Gastrointestinal

Hepatic encephalopathy: precipitants and management

Clinical Overview and When to Suspect Hepatic Encephalopathy

— Type A: acute liver failure (e.g., acetaminophen toxicity) — risk of cerebral edema

— Type B: portosystemic bypass without intrinsic liver disease (congenital shunts, TIPS)

— Type C: cirrhosis with portal hypertension — by far the most common Step 3 stem

— Covert (minimal + Grade 1): subtle attention/psychomotor deficits, mild confusion, sleep reversal

— Grade 2: lethargy, asterixis, disorientation to time, inappropriate behavior

— Grade 3: somnolent but rousable, gross disorientation, marked confusion

— Grade 4: coma, unresponsive to pain

— Known cirrhotic with acute change in mentation, sleep-wake reversal, or "found confused at home"

— Post-TIPS patient with new cognitive complaints (incidence ~20–45% post-TIPS)

— Driving safety concerns, work errors, or family-reported personality change in a stable cirrhotic — think covert HE

— Acute liver failure with INR >1.5 and any neuro change — assume HE until proven otherwise

— Ammonia is generated by colonic urease-producing bacteria and intestinal glutaminase; the failing liver cannot convert it to urea

— Astrocytes detoxify ammonia via glutamine synthesis → osmotic swelling → Alzheimer type II astrocytes

Board pearl: Ammonia levels correlate poorly with HE severity in chronic liver disease — diagnosis is clinical. Do not anchor management on a single ammonia value; routine ammonia testing is not recommended for diagnosis or monitoring of cirrhotic HE per AASLD.

Definition: Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome from hepatic dysfunction and/or portosystemic shunting, driven primarily by gut-derived neurotoxins (ammonia, manganese, inflammatory cytokines, GABA-ergic compounds) crossing into the CNS.

Spectrum:

West Haven grading:

When to suspect on Step 3:

Epidemiology: Lifetime risk in cirrhosis ~30–40%; once overt HE occurs, 1-year survival without transplant ~40%.

Pathophysiology pearls:

Presentation Patterns and Key History

— Infection: SBP is the #1 occult precipitant — fever may be absent; always do diagnostic paracentesis in any cirrhotic with new HE plus ascites

— GI bleeding: melena, hematemesis, NSAID use — blood is a massive nitrogen load

— Constipation: missed lactulose doses, opioids, anticholinergics

— Electrolyte disturbance: overdiuresis → hypokalemia and metabolic alkalosis (both shift NH₃ across BBB) and hyponatremia

— Dehydration / AKI / hypovolemia: large-volume paracentesis without albumin, diarrhea from excess lactulose

— Medications: benzodiazepines, opioids, zolpidem, sedating antihistamines

— Dietary protein bolus (less commonly invoked now — do not restrict protein chronically)

— TIPS placement or spontaneous portosystemic shunt

— Alcohol relapse, HCC development, portal vein thrombosis

— Family reports "personality change," day-night reversal, forgetting appointments, near-miss MVCs

— Patient may deny symptoms entirely (anosognosia)

— New opioids post-procedure, sleep aids, PPIs (associated with HE risk via dysbiosis), recent antibiotics

Step 3 management: When a cirrhotic presents with altered mentation, your reflex differential checklist is "I HAVE TIPS" — Infection, Hemorrhage (GI), Alkalosis/electrolytes, Volume depletion, Excess protein, Tranquilizers/sedatives, Increased shunt (TIPS/portal vein thrombosis), Plus constipation, Sugar (hypoglycemia/DKA) and SBP. Identify and treat the precipitant — it is found in >90% of episodes.

Classic stem: A 58-year-old man with alcohol-associated cirrhosis is brought in by family for 2 days of confusion, slurred speech, and reversed sleep cycle after running out of lactulose.

High-yield history elements — always ask about precipitants:

Subjective clues:

Medication reconciliation is mandatory:

Adherence review: Lactulose titration to 2–3 soft stools/day is the single most important home metric — ask specifically.

Physical Exam Findings and Hemodynamic Assessment

— Inattention on serial 7s, months backward, or number connection test (sensitive for covert HE)

— Disorientation to time precedes place, which precedes person

— Dysarthria, slow responses, perseveration

— Asterixis: "liver flap" — sudden loss of postural tone with wrists extended; not specific (also uremia, CO₂ narcosis, drug toxicity)

— Hyperreflexia, sustained clonus, upgoing toes in advanced stages

— Late: decerebrate posturing, coma (consider cerebral edema in Type A HE)

— Scleral icterus, jaundice, spider angiomata, palmar erythema, gynecomastia, testicular atrophy, Dupuytren contractures, caput medusae, parotid enlargement

— Muscle wasting (sarcopenia) — independent predictor of HE and mortality

— Ascites — perform diagnostic paracentesis in every cirrhotic with HE and ascites, regardless of fever

— Hepatosplenomegaly, fluid wave, shifting dullness

— Tender abdomen → SBP until proven otherwise (PMN ≥250/mm³)

— Hyperdynamic circulation: high cardiac output, low SVR, relative hypotension

— Watch for hepatorenal physiology — splanchnic vasodilation with renal vasoconstriction

— MAP <82 mmHg associated with worse outcomes; consider midodrine if chronic

— Orthostatics, mucous membranes, JVP, capillary refill

— Overdiuresis is a top reversible precipitant — hold diuretics if AKI or hypovolemia

CCS pearl: On day 1 of a CCS HE case, order vitals q4h, neuro checks q2–4h, fingerstick glucose, weight daily, strict I/O, and diagnostic paracentesis if ascites present. Place patient in monitored bed if Grade ≥2. Hold diuretics, benzodiazepines, and opioids on the medication reconciliation screen.

Mental status:

Motor signs:

Stigmata of chronic liver disease:

Abdominal exam:

Hemodynamics in decompensated cirrhosis:

Fetor hepaticus: sweet, musty breath from dimethyl sulfide — pathognomonic but insensitive.

Volume assessment is critical:

Diagnostic Workup — Initial Labs, Imaging, and Bedside Studies

— CBC with diff: anemia (GI bleed), leukocytosis (infection), thrombocytopenia (portal HTN)

— CMP: Na⁺ (hyponatremia common and precipitates HE), K⁺ (hypokalemia), creatinine (AKI/HRS), glucose (hypoglycemia mimics HE)

— LFTs: AST/ALT, bilirubin, alk phos, GGT, albumin

— INR/PT: synthetic function; component of MELD

— Lactate, VBG: alkalosis worsens NH₃ diffusion

— TSH, B12, folate, RPR if first presentation of confusion to rule out mimics

— UA + urine culture, blood cultures × 2, CXR — pan-culture for occult infection

— Not required for diagnosis in cirrhotic HE; high false positives (tourniquet, delayed processing, muscle activity)

— A normal ammonia in a cirrhotic with altered mentation argues against HE — useful as a rule-out

— In acute liver failure (Type A), ammonia >150–200 μmol/L predicts cerebral edema and herniation risk

— UDS, salicylate, acetaminophen, ethanol — overdose mimics or co-exists

— Cell count with differential, total protein, albumin (calculate SAAG), Gram stain, culture in blood culture bottles at bedside

— PMN ≥250/mm³ = SBP — start empiric cefotaxime + IV albumin 1.5 g/kg day 1, 1 g/kg day 3

— Non-contrast head CT if focal deficits, trauma, anticoagulation, first episode, or Grade ≥3 HE — rule out subdural hematoma (cirrhotics fall and are coagulopathic)

— Abdominal US with Doppler if new HE — assess for portal vein thrombosis and screen for HCC

Key distinction: Ammonia is a research/prognostic marker in chronic HE but a diagnostic and triage marker in acute liver failure. Do not delay treatment awaiting a level in cirrhotics.

Core labs on admission:

Ammonia level:

Toxicology and drug screen:

Diagnostic paracentesis:

Imaging:

ECG: baseline QTc (cirrhotic cardiomyopathy prolongs QT; rifaximin and ondansetron compound risk).

Diagnostic Workup — Advanced and Confirmatory Studies

— Psychometric Hepatic Encephalopathy Score (PHES): gold standard battery — number connection A/B, digit symbol, line tracing, serial dotting

— Stroop EncephalApp: smartphone-based, validated, easily deployed in clinic — abnormal on/off times

— Critical flicker frequency: <39 Hz suggests minimal HE

— Inhibitory control test: measures attention/response inhibition

— Indicated when family reports functional decline, driving concerns, or after first overt episode

— Triphasic waves, generalized slowing (theta/delta) — supportive but nonspecific

— Useful when nonconvulsive status epilepticus is on the differential

— T1 hyperintensity in globus pallidus from manganese deposition — chronic HE signature

— Indicated if focal findings or atypical course; rules out structural lesions

— Reserved for suspected CNS infection (fever, meningismus, immunosuppression)

— Correct coagulopathy first; cirrhotic INR does not reliably predict bleeding — use platelets and fibrinogen

— Calculate at admission; MELD-Na ≥15 triggers transplant referral discussion

— HE is part of Child-Pugh, not MELD

— RUQ US with Doppler for PVT, HCC surveillance with AFP

— Echo if cardiac symptoms — cirrhotic cardiomyopathy

— Screening for spontaneous portosystemic shunts on CT/MR angiography if HE is refractory — embolization may be curative

— EGD if any concern for variceal bleed (melena, drop in Hgb, hematemesis) — even occult bleeding can precipitate HE

Board pearl: A cirrhotic with recurrent HE despite optimal medical therapy should be evaluated for a large spontaneous portosystemic shunt with cross-sectional venography; shunt embolization can dramatically reduce recurrence and is a high-yield "next best step" answer.

Neuropsychometric testing (for covert/minimal HE):

EEG:

MRI brain:

Lumbar puncture:

MELD-Na and Child-Pugh scoring:

Workup for new or recurrent HE in a "stable" cirrhotic:

Endoscopy:

Risk Stratification and First-Line Management Logic

— Covert/Grade 1: outpatient management feasible if reliable caregiver, no precipitant requiring admission, safe home environment

— Grade 2: admit to floor with monitored bed and aspiration precautions

— Grade 3–4: ICU for airway protection (intubate if Grade 4 or unable to protect airway), continuous monitoring

1. Stabilize ABCs — intubate if GCS ≤8 or cannot protect airway; aspiration is the leading cause of in-hospital death

2. Identify and treat the precipitant — paracentesis, cultures, hold offending drugs, transfuse + endoscopy for GI bleed, correct K⁺/Na⁺/volume

3. Reduce nitrogenous load — lactulose ± rifaximin

4. Nutritional support — do not restrict protein

5. Plan secondary prevention and transplant evaluation

— Admit to telemetry/ICU per grade; NPO until airway/aspiration risk assessed; HOB 30°

— IV access, fingerstick glucose now and q6h

— Lactulose 25 mL PO/NG q1–2h until BM, then titrate to 2–3 soft stools/day; or lactulose enema 300 mL in 700 mL water if obtunded

— Add rifaximin 550 mg PO BID if Grade ≥2 or breakthrough on lactulose

— Diagnostic paracentesis if ascites; cultures, CXR, UA

— Hold diuretics, sedatives, opioids, NSAIDs, nephrotoxins

— Thiamine 100 mg IV, folate, MVI if alcohol use disorder

— DVT prophylaxis (mechanical preferred if coagulopathic and bleeding risk)

— Empiric benzodiazepines for agitation — use low-dose haloperidol if essential

— Routine FFP for elevated INR without bleeding

— Protein restriction beyond 24–48 h

Step 3 management: The single highest-yield action when overt HE is identified is search for and treat the precipitant — lactulose alone without addressing SBP, GI bleed, or hypokalemia will fail. Paracentesis in any cirrhotic admitted with HE and ascites is essentially mandatory.

Triage by West Haven grade:

Five-step management framework:

Hospital-day-1 order set (CCS-flavor):

Avoid:

Pharmacotherapy — First-Line Regimens

— Mechanism: colonic bacteria ferment lactulose → lactic/acetic acid → lowers colonic pH → traps NH₃ as NH₄⁺ → cathartic effect expels nitrogen; also shifts microbiome away from urease producers

— Acute dosing: 25 mL PO/NG every 1–2 hours until first bowel movement, then titrate to 2–3 soft stools per day

— Obtunded patients: retention enema — 300 mL lactulose in 700 mL water or NS, hold 30–60 min, repeat q4–6h

— Maintenance: typical 15–30 mL PO BID–QID, patient self-titrated

— Side effects: diarrhea, dehydration (paradoxically worsens HE), hypernatremia, hypokalemia, abdominal cramping, bloating

— Pitfall: overshooting to >5 stools/day causes volume depletion and recurrent HE — counsel patient explicitly

— Mechanism: suppresses urease-producing gut flora; <0.4% systemic absorption

— Dose: 550 mg PO BID

— Indication: added to lactulose for prevention of recurrence after a second overt HE episode (Class I); also used acutely for breakthrough HE

— Reduces recurrence by ~58% and HE-related hospitalizations vs. lactulose alone

— Side effects: minimal; rare C. difficile, peripheral edema; expensive — prior authorization often required

— 4 L over 4 hours via NG — single-dose alternative shown to resolve HE faster than lactulose in some RCTs; useful when lactulose intolerable

— IV formulation available outside the US; promotes hepatic urea cycle and muscle glutamine synthesis; adjunct, not first-line

— Oral supplementation may benefit refractory HE and sarcopenia; not first-line

— Replete if deficient (common in cirrhosis); cofactor for urea cycle enzymes

Board pearl: Lactulose + rifaximin is the secondary-prevention combination after a second overt HE episode. After a single episode, lactulose monotherapy is the default unless breakthrough occurs.

Lactulose (non-absorbable disaccharide) — cornerstone:

Rifaximin (non-absorbable rifamycin antibiotic) — add-on:

Polyethylene glycol (PEG 3350):

L-ornithine L-aspartate (LOLA):

Branched-chain amino acids (BCAAs):

Zinc supplementation:

Avoid: neomycin (nephrotoxic, ototoxic — historical only), metronidazole long-term (neuropathy), flumazenil (only for confirmed BZD overdose)

Expanded Pharmacology and Procedural Considerations

— Optimize lactulose to 2–3 stools/day (confirm adherence with stool diary)

— Add rifaximin 550 mg BID

— Replete zinc, treat sarcopenia with high-protein nutrition + late evening snack

— Evaluate for large spontaneous portosystemic shunts via CT/MR venography → interventional radiology for shunt embolization; effective in selected patients

— Reduce or revise TIPS — narrow or occlude shunt if HE is shunt-driven and patient can tolerate higher portal pressures

— List for liver transplantation — HE is a soft indication; MELD exception points generally not granted, so refractory HE drives clinical urgency without numerical reward

— Incidence 20–45% post-TIPS; risk factors: age >65, prior HE, MELD >15, hyponatremia, sarcopenia

— Prophylactic rifaximin peri-TIPS reduces post-TIPS HE

— Refractory cases: TIPS reduction or occlusion by IR

— Cerebral edema is the proximate killer

— Elevate HOB 30°, avoid hypotonic fluids, maintain Na 145–155

— Hyperventilation to PaCO₂ 30–35 for acute herniation

— Mannitol 0.5–1 g/kg or hypertonic saline for ICP spikes

— CRRT for ammonia >150 and Grade 3–4 HE

— Transfer to transplant center early; King's College criteria for listing

— Benzodiazepines, opioids (especially long-acting), NSAIDs (AKI/HRS), aminoglycosides

— PPIs — use only with clear indication; chronic use associated with HE and SBP

— Acetaminophen — safe at ≤2 g/day in compensated cirrhosis without active alcohol use

— Propofol preferred (short half-life); avoid midazolam infusions

CCS pearl: If a patient on the CCS interface has recurrent HE despite lactulose + rifaximin, the next best step is CT/MR abdominal angiography to identify a spontaneous portosystemic shunt followed by IR consultation. Don't forget to re-list or refer for liver transplant evaluation.

Refractory HE — escalation ladder:

TIPS-related HE:

Acute liver failure (Type A) HE — different beast:

Drugs to specifically avoid/dose-reduce in cirrhotics:

Sedation in ventilated HE patients:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher baseline cognitive impairment — distinguish HE from dementia, delirium, polypharmacy

— MoCA before discharge to establish baseline cognition for future comparisons

— Falls risk amplified by asterixis, sarcopenia, orthostasis — PT/OT evaluation pre-discharge

— Polypharmacy review: deprescribe anticholinergics, sedating antihistamines, sleep aids, gabapentinoids (accumulate in CKD)

— Driving safety: AASLD recommends counseling patients with HE about driving; covert HE doubles MVC risk; refer to DMV per state law

— AKI precipitates HE via reduced ammonia clearance, electrolyte shifts

— Hold diuretics, NSAIDs, ACEi/ARBs, nephrotoxins

— Volume challenge with albumin 1 g/kg/day × 2 days if creatinine rising; if no response and HRS-AKI criteria met → terlipressin + albumin (FDA-approved 2022) or norepinephrine + albumin in ICU

— Rifaximin is non-absorbed → safe in renal failure

— Lactulose safe but watch for electrolyte derangement with excessive stooling

— Most drugs require dose reduction; check Child-Pugh-specific dosing

— Acetaminophen: ≤2 g/day or avoid

— Statins: generally safe in compensated cirrhosis; hold in decompensation

— Anticoagulation for PVT or AF: prefer LMWH; DOACs reasonable in Child-Pugh A–B (apixaban best evidence), avoid in C

— Skeletal muscle is a major site of ammonia detoxification via glutamine synthesis

— Aggressive nutritional rehab: 1.2–1.5 g/kg/day protein, 35 kcal/kg/day, late evening snack to prevent nocturnal catabolism

— Resistance exercise as tolerated

Board pearl: A cirrhotic with rising creatinine and worsening HE — your first move is hold diuretics and nephrotoxins, give albumin 1 g/kg, and rule out SBP with paracentesis. Do not reach for terlipressin until HRS-AKI criteria are met and infection is excluded/treated.

Elderly cirrhotic:

Renal impairment / hepatorenal syndrome (HRS):

Severe hepatic impairment (Child-Pugh C, MELD ≥20):

Sarcopenia:

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Cirrhosis in pregnancy is uncommon but increasing (NAFLD, HCV)

— Pregnancy-specific liver failure causing encephalopathy: acute fatty liver of pregnancy (AFLP) and HELLP syndrome — both require urgent delivery

— Swansea criteria help diagnose AFLP; hypoglycemia and coagulopathy are hallmarks

— Lactulose: safe in pregnancy (Category B equivalent); first-line

— Rifaximin: limited data; generally avoided in first trimester; can be used in 2nd/3rd trimester if benefits outweigh risks

— Avoid benzodiazepines, opioids; manage variceal bleeding with band ligation, octreotide (preferred over terlipressin in pregnancy)

— HE in children often signals Reye syndrome (avoid aspirin in viral illness), inborn errors of metabolism (urea cycle defects — OTC deficiency), Wilson disease (always check in child/young adult with HE)

— Ammonia level is more diagnostically meaningful in pediatric and acute settings

— Specialized pediatric hepatology referral; transplant evaluation

— Suspect in any patient <40 with new HE; check ceruloplasmin, 24-h urine copper, slit-lamp for Kayser-Fleischer rings

— Fulminant Wilson with HE → transplant; chelation (penicillamine, trientine) for chronic

— Distinguish HE from Wernicke encephalopathy — give thiamine 100 mg IV before any glucose

— Alcohol withdrawal can coexist; use phenobarbital or low-dose lorazepam with caution — benzodiazepines precipitate HE

— CIWA-guided management with careful neuro monitoring

— New encephalopathy → consider tacrolimus/cyclosporine neurotoxicity (PRES), CMV, rejection-related dysfunction

Key distinction: A young patient (<40) with new HE — always check ceruloplasmin and 24-hour urine copper for Wilson disease before attributing to chronic cirrhosis of another cause. Missing Wilson is a classic Step 3 trap.

Pregnancy:

Pediatrics:

Wilson disease:

Patients with alcohol use disorder:

Post-transplant patients:

Complications and Adverse Outcomes

— Aspiration pneumonia: leading cause of in-hospital death in HE; NPO + HOB 30°, intubate Grade 4

— Cerebral edema and herniation: primarily in acute liver failure (Type A), uncommon in chronic HE; suspect if cushing reflex, pupillary changes

— Acute kidney injury / HRS: triggered by overdiuresis, paracentesis without albumin, SBP, NSAIDs

— Falls and traumatic injury: subdural hematomas in coagulopathic cirrhotics — low threshold for head CT

— Recurrent HE: ~40% within 1 year of first episode without secondary prevention

— Persistent cognitive deficits: even after clinical resolution, deficits in attention, working memory, psychomotor speed may persist — particularly after recurrent episodes

— Reduced health-related quality of life: depression, work disability, caregiver burden

— Loss of driving privileges: legal and functional implications

— Increased mortality: 1-year survival ~40% after first overt episode; transplant evaluation should be initiated

— Lactulose overdose → severe diarrhea, dehydration, hypernatremia → paradoxical worsening of HE

— Rifaximin: rare C. difficile, drug interactions via P-gp

— TIPS placement: HE in 20–45%, accelerated heart failure in cirrhotic cardiomyopathy

— Continued protein restriction worsens sarcopenia and increases HE recurrence

— Refeeding syndrome in malnourished alcoholics — monitor phos, K, Mg

— Family caregiver strain — counsel and connect with support resources

— Cost of rifaximin a frequent barrier; engage social work and pharmacy benefits

Board pearl: A cirrhotic with HE who develops a sudden focal neuro deficit is not having HE — order non-contrast head CT immediately to rule out subdural hematoma or intracranial hemorrhage. HE is a diagnosis of exclusion for focal findings.

Acute complications:

Long-term sequelae:

Iatrogenic complications:

Nutritional complications:

Psychosocial:

When to Escalate Care — ICU, Consult, and Transfer

— West Haven Grade ≥3 (somnolent, severely disoriented)

— GCS ≤8 or inability to protect airway — intubate

— Hemodynamic instability, vasopressor requirement

— Concurrent variceal hemorrhage requiring massive transfusion

— Acute liver failure with INR >1.5 and any HE — high risk of cerebral edema

— Severe metabolic derangement: pH <7.25, Na <120, profound hypoglycemia

— Suspected status epilepticus on EEG

— Every admission for overt HE — for management of underlying cirrhosis, transplant referral, EGD planning

— Urgent if variceal bleed, refractory ascites, HRS, or recurrent HE despite optimized therapy

— TIPS for refractory ascites or variceal bleeding (consider risk of post-TIPS HE)

— Shunt embolization for refractory HE with documented spontaneous portosystemic shunt

— TIPS revision/reduction in shunt-driven HE

— Acute liver failure meeting King's College criteria (acetaminophen: pH <7.3 or INR >6.5 + Cr >3.4 + Grade 3–4 HE)

— Chronic liver failure with MELD-Na ≥15 not already listed

— Refractory HE in otherwise transplant-eligible patient

— Wilson disease with fulminant presentation

— Mental status returned to baseline (use family corroboration)

— Stable vitals, eating, ambulating, having 2–3 soft stools/day on lactulose

— Precipitant identified and treated/resolved

— Reliable caregiver and follow-up arranged within 7 days

— Medication reconciliation with high-risk drugs discontinued

— Patient/family education on dose titration and red flags

Step 3 management: Do not discharge a patient who is "still a little confused" — confirm cognitive return to baseline through family report or neuropsychometric assessment. Premature discharge with residual HE is a Step 3 patient-safety vignette and a major readmission driver.

ICU admission criteria:

GI/hepatology consult:

Interventional radiology consult:

Transplant center transfer indications:

Discharge readiness checklist:

Key Differentials — Other Causes of Altered Mentation in Cirrhotics

— Triad: confusion, ophthalmoplegia, ataxia — often incomplete

— Common in alcohol use disorder cirrhotics — give thiamine 100 mg IV before glucose

— Coexists with HE — treat both empirically

— 48–96 h after last drink; autonomic hyperactivity, tremor, hallucinations

— Cirrhotics with HE who also withdraw are a clinical landmine — benzodiazepines worsen HE but DTs kill; use phenobarbital or low-dose, short-acting BZD with vigilant neuro checks

— Na <125 in cirrhotic on diuretics; correct slowly (≤8 mEq/24 h) to avoid osmotic demyelination

— Hold diuretics, fluid restrict, consider tolvaptan (caution in cirrhosis — hepatotoxicity risk)

— BUN >100, asterixis indistinguishable from HE; uremic frost, pericardial rub

— Treatment is dialysis

— Failing liver loses gluconeogenic capacity; always check fingerstick first in any altered cirrhotic

— Cirrhotics with COPD, OSA, sedating drugs — VBG with pCO₂

— Benzodiazepines, opioids, zolpidem, anticholinergics, gabapentinoids — review MAR/home meds line by line

— Rare but consider focal deficits or seizures

— Often the precipitant for HE; can also cause encephalopathy independent of ammonia

Key distinction: Wernicke and HE coexist commonly. If a cirrhotic with alcohol use has any ophthalmoplegia, ataxia, or new confusion — give IV thiamine empirically before D5W — Wernicke is reversible but only if treated within the first 48–72 hours.

Wernicke encephalopathy:

Delirium tremens / alcohol withdrawal:

Hyponatremic encephalopathy:

Uremic encephalopathy:

Hypoglycemia:

CO₂ narcosis:

Drug-induced delirium:

Hepatocellular carcinoma with brain metastases:

Spontaneous bacterial peritonitis with sepsis-associated encephalopathy:

Key Differentials — Non-Hepatic Causes of Encephalopathy

— Meningitis, encephalitis (HSV, listeria in cirrhotics on immunosuppressives, fungal in transplant)

— Fever, neck stiffness, photophobia — LP after correcting coagulopathy

— Cirrhotics are at increased bleeding risk; subdurals are particularly insidious — falls + asterixis + coagulopathy

— Focal deficits, lateralizing signs → urgent non-contrast head CT

— Can mimic HE perfectly; EEG diagnostic

— Suspect in HE that fails to respond to lactulose despite low ammonia

— Hypercalcemia (HCC paraneoplastic), hypothyroidism (myxedema coma), hypoadrenalism (relative adrenal insufficiency common in cirrhosis)

— Carbon monoxide, heavy metals

— Major depression with psychomotor slowing, bipolar mania, acute psychosis

— Catatonia

— Opioid overdose, anticholinergic toxicity, serotonin syndrome, NMS

— Synthetic cannabinoids, GHB, methamphetamine — UDS

— OSA with daytime somnolence — common in cirrhotics; sleep study if isolated daytime hypersomnolence

— NMDA receptor, LGI1 — consider in atypical psychiatric/neuro presentations in young patients

— Post-transplant on calcineurin inhibitors; hypertension, visual changes, seizures; MRI confirms

Board pearl: When HE fails to improve within 24–48 hours of appropriate therapy, broaden the differential — consider subdural hematoma, nonconvulsive status epilepticus, occult sepsis, and CNS infection. Always re-examine, re-image, and re-culture; don't double down on lactulose alone.

CNS infections:

Stroke / intracranial hemorrhage:

Nonconvulsive status epilepticus:

Toxic-metabolic:

Psychiatric:

Medication and substance:

Sleep disorders:

Autoimmune encephalitis:

Posterior reversible encephalopathy syndrome (PRES):

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Lactulose 15–30 mL PO BID–TID, titrated by patient to 2–3 soft stools/day

— Continue indefinitely unless underlying liver disease reverses or transplant

— Explicit patient education: "Hold one dose if >4 stools per day; resume when normalized"

— Add rifaximin 550 mg PO BID — AASLD Class I recommendation

— Combination reduces recurrence by ~58% vs lactulose alone

— Help patient navigate insurance prior authorization; engage social work

— Protein 1.2–1.5 g/kg/day — emphasize plant and dairy proteins (better tolerated)

— Late evening snack (carbohydrate + protein) to shorten nocturnal fast and reduce muscle catabolism

— 35 kcal/kg/day total caloric intake

— Salt restriction <2 g/day for ascites; fluid restriction <1.5 L only if Na <125

— Strict alcohol abstinence — refer to AUD treatment (naltrexone, acamprosate; baclofen if decompensated cirrhosis)

— HCC surveillance: US ± AFP every 6 months

— EGD per variceal screening protocol

— Hepatitis A/B vaccination if not immune; annual influenza, pneumococcal, COVID, RSV (≥60), HZV

— Bone health: vitamin D, DEXA — osteoporosis common

— Benzodiazepines, opioids (use acetaminophen ≤2 g/day or topical agents), NSAIDs, PPIs without clear indication

— Sedating antihistamines, anticholinergics, gabapentinoids in high doses

— Refer if MELD-Na ≥15, refractory HE, refractory ascites, or any decompensation

— Begin pre-transplant workup early (cardiac, dental, psychosocial, AUD treatment if applicable)

Step 3 management: Lactulose for life after first episode, lactulose + rifaximin after second episode, and transplant referral with any decompensation — this triad is the high-yield Step 3 discharge plan for cirrhotic HE.

Discharge medication regimen after first overt HE episode:

After second overt HE episode (or breakthrough on lactulose alone):

Lifestyle and dietary counseling:

Risk factor management:

Avoid/deprescribe:

Transplant evaluation:

Follow-Up, Monitoring, and Counseling

— 7–14 days post-discharge: hepatology or PCP — verify mental status at baseline, lactulose titration, medication adherence, address insurance/cost issues with rifaximin

— Every 1–3 months thereafter for compensated patients; more frequently if MELD ≥15 or recurrent decompensation

— Telehealth check-ins for cognitive symptom monitoring and caregiver concerns

— Cognitive screen (Stroop EncephalApp, MoCA, or family-reported function)

— Stool frequency log — target 2–3/day

— Weight, abdominal girth (ascites), BP, orthostatics

— Labs: CMP, CBC, INR, MELD-Na q3 months; AFP + US q6 months for HCC surveillance

— Medication reconciliation each visit

— Patients with overt HE should not drive until cleared

— Patients with minimal/covert HE have impaired reaction time — discuss risk explicitly and document

— State laws vary on physician reporting; know local mandatory reporting requirements

— Physical therapy for sarcopenia and falls prevention

— Nutrition referral for protein and caloric optimization

— Occupational therapy if functional decline at home

— Speech-language pathology for dysarthria or swallowing concerns

— Screen for depression (PHQ-9) and anxiety at each visit

— Active AUD treatment is non-negotiable for alcohol-associated cirrhosis — referral to addiction medicine, counseling, AA, medications

— Recognize early HE signs: sleep reversal, irritability, missed appointments, mild confusion

— Have a "rescue" plan — escalate lactulose, call provider, when to go to ED

— Provide written action plan

Board pearl: Driving is a routine Step 3 ethics question — counsel and document. A patient with covert HE who has an MVC after you failed to counsel about driving risk is a malpractice and patient-safety pitfall. The Stroop test or DMV referral is a defensible standard.

Follow-up cadence:

Monitoring parameters at each visit:

Driving counseling:

Rehabilitation and functional support:

Mental health and AUD:

Caregiver education:

Ethical, Legal, and Patient Safety Considerations

— Patients with overt HE lack decisional capacity for major medical decisions

— Identify surrogate decision-maker per state hierarchy (spouse, adult children, etc.) or activate prior healthcare proxy/advance directive

— Reassess capacity as HE resolves — capacity is decision-specific and fluctuates

— Document the capacity assessment elements: communicate choice, understand, appreciate, reason

— For procedures (paracentesis, EGD, TIPS), if patient lacks capacity, obtain consent from surrogate; in emergencies invoke implied/emergency consent doctrine

— Liver transplant listing requires capacity; defer formal discussions to a window of clarity, often with rifaximin/lactulose optimization

— Counsel patient and family that overt HE precludes driving until cleared

— Document discussion; know state-specific mandatory physician reporting requirements (e.g., California, Pennsylvania, Oregon mandate reporting of certain cognitive impairments)

— Failure to counsel about driving in covert HE is a medico-legal exposure

— Suspected abuse/neglect of vulnerable adults (cirrhotic with HE may meet criteria) — adult protective services

— Suspected child abuse if pediatric Reye-like presentation with suspicious history

— Medication reconciliation is mandatory — sedatives/opioids/NSAIDs/diuretics added during admission must be reviewed at discharge

— Schedule follow-up within 7 days; document warm handoff to PCP/hepatology

— Provide written discharge instructions in patient's preferred language with lactulose titration instructions

— Caregiver presence at discharge teaching reduces readmission

— Decompensated cirrhosis with recurrent HE not transplant-eligible → introduce palliative care early

— Discuss DNR/DNI, code status, hospice when MELD trajectory worsens

— Do not condition treatment on sobriety, but transplant centers require sustained abstinence (varies by center; trend toward shorter mandatory periods with intensive AUD treatment)

— Engage AUD treatment from index admission

Board pearl: A confused cirrhotic refusing paracentesis — assess capacity first. If they lack capacity, obtain consent from surrogate; do not let an HE-impaired refusal block lifesaving care, but also do not coerce a capacitated patient who declines.

Capacity assessment:

Informed consent edge cases:

Driving and public safety:

Mandatory reporting:

Transition-of-care safety:

Goals of care:

Alcohol use disorder ethics:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: When the Step 3 stem describes a cirrhotic newly confused, the highest-yield single action is diagnostic paracentesis to rule out SBP. SBP is the #1 occult precipitant and may be afebrile.

"I HAVE TIPS" precipitants: Infection (SBP #1), Hemorrhage (GI), Alkalosis/electrolytes (hypoK, hypoNa), Volume depletion, Excess protein (less common), Tranquilizers/sedatives/opioids, Increased shunt (TIPS, spontaneous), Plus constipation

Asterixis differential: HE, uremia, CO₂ narcosis, hypoglycemia, hyponatremia, drug toxicity (phenytoin, lithium, gabapentin)

Fetor hepaticus: dimethyl sulfide — pathognomonic but insensitive

EEG finding: triphasic waves, generalized slowing — supportive not specific

MRI brain: T1 hyperintensity in globus pallidus from manganese deposition — chronic HE signature

Lactulose target: 2–3 soft stools/day — not maximum tolerated dose; overshoot worsens HE via dehydration

Rifaximin indication: prevent recurrence after second overt HE episode

Ammonia level: not routine for diagnosis in cirrhotic HE; useful as rule-out (normal level argues against HE) and for prognosis in acute liver failure

Protein intake: 1.2–1.5 g/kg/day — do not restrict; favor plant/dairy

Late evening snack: reduces sarcopenia and nocturnal protein catabolism

PPIs and cirrhosis: associated with HE and SBP — use only with clear indication

Acetaminophen: safe at ≤2 g/day in compensated cirrhosis without active alcohol use; preferred over NSAIDs/opioids

Acute liver failure HE: cerebral edema is the killer; ammonia >150 predicts herniation

TIPS HE risk: 20–45%; reduce risk with prophylactic rifaximin, narrow shunt if refractory

Spontaneous portosystemic shunt: consider embolization in refractory HE

Wilson disease: check ceruloplasmin in any patient <40 with new HE

Wernicke encephalopathy: give thiamine before glucose in any alcohol-related presentation

Driving: overt HE — no driving; covert HE — counsel and consider Stroop testing

Transplant: refer at MELD-Na ≥15 or after first decompensation; HE alone rarely earns MELD exception

Mortality: 1-year survival ~40% after first overt HE episode without transplant

Board Question Stem Patterns

— A 60-year-old man with alcohol-associated cirrhosis presents with 2 days of confusion. Exam: asterixis, ascites, no fever. Labs: WBC 9, ammonia 80. Next best step? → Diagnostic paracentesis (SBP is the most common occult precipitant; do not anchor on ammonia level)

— Cirrhotic on furosemide/spironolactone with confusion, K 2.8, HCO₃ 32. Best step? → Hold diuretics, replete potassium, start lactulose; alkalosis shifts NH₃ across BBB

— Cirrhotic with 2nd HE episode in 6 months on lactulose 30 mL TID. Best addition? → Rifaximin 550 mg BID

— Cirrhotic with 4 HE admissions/year on lactulose + rifaximin. Next step? → CT/MR angiography for spontaneous portosystemic shunt ± transplant referral

— Young woman, acetaminophen ingestion, INR 7, Cr 4, Grade 3 HE. Step? → Transfer to transplant center (meets King's College criteria); N-acetylcysteine; ICU; CRRT for ammonia

— 25-year-old with new HE, hemolysis, K-F rings. Diagnostic test? → Ceruloplasmin (low), 24-hour urine copper (high); transplant referral

— Alcoholic cirrhotic with ataxia, ophthalmoplegia, confusion. Step? → Thiamine 100 mg IV before glucose, then treat HE

— Cirrhotic with normal exam, family reports near-miss MVCs. Step? → Test for covert HE (Stroop EncephalApp/PHES); counsel about driving; consider DMV report per state law

— Cirrhotic recovering from first HE episode. Discharge meds? → Lactulose titrated to 2–3 stools/day, hold diuretics until stable, follow-up in 1 week

— Cirrhotic with HE who develops left-sided weakness. Step? → Non-contrast head CT — focal deficits are not HE

Step 3 management: The recurring exam theme is "find and treat the precipitant first; pharmacology second." When the question asks "next best step," the answer is usually a diagnostic action (paracentesis, head CT, EGD, electrolyte correction) rather than escalating lactulose dosing.

Stem 1 — The classic precipitant hunt:

Stem 2 — The hypokalemic alkalotic patient:

Stem 3 — Recurrent HE despite lactulose:

Stem 4 — Refractory HE:

Stem 5 — Acute liver failure:

Stem 6 — Wilson trap:

Stem 7 — Wernicke vs. HE:

Stem 8 — Driving safety:

Stem 9 — Discharge planning:

Stem 10 — Subdural hematoma masquerader:

One-Line Recap

Hepatic encephalopathy is a clinical diagnosis in cirrhotics with altered mentation, treated by identifying and reversing the precipitant (most often SBP, GI bleed, electrolyte disturbance, sedatives, or constipation) while administering lactulose titrated to 2–3 soft stools per day, adding rifaximin after a second episode, and referring decompensated patients for liver transplantation.

Board pearl: The three Step 3 reflexes for a confused cirrhotic — paracentesis, precipitant search, lactulose — get them right and the rest of the case writes itself.

Diagnosis: Clinical — asterixis + altered mentation + cirrhosis; ammonia level is not required and does not correlate with severity in chronic HE; always do diagnostic paracentesis to rule out SBP and head CT if focal findings or first/severe episode.

Precipitants (find and treat — present in >90%): Infection (SBP #1), GI bleed, hypokalemia/alkalosis, volume depletion, sedatives/opioids/benzodiazepines, constipation, increased shunt (TIPS or spontaneous portosystemic shunt), AKI/HRS, dietary indiscretion.

Treatment: Lactulose to 2–3 stools/day is first-line; add rifaximin 550 mg BID after second episode for secondary prevention; do not restrict protein (target 1.2–1.5 g/kg/day with a late evening snack); hold diuretics, NSAIDs, benzodiazepines, opioids; supplement zinc and thiamine; intubate Grade 4 for airway protection; CRRT and transfer in acute liver failure with cerebral edema risk.

Long-term: MELD-Na assessment, transplant referral at ≥15 or with any decompensation; HCC surveillance with US + AFP q6 months; AUD treatment; vaccinations (HAV, HBV, influenza, pneumococcal, COVID, HZV); driving counseling for both overt and covert HE; written caregiver action plan and follow-up within 7–14 days of discharge.