.

Etiology-directed second-tier testing:

Transjugular liver biopsy indications: diagnostic uncertainty (autoimmune, malignancy, HSV) when result will change management; coagulopathy is not a contraindication via transjugular route

Ammonia:

Advanced neuro monitoring (ICU/transplant center):

Risk Stratification and Transplant Referral Logic

— Arterial pH <7.30 after resuscitation, OR

— All three: INR >6.5 (PT >100s), Cr >3.4 mg/dL, grade III/IV HE

— Lactate >3.5 after early resuscitation or >3.0 after full resuscitation also predicts poor outcome

— INR >6.5, OR any 3 of 5: age <10 or >40; non-A/non-B hepatitis or DILI etiology; jaundice >7 days before HE; INR >3.5; bilirubin >17.5 mg/dL

— ALF onset <8 weeks, no preexisting liver disease, ICU, and one of: ventilator dependence, RRT, or INR >2.0

— Severe, irreversible extrahepatic disease

— Active uncontrolled sepsis

— Sustained ICP >50 or CPP <40 for hours

— Severe ARDS

— Active suicidality without psychiatric clearance in APAP overdose — does NOT automatically disqualify; requires psychiatric evaluation and demonstrated insight/support

Step 3 management: Don't wait for King's criteria to be met to transfer — transfer when ALF is recognized, because once the patient meets criteria, they are often too unstable to fly. The receiving center, not the referring ED, decides listing. Threshold to call is low; threshold to transfer is also low.

Early transplant center contact is the single most important decision. Once INR ≥1.5 + any HE is documented, call the regional liver transplant center within hours, not after deterioration

King's College Criteria — APAP ALF (predict poor spontaneous survival → list for transplant):

King's College Criteria — Non-APAP ALF:

MELD is useful but criteria above are the validated triggers for Status 1A listing (highest priority — expected survival <7 days without transplant)

UNOS Status 1A criteria:

Contraindications to transplant to identify early (often non-modifiable, requires goals-of-care conversation):

Pharmacotherapy — First-Line Regimens by Etiology

— IV protocol (21h): 150 mg/kg over 1h → 50 mg/kg over 4h → 100 mg/kg over 16h

— APAP-ALF: continue NAC until INR <1.5 and HE resolves or transplant

— Non-APAP early ALF (grade I–II HE): NAC improves transplant-free survival — give it

— Adverse effect: anaphylactoid reaction (flushing, urticaria, bronchospasm) in ~15% — slow infusion, give antihistamine, do not stop unless severe

— HBV: entecavir or tenofovir even in ALF (slows progression, prevents post-transplant recurrence)

— HSV hepatitis: acyclovir 10 mg/kg IV q8h empirically while PCR pending

— Autoimmune hepatitis: prednisolone 40–60 mg/d — but only after biopsy confirms and infection ruled out; does not preclude listing, and steroids should not delay transfer

— Amanita mushroom: IV penicillin G + silibinin (NAC adjunct); aggressive supportive care

— Wilson: plasma exchange as bridge; transplant is definitive (chelation too slow for ALF)

— AFLP/HELLP: prompt delivery is the treatment

— Budd-Chiari: anticoagulation; TIPS or transplant

— Glucose: D10 or D20 infusion to keep glucose >70 — hypoglycemia from impaired gluconeogenesis is common

— PPI for stress ulcer ppx

— Lactulose: evidence weak in ALF (vs cirrhotic HE), may worsen ileus/distension; not first-line — focus on the cause

— Avoid sedatives, benzodiazepines, NSAIDs, nephrotoxins

— Empiric broad-spectrum antibiotics + antifungal if grade III/IV HE, on the transplant list, or any sign of SIRS — infection is the leading cause of death

Board pearl: NAC is safe, cheap, and helps in non-APAP early ALF. If you're unsure of the etiology, start NAC while you work it up — exam classic.

N-acetylcysteine (NAC) — the universal first move:

Etiology-specific therapy:

Supportive pharmacotherapy in ED/ICU:

Procedural and Advanced Management

— Intubate at grade III HE or earlier if unable to protect airway; use propofol (decreases CMRO2 and ICP); avoid benzodiazepines

— Target normocapnia (PaCO2 35–40); brief hyperventilation only for acute herniation signs

— Balanced crystalloid resuscitation → norepinephrine first-line for MAP <65

— Vasopressin as second agent (caution: may raise ICP)

— Hydrocortisone 200–300 mg/d for vasopressor-refractory shock (relative adrenal insufficiency common)

— Early continuous renal replacement therapy (CRRT) preferred over intermittent HD — less hemodynamic and ICP swings

— Indications: AKI with acidosis, hyperammonemia >150–200, volume overload, hyperkalemia

— Do NOT correct INR prophylactically — INR is a transplant listing biomarker; correction with FFP obscures it

— Transfuse only for active bleeding or before procedures (ICP monitor, central line in high-risk site)

— Platelets <50 if bleeding/procedure; fibrinogen <100–150 → cryoprecipitate

— TEG/ROTEM increasingly used to guide

— Head of bed 30°, neutral neck, minimize stimulation, target sodium 145–155 with hypertonic saline (3%) infusion

— Mannitol 0.5–1 g/kg bolus for acute spikes (avoid if osmolar gap >20 or AKI)

— Therapeutic hypothermia (33–35°C) and indomethacin are rescue

— High-volume plasma exchange (HVP) improves transplant-free survival in ALF (single RCT, increasingly used)

— MARS/albumin dialysis: improves HE but not survival; bridge in select centers

CCS pearl: On CCS, after stabilization, the high-yield orders are "transfer to ICU at transplant center," "consult hepatology," "consult transplant surgery," and "consult psychiatry" if APAP intentional. Move the clock forward in short increments while the patient is unstable.

Airway/ventilation:

Hemodynamics:

Renal:

Coagulopathy management — counterintuitive:

ICP management (grade III/IV HE):

Bridge to transplant:

Definitive therapy: orthotopic liver transplantation — only intervention that consistently improves survival in severe ALF (1-yr survival ~80%)

Special Populations — Elderly and Renal/Hepatic Impairment

— Worse outcomes in ALF independent of etiology; age >40 is one of the non-APAP King's criteria for a reason

— Higher rates of DILI from polypharmacy: amoxicillin-clavulanate is the #1 DILI culprit in older adults; also nitrofurantoin, statins, isoniazid

— Subtle encephalopathy easily attributed to dementia/delirium — always check INR and ammonia in a jaundiced elderly patient with confusion

— Transplant candidacy: age alone is not absolute exclusion, but functional status, frailty, and comorbidities tighten eligibility — early goals-of-care discussion is essential

— Hepatorenal-type AKI in ALF: pre-renal physiology + ATN from hypoperfusion/NAC contrast

— Avoid nephrotoxins: IV contrast, aminoglycosides, NSAIDs, ACEi/ARBs

— Dose adjust: piperacillin-tazobactam, vancomycin (trough-guided), antivirals

— CRRT > intermittent HD (gentler on ICP and hemodynamics)

— Cr is a King's criterion for APAP-ALF → AKI accelerates listing

— ALF definition technically excludes cirrhosis — these patients have acute-on-chronic liver failure (ACLF), which has different listing rules (MELD-based, CLIF-C ACLF score) and prognosis

— Wilson, autoimmune hepatitis, and vertical HBV are exceptions where unrecognized chronic disease can still be listed as ALF

— Avoid CYP-heavily metabolized drugs: most benzos (use oxazepam, lorazepam, temazepam if needed — glucuronidated), opioids (avoid morphine, codeine; fentanyl preferred)

— Acetaminophen: cap at 2 g/day in stable chronic liver disease; avoid entirely in ALF

Key distinction: ALF vs ACLF changes listing pathway (Status 1A vs MELD), prognosis discussion, and transplant urgency — recognize cirrhotic stigmata on exam and imaging before assuming pure ALF.

Elderly (>60 yrs):

Preexisting CKD or AKI on presentation:

Underlying chronic liver disease:

Drug dosing in hepatic impairment:

Special Populations — Pregnancy, Pediatrics, Immunocompromised

— Acute fatty liver of pregnancy (AFLP):

— Jaundice, RUQ pain, nausea/vomiting, hypoglycemia, DIC, modest AST/ALT (300–500), elevated bilirubin/ammonia

— Associated with fetal LCHAD deficiency

— Treatment: prompt delivery + supportive care; usually self-resolves but transplant occasionally needed

— HELLP: hemolysis, elevated LFTs, low platelets; hypertension/proteinuria distinguish from AFLP; delivery is treatment

— HEV in pregnancy: mortality up to 20–25%, especially in 3rd trimester — endemic in South Asia, Africa

— HSV hepatitis: often anicteric, very high transaminases, fever — empiric acyclovir lifesaving

— Etiologies shift: indeterminate (40%), metabolic (Wilson, mitochondrial, galactosemia, tyrosinemia), neonatal hemochromatosis, autoimmune, HSV

— Encephalopathy hard to assess in infants/young children — irritability, sleep changes, poor feeding count

— APAP toxicity in adolescents (intentional ingestion) common

— Transfer to pediatric transplant center early

— HBV reactivation under rituximab, anti-TNF, chemotherapy — screen and treat all HBsAg+ and anti-HBc+ patients before immunosuppression

— HSV, VZV, CMV, adenovirus hepatitis — empiric antivirals

— DILI from HAART (especially older PIs, NNRTIs), TB drugs (INH, rifampin, pyrazinamide)

Step 3 management: A pregnant woman in the 3rd trimester with jaundice, hypoglycemia, and elevated INR — deliver the baby. Don't wait for liver transplant evaluation; obstetric delivery is both diagnostic and therapeutic for AFLP/HELLP.

Pregnancy-specific ALF (third trimester):

Pediatric ALF (PALF):

Immunocompromised (HIV, transplant, chemo, biologics):

Acetaminophen in pregnancy: still first-line analgesic; NAC is pregnancy category B and given normally in overdose — fetal outcome tracks maternal outcome

Complications and Adverse Outcomes

— Leading neurologic cause of death; risk highest in hyperacute APAP and grade III/IV HE

— Ammonia >150–200 µmol/L is a key marker

— Manifests as posturing, pupillary changes, Cushing reflex

— Management: hypertonic saline, mannitol, hyperventilation (transient), HVP, transplant

— Leading overall cause of death. Bacterial (gram-positive skin/IV catheter, gram-negative gut translocation) and fungal (candida) common

— Surveillance cultures every 48–72h in ICU; low threshold for empiric antimicrobials including antifungal in grade III/IV HE

— Fever may be absent — relative adrenal insufficiency and impaired acute phase response

— GI bleed, intracranial bleed (especially with ICP monitor placement)

— Paradoxically, balanced hemostasis — pro- and anticoagulant factors both reduced; thrombosis (DVT, line clot) still occurs

— VTE prophylaxis indicated unless actively bleeding

— Hypoglycemia (impaired gluconeogenesis/glycogenolysis) — check q1–2h, D10 drip

— Hyponatremia (avoid; worsens cerebral edema — target 145–155)

— Lactic acidosis, hypophosphatemia, hypokalemia, hypomagnesemia

Board pearl: A patient with ALF who suddenly drops sodium or glucose decompensates fast — both are reversible and both directly worsen cerebral edema. Catch them on the q1–2h flowsheet.

Cerebral edema / intracranial hypertension:

Infection/sepsis:

AKI: ~50% of ALF; multifactorial (pre-renal, ATN, hepatorenal physiology)

Coagulopathy and bleeding:

Metabolic:

Cardiopulmonary: ARDS, hepatopulmonary syndrome, high-output failure, arrhythmias

Pancreatitis: ~10%, especially APAP

Long-term post-transplant complications: rejection, recurrence (HBV, autoimmune), CNI nephrotoxicity, malignancy

When to Escalate Care — ICU, Consults, and Transfer

— As soon as ALF criteria are met (INR ≥1.5 + any HE, no cirrhosis, <26 wks)

— Even if patient looks "stable" in the ED — they decompensate rapidly

— Earlier is better: patients with grade III/IV HE often cannot be safely flown

— Hepatology (medical management, listing eligibility)

— Transplant surgery (operative evaluation)

— Critical care (ICU management, ICP, RRT)

— Psychiatry for any intentional ingestion — required before listing in many programs but should not delay transfer

— Social work / ethics for goals-of-care, family

— Toxicology / Poison Control (1-800-222-1222) for APAP, mushroom, herbal, complex co-ingestions

— Etiology suspected; timeline of ingestion or symptoms

— Current HE grade, GCS, pupils

— Labs: INR, bilirubin, Cr, lactate, ammonia, glucose, ABG pH

— Vasopressor status, ventilator status, RRT

— Active issues (bleeding, infection, AKI)

— Psychiatric history, social support, contact info for next of kin

— Pregnancy status

Step 3 management: Document time of first transplant center call — this is a quality metric and a medicolegal touchpoint. Don't accept "we'll call you back" — get a transplant hepatologist on the phone now. Transfer-of-care handoffs in ALF are high-risk patient safety events (see chunk 17).

All ALF goes to the ICU. Floor-level monitoring is inadequate because hourly mental status checks, glucose monitoring, and ICP risk surveillance are required

Transfer to a liver transplant center:

Mandatory consults at the receiving (or referring) center:

Communication checklist for transfer call:

Air vs ground transport: Air for distance >100 mi or unstable; ensure intubation before flight if grade ≥II HE because of altitude effects on ICP

Key Differentials — Same-Category Hepatic Causes

— Elevated AST/ALT ± INR ≥1.5 but mentation intact

— Watch closely; many evolve to ALF, but not yet listable as Status 1A

— Treatment of underlying cause + serial INR/mental status q4–6h

— Cirrhotic patient with acute decompensation + organ failures (CLIF-C)

— Listed by MELD-Na, not Status 1A

— Look for stigmata: spider angiomas, splenomegaly, varices on EGD, nodular liver on US, thrombocytopenia

— Variceal bleed, ascites, SBP, hepatic encephalopathy — chronic course

— Lactulose + rifaximin for HE, not the cause-directed therapy of ALF

— Often in cirrhotic substrate, recent heavy use, bilirubin >3, AST <400, AST:ALT >1.5

— Maddrey discriminant function ≥32 or MELD ≥20 → consider prednisolone (Lille score at day 7)

— Early liver transplant in select non-cirrhotic responders

— Massive AST/ALT spike post-hypotension, rapid downtrend in 7–10 days, LDH high, AST:ALT >1 early

— Treat the cause of shock; rarely progresses to true ALF unless ongoing hypoperfusion

— Charcot triad, dilated ducts on US, leukocytosis, ALP/bilirubin pattern dominates, not transaminitis

— ERCP, not transplant

Key distinction: AST/ALT in the thousands + falling rapidly = ischemic hepatitis, not APAP. AST/ALT in the thousands + rising bilirubin + rising INR over days = APAP-ALF — these have totally different trajectories and management.

Distinguishing ALF from look-alikes within liver disease is essential — both treatment and listing differ.

Acute liver injury (ALI) without encephalopathy:

Acute-on-chronic liver failure (ACLF):

Decompensated cirrhosis (non-ACLF):

Severe alcoholic hepatitis:

Ischemic hepatitis ("shock liver"):

Biliary obstruction with cholangitis:

Key Differentials — Other-Category Causes of Encephalopathy and Coagulopathy

— Salicylate poisoning — mixed acidosis, tinnitus, AMS, elevated AG

— Methanol/ethylene glycol — high AG, osmolar gap, AKI

— Carbon monoxide — AMS, low SpCO; co-oximetry

— Thyroid storm, myxedema coma, adrenal crisis — AMS without coagulopathy

— Subdural hematoma in alcoholics — get head CT

— Wernicke encephalopathy — give thiamine before glucose

— Non-convulsive status epilepticus — EEG

— Drug intoxication / withdrawal

Board pearl: In any encephalopathic patient with elevated transaminases, don't anchor on the liver. Get a head CT, glucose, ammonia, thiamine, blood/urine cultures, tox screen, and TSH before declaring this "hepatic encephalopathy." Step 3 loves the diagnostic-curveball stem (e.g., thyroid storm mistaken for ALF).

Sepsis with multiorgan dysfunction: coagulopathy + altered mental status + elevated transaminases can mimic ALF; cultures, lactate, source control sort it out

DIC of other cause: INR elevated but fibrinogen low and D-dimer very high; underlying obstetric, oncologic, or septic trigger

Heat stroke: core temp >40°C, AMS, AST/ALT in thousands, rhabdomyolysis (CK markedly elevated), coagulopathy — distinguishes by history and temperature

HLH (hemophagocytic lymphohistiocytosis): fever, splenomegaly, cytopenias, ferritin >10,000, hypertriglyceridemia, hypofibrinogenemia, elevated LFTs — pediatric and adult; rheumatology/heme-onc consult

TTP/HUS: thrombocytopenia + MAHA + AKI + neuro symptoms ± fever — schistocytes on smear, ADAMTS13 activity — needs plasma exchange

Toxic ingestions mimicking ALF:

Endocrine emergencies:

Neurologic mimics of HE:

Reye syndrome: child + aspirin + viral illness + AMS + hepatic dysfunction — rare but classic; avoid ASA in children

Secondary Prevention, Discharge Planning, Long-Term Management

— LFTs typically normalize within weeks to months

— Etiology-specific follow-up:

— APAP (intentional): psychiatric care, safety plan, lethal-means counseling, outpatient follow-up within 1 week

— APAP (unintentional/therapeutic misadventure): dose education — max 3 g/day if any liver risk, no combo OTC products, no alcohol concurrent

— HBV: lifelong nucleos(t)ide analog if HBeAg+ or high VL, HCC surveillance

— HAV: counseling, vaccination of contacts, no specific long-term therapy

— Autoimmune hepatitis: long-term immunosuppression (prednisone taper + azathioprine), monitor for relapse

— Wilson: lifelong chelation (penicillamine, trientine) or zinc, low-copper diet, screen first-degree relatives

— DILI: avoid offending agent for life, list in chart and patient portal; report to FDA MedWatch

— Lifelong immunosuppression (tacrolimus-based ± mycophenolate ± steroid taper)

— Drug interactions: avoid CYP3A4 inducers/inhibitors without dose check

— Infection prophylaxis: TMP-SMX (PJP), valganciclovir (CMV high-risk), antifungal early post-op

— Vaccinations before transplant if possible: HAV, HBV, pneumococcal, influenza, COVID, HPV; no live vaccines post-transplant (MMR, VZV, yellow fever)

— Cancer screening: skin (annual derm), colon, breast, cervical, HCC if HBV/HCV underlying

— Metabolic: hypertension, diabetes, dyslipidemia from CNIs/steroids

— Alcohol abstinence (especially post-transplant: lifelong)

— Avoid hepatotoxic herbals

— Vaccinate against HAV, HBV

— Annual flu, COVID, pneumococcal per schedule

Step 3 management: At discharge, a medication reconciliation that explicitly removes acetaminophen-containing products (Percocet, Norco, NyQuil, Excedrin) is a quality measure for APAP-ALF survivors. Patients routinely return with a second overdose from a different combo product they didn't recognize.

Survivors without transplant (spontaneous recovery):

Post-liver transplant patients:

Lifestyle counseling for all survivors:

Follow-Up, Monitoring, Rehabilitation, Counseling

— 1 week: hepatology and PCP — LFTs, INR, CBC, BMP; medication reconciliation

— 2–4 weeks: repeat labs; assess return-to-baseline mentation, function

— 3 months: if normalized, taper monitoring to etiology-specific schedule

— 6–12 months: annual hepatology follow-up if any residual abnormality

— Weekly labs for first month: CBC, BMP, LFTs, tacrolimus level, BK/CMV PCR

— Months 1–3: every 2 weeks → monthly

— After 1 year: every 3–6 months indefinitely

— Annual imaging (US for biliary, vascular complications); EGD if portal HTN history

— Post-ICU syndrome common: cognitive impairment, ICU-acquired weakness, PTSD

— Physical therapy, occupational therapy, cognitive rehab, mental health follow-up

— Driving: defer until cognition normalized — document clearance

— Return to work: graduated, hepatology to clear

— Suicide prevention (intentional APAP): outpatient psychiatry within 1 week, lethal-means counseling, family/social engagement; consider involuntary hold criteria if ongoing risk

— Substance use disorder (alcohol, IVDU): treatment program referral; for transplant candidacy, programs commonly require 6 months sobriety (relative, not absolute, especially in ALF context)

— Genetic counseling: Wilson (autosomal recessive — siblings need screening with ceruloplasmin, urine copper); hemochromatosis

— Family planning: post-transplant pregnancy possible after 1–2 years stable, off mycophenolate; refer to MFM

CCS pearl: On CCS write "schedule follow-up in 1 week with hepatology" and "schedule outpatient psychiatry" before ending the case — Step 3 grades transitions of care explicitly.

Outpatient follow-up cadence after ALF survival (no transplant):

Post-transplant follow-up:

Rehab and functional recovery:

Counseling domains:

Vaccination plan: complete HAV/HBV series if not immune; document in registry

Ethical, Legal, and Patient Safety Considerations

— Grade III/IV HE patients cannot consent — use surrogate decision-makers per state hierarchy (spouse → adult children → parents → siblings)

— If advance directive exists, honor it; if patient previously expressed refusal of transplant, this should be respected

— Document capacity assessment at each decision point

— Suicide attempt is not an automatic contraindication to transplant — requires psychiatric evaluation, demonstrated insight, social support

— Ethics consult helpful when listing is contested

— Mandatory safety holds and suicide precautions in ED/ICU per state law

— Suspected child abuse if pediatric ALF from caregiver-administered APAP or unexplained

— Suicide attempt — reportable per local mental health statutes (varies by state)

— Adverse drug events / DILI → FDA MedWatch (especially herbals, new agents)

— Suspected criminal poisoning → law enforcement

— Inter-facility transfer is the highest-risk handoff in ALF. Ensure: verbal sign-out hepatologist-to-hepatologist, written summary, all labs and imaging accompany the patient, NAC continued in transit, glucose protocol in transit, intubation before transport if grade ≥II

— EMTALA applies — receiving facility must accept if they have capacity for transplant care and referring facility lacks it

— Status 1A listing is national priority — ethically grounded in medical urgency, not social worth

— Re-transplantation, alcohol use, and substance use raise contested allocation questions — handled by transplant ethics committees, not the floor team

— VTE prophylaxis (mechanical if coagulopathic; pharmacologic if INR <1.5)

— Pressure injury, aspiration, line/catheter infection bundles

— Medication reconciliation at every transition — the highest-yield error category is reintroduction of acetaminophen-containing combo products

Board pearl: A psychiatric history alone does not disqualify a patient from transplant. Step 3 stems testing bias and equitable care expect you to list the patient and consult psychiatry, not refuse.

Informed consent for transplant in encephalopathic patients:

Intentional APAP overdose:

Mandatory reporting:

Transition-of-care risks (Step 3 hot topic):

Allocation ethics:

Patient safety bundles:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: When the stem mentions a healthy young adult with flu-like symptoms, AST >5,000, and then confusion 3 days later — it's APAP, even if the patient denies it. Send the level and start NAC.

APAP is the #1 cause of ALF in the US (~45%); idiosyncratic DILI #2

Amox-clavulanate = most common DILI agent in the elderly

Maximum APAP dose: 4 g/day healthy adult; 3 g/day if chronic alcohol or liver disease; 2 g/day stable cirrhotic

NAC: IV 21h protocol; works best <8h of APAP ingestion but give regardless of time if AST elevated or APAP detectable

Rumack-Matthew nomogram: only valid for single acute APAP ingestion, starts at 4h post-ingestion, treatment line at 150 µg/mL at 4h

King's College APAP criteria: pH <7.30 OR (INR >6.5 + Cr >3.4 + grade III/IV HE)

King's non-APAP: INR >6.5 alone, or any 3 of 5 (age, etiology, jaundice-to-HE >7d, INR >3.5, bili >17.5)

Status 1A UNOS: ALF, ICU, plus vent or RRT or INR >2.0; <8 weeks onset

Wilson disease ED clues: AST:ALT >2, ALP:bilirubin <4, Coombs-negative hemolysis, low uric acid, KF rings

AFLP: 3rd trimester, hypoglycemia, modest AST/ALT, DIC, hyperammonemia → deliver

HEV kills pregnant women (20–25% mortality, 3rd trimester)

HSV hepatitis: anicteric, fever, very high AST/ALT, immunocompromised/pregnant → empiric acyclovir

Mushroom = Amanita phalloides → penicillin G + silibinin

Avoid in ALF: sedatives, benzos, NSAIDs, aminoglycosides, nephrotoxins, lactated Ringer (some prefer plasmalyte), hypotonic fluids

Target Na 145–155 in grade III/IV HE

Hypoglycemia is the most rapidly fatal reversible complication — q1–2h glucose

Sepsis is the leading cause of death in ALF

Asterixis = grade II HE, the threshold sign

Continue NAC until INR <1.5 + HE resolved or transplant

High-volume plasma exchange improves transplant-free survival

Board Question Stem Patterns

— 22-year-old woman, post-breakup, found drowsy by roommate; AST 6,800, ALT 5,400, INR 3.2, bilirubin 4.5, pH 7.28, Cr 2.9, somnolent — Answer: Activate liver transplant evaluation + continue NAC. Meets King's criteria (pH <7.30)

— Chronic alcohol user takes "regular" doses of APAP for back pain over 4 days; jaundice, INR 2.1, AST 4,500 — Answer: IV NAC. APAP level may be low/undetectable; staggered ingestion still causes toxicity

— Family forages, eats mushrooms; 12h later vomiting/diarrhea, 36h later transaminitis with INR rising — Answer: Amanita phalloides poisoning; supportive + penicillin G + silibinin + transplant referral

— 22-year-old with jaundice, hemolytic anemia, low alk phos, AST 280, ALT 110, Coombs negative, KF rings — Answer: Wilson disease; refer for emergent transplant (chelation too slow)

— 35F, ANA+, ASMA+, IgG elevated, jaundice + HE; biopsy shows interface hepatitis — Answer: IV steroids, but list for transplant if no response in 7 days

— Pregnant or immunosuppressed patient, anicteric, fever, AST 8,000, no APAP exposure — Answer: empiric IV acyclovir, send HSV PCR

— 32-week pregnancy, RUQ pain, hypoglycemia, INR 2.0, AST 380, NH3 110 — Answer: emergent delivery

— Post-cardiac arrest, AST/ALT 5,000, LDH 4,000, rapid downtrend over 5 days — Answer: supportive; not ALF, not transplant

Step 3 management: When two answer choices are reasonable, pick the one that gets the patient to a transplant center fastest — that is almost always the right Step 3 move in ALF.

Classic stem 1 — APAP recognition:

Classic stem 2 — Therapeutic misadventure:

Classic stem 3 — Mushroom ingestion:

Classic stem 4 — Wilson:

Classic stem 5 — Autoimmune flare:

Classic stem 6 — HSV hepatitis:

Classic stem 7 — AFLP:

Classic stem 8 — Ischemic hepatitis:

Stem trap: "INR can be corrected with FFP before transfer" — wrong; corrects the King's criterion artificially and hampers listing

Stem trap: "Refer to psychiatry before starting NAC" in intentional overdose — wrong; NAC is time-critical, psychiatry follows

One-Line Recap

Acute liver failure = INR ≥1.5 + any encephalopathy + no cirrhosis within 26 weeks, and your job is to start N-acetylcysteine empirically, search hard for a reversible cause, and call a liver transplant center early — before the patient is too sick to fly.

Board pearl: The single most tested Step 3 decision in ALF is early transplant center contact. If the stem offers "transfer to liver transplant center" as an option for a patient with INR ≥1.5 and any encephalopathy — that is the answer, even if the patient currently looks stable, even if the etiology is not yet known, even if NAC has just been started. Speed and the right phone call save the liver and the life.

Recognize: any jaundiced patient with confusion gets INR, ammonia, APAP level, viral panel, RUQ Doppler US, and serial glucose checks — asterixis + INR ≥1.5 is ALF until proven otherwise

Treat: IV NAC for everyone with possible APAP or early-stage non-APAP ALF; etiology-specific therapy layered on (entecavir for HBV, acyclovir for HSV, penicillin G + silibinin for Amanita, steroids for AIH after biopsy, delivery for AFLP/HELLP); supportive ICU care emphasizes glucose >70, Na 145–155, MAP ≥65 with norepinephrine, CRRT over HD, intubation at grade III HE, propofol sedation, head of bed 30°, no prophylactic FFP

Triage: King's College criteria (APAP: pH <7.30 OR INR>6.5 + Cr>3.4 + grade III/IV HE; non-APAP: INR>6.5 or 3 of 5 risk factors) drive UNOS Status 1A listing; transfer to a transplant center as soon as ALF is recognized, not when criteria are met

Disposition: survivors get hepatology follow-up at 1 week, psychiatric care for intentional overdose, hepatotoxin avoidance counseling, HAV/HBV vaccination, lifelong alcohol abstinence; post-transplant patients enter lifelong immunosuppression with infection and cancer surveillance