Hepatic Encephalopathy (HE)

Definition

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1815

Classification

By Underlying Disease (EASL/AASLD Types)

Severity: West Haven Criteria + SONIC Classification

• Bradley and Daroff's Neurology in Clinical Practice, p. 1781

Pathophysiology

Fig. 94.1 - Proposed pathophysiology of HE. (Sleisenger and Fordtran's GI and Liver Disease)

1. Ammonia - The Central Neurotoxin

• Source: Colon bacteria metabolize proteins/nitrogenous products → ammonia; enterocytes synthesize ammonia from glutamine
• Ammonia enters the portal circulation and is normally cleared by hepatocytes
• In cirrhosis: reduced hepatocyte function + portosystemic shunting → arterial hyperammonemia (seen in up to 90% of HE patients)
• Ammonia crosses the blood-brain barrier (increased permeability): preferentially taken up by the cerebellum and basal ganglia
• Effects on the brain: astrocyte swelling, cytotoxic brain edema, impaired transport of neuroactive compounds (e.g., myoinositol), direct inflammatory response in astrocytes
• Astrocytes respond by converting glutamate → glutamine (via glutamine synthetase) → osmotic astrocyte swelling

2. GABA-Benzodiazepine System

• Increased sensitivity of astrocyte peripheral-type benzodiazepine receptors enhances activation of the GABA-A/benzodiazepine system
• A feed-forward loop: astrocytes produce neurosteroids (allopregnanolone, tetrahydrodeoxycorticosterone) → further activates GABA-A receptors → net CNS inhibition
• This explains why benzodiazepines can precipitate/worsen HE

3. Other Factors

• Manganese deposition: accumulates in basal ganglia (especially globus pallidus) → dopaminergic dysfunction; produces characteristic T1-hyperintensity on MRI
• Altered amino acid profile: increased aromatic amino acids (false neurotransmitters), decreased branched-chain amino acids
• Inflammatory mediators: systemic inflammation (from bacterial translocation, infections) synergizes with hyperammonemia
• Nitric oxide, serotonin, short-chain fatty acids, mercaptans: additional contributing neurotoxins
• Gut microbiome: differences in colonic mucosal microbiota between cirrhotic patients with and without HE
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1815-1816

Precipitating Factors

• Bradley and Daroff's Neurology in Clinical Practice, p. 1781

Clinical Features

• Early/covert: forgetfulness, alterations in handwriting, difficulty driving, sleep-wake cycle reversal
• Overt: asterixis (flapping tremor), agitation, disinhibited behavior, disorientation, confusion
• Severe: somnolence, stupor, coma, seizures

• ALF: mania evolving to deep coma, nausea/vomiting common, abdominal pain common
• Chronic HE (portal-systemic): blunted consciousness, onset may be insidious, rarely presents with N/V or abdominal pain

Diagnosis

Blood Tests

• Serum ammonia: elevated in up to 90% of HE, but neither sensitive nor specific - normal ammonia does NOT exclude HE; elevated ammonia does not confirm it
• Standard LFTs (bilirubin, enzymes, albumin, INR) are usually abnormal
• Arterial ammonia offers no advantage over venous in chronic liver disease

Neuropsychometric Tests

• Stroop test (psychomotor speed, cognitive flexibility) - validated for HE; available as a smartphone app (EncephalApp)
• Portosystemic Encephalopathy Syndrome Test
• These are especially useful for detecting covert/minimal HE

EEG

• Characteristic: bursts of moderate-to-high amplitude (100-300 μV), low-frequency (1.5-2.5 Hz) waves with frontal predominance in severe HE
• Even patients without clinical signs may show reduced mean dominant frequency

MRI / MR Spectroscopy

• T1-weighted MRI: bilateral T1-hyperintensity in the globus pallidus (from manganese deposition) - regression occurs after successful LT
• MR Spectroscopy: increased glutamine/glutamate peak (Glx) at ~2.5 ppm; decreased myoinositol and choline signals; N-acetylaspartate (neuronal marker) remains normal
• MRI is useful to exclude structural causes (subdural hematoma, Wernicke's, cerebellar atrophy)

Critical Flicker Frequency (CFF)

• Assesses cerebral cortex function; reliable marker of minimal HE

Important: None of these findings are specific for HE. Diagnosis requires exclusion of other causes of cerebral dysfunction (hypoglycemia, hyponatremia, medication ingestion, intracranial hemorrhage especially if focal deficits present).

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1816; Bradley and Daroff's Neurology, p. 1782

Treatment

Step 1: Identify and Correct Precipitating Factors

Step 2: Reduce Ammonia Production/Absorption

• First-line treatment - cornerstone of HE management
• Dose: 30-60 g/day orally; titrate to 2-3 soft stools/day
• Mechanism: metabolized by colonic bacteria → acidic byproducts → catharsis + reduced intestinal pH → inhibits NH₃ absorption (NH₃ → NH₄⁺, which is not absorbed)
• Can be given per rectum (enema) in patients at aspiration risk
• Side effects: abdominal cramping, flatulence, diarrhea, electrolyte imbalance

• Non-absorbable antibiotic targeting gut flora
• 400 mg PO every 8 hours (or 550 mg twice daily for secondary prophylaxis)
• Used alone or (preferably) in combination with lactulose for overt HE and prevention of recurrence
• Superior to other antibiotics; used in the pivotal trial that led to its FDA approval for HE
• Side effects minimal given negligible systemic absorption

Step 3: Nutritional Management

• Do NOT restrict protein - previous practice of protein restriction is not beneficial and may worsen sarcopenia (which itself is a risk factor for HE)
• Vegetable and dairy proteins preferred over animal proteins (more favorable calorie-to-nitrogen ratio)
• Branched-chain amino acid (BCAA) supplementation: shown to have beneficial effect on HE and reduces hospitalizations; does not affect mortality or quality of life (oral BCAAs); IV BCAAs show benefit without increased mortality
• Small, frequent meals; avoid prolonged fasting

Additional Therapies

• Zinc supplementation: zinc deficiency is common in cirrhosis; supplementation may improve HE
• Probiotics/prebiotics: modulate gut microbiome; emerging evidence for secondary prophylaxis
• TIPS management: if TIPS-related HE, TIPS embolization with coils to reduce shunted volume in refractory cases

Definitive Treatment

• Liver transplantation (LT): the only definitive treatment; generally reverses HE
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1817; Rosen's Emergency Medicine, p. 1235

Prognosis

• Development of HE indicates advanced cirrhosis and poor prognosis
• Cumulative 1-year survival: 20-42%; 3-year survival: 15-23% without LT
• Minimal/covert HE affects ~50% of all cirrhotic patients and impairs driving, quality of life, and work performance - it increases risk of progression to overt HE
• About 20,000 patients per year are hospitalized in the US for HE (2005-2009 data)

Summary Table: Key Management Points

Stroke Treatment Guidelines 2026

The 2026 AHA/ASA Guideline - Overview

Key Updates at a Glance

1. Intravenous Thrombolysis (IVT)

Drug Choice: Tenecteplase is Now Equal to Alteplase

Extended Time Window for IVT (New)

1. Patients who awaken with stroke within 9 hours from the midpoint of sleep (wake-up stroke)
2. Patients 4.5 to 9 hours from last known well with evidence of salvageable ischemic penumbra on advanced imaging

Modified Contraindications

2. Endovascular Thrombectomy (EVT / Mechanical Thrombectomy)

Expanded Eligibility (Major Update)

• Time window: Up to 24 hours from symptom onset (or last known well) when advanced imaging (CT perfusion/MRI) demonstrates salvageable brain tissue - previously 16-24 hours was only for selected patients
• Large infarct cores: Selected patients with larger established infarcts may now be eligible based on imaging criteria (reflecting ASPECTS score data and DEFUSE/DAWN trial concepts extended)
• Posterior circulation strokes: New evidence incorporated supporting EVT for basilar artery occlusion and other posterior circulation LVO
• Bridging therapy: Patients eligible for both IVT and EVT should receive both sequentially without delaying EVT for the IVT infusion to complete

3. Blood Pressure Management

Before IVT

• BP must be < 185/110 mmHg before initiating IVT (unchanged)
• Maintain < 180/105 mmHg during and for 24 hours after IVT

After IVT - New Recommendation

• Intensive SBP lowering to < 140 mmHg in the first 24 hours after IVT is NOT recommended - it has not been associated with improved functional outcomes and may be harmful
• This is a change from prior practice that sometimes pushed for aggressive BP lowering post-thrombolysis

After Successful EVT (ESO 2026 Update)

• Against intensive SBP < 140 mmHg in the first 24 hours after successful mechanical thrombectomy (high-certainty evidence)
• Routine pre-hospital BP lowering in suspected stroke: not advised (moderate-certainty evidence)

In Intracerebral Hemorrhage (ICH)

• Early SBP reduction to < 140 mmHg supported in patients with small-to-moderate hematomas to limit expansion (expert consensus; net benefit remains uncertain for all ICH)

4. Glycemic (Blood Sugar) Management

• Less aggressive glycemic control is now endorsed for patients with persistent hyperglycemia after AIS
• Intensive insulin therapy targeting tight glucose control is not recommended - evidence shows no benefit and potential for hypoglycemic harm
• A reasonable target is generally treating significant hyperglycemia (e.g., glucose > 180 mg/dL) without pursuing intensive normalization

5. Pediatric Acute Ischemic Stroke - First-Ever Dedicated Recommendations

• Age-appropriate diagnostic criteria and imaging
• Eligibility criteria for IVT and EVT in the pediatric population
• Pediatric-specific dosing considerations
• Recognition that children have different stroke etiologies (e.g., cardiac, hematologic) than adults

6. Prehospital Care and Systems of Care

• Mobile Stroke Units (MSUs): Formally endorsed - vehicles equipped with CT scanners and telemedicine capability that allow diagnosis and IVT administration before hospital arrival, shown to significantly reduce time-to-treatment and long-term disability
• EMS triage refinement: Improved protocols for bypassing closer non-thrombectomy-capable hospitals to go directly to comprehensive stroke centers (CSCs) for patients with suspected LVO
• Telestroke: Continued strong endorsement for rural/underserved areas

7. Secondary Prevention Updates

Antiplatelet Therapy

• Dual antiplatelet therapy (DAPT) with aspirin + clopidogrel or aspirin + ticagrelor for 21 days is endorsed for non-disabling minor ischemic stroke or high-risk TIA (POINT/CHANCE trial data), then transition to single antiplatelet
• For patients within the 4.5-hour window with minor stroke, DAPT without thrombolysis is an option

Lipid Management (ILEP 2026 Consensus)

• LDL-C contributes to ~1/3 of all ischemic strokes
• Up to 40% of post-stroke patients receive no lipid-lowering therapy - a major gap
• Intensive upfront combination LLT (statin + ezetimibe ± PCSK9 inhibitor) recommended for secondary stroke prevention
• LDL-C target for secondary prevention: < 55 mg/dL (< 1.4 mmol/L)
• Early and aggressive treatment emphasized to prevent recurrence (40% recurrence risk within 5 years without adequate LLT)

Atrial Fibrillation Detection

• Prolonged cardiac monitoring (≥ 72 hours, preferably long-term implantable loop recorder) recommended after cryptogenic stroke to detect paroxysmal AF

Patent Foramen Ovale (PFO)

8. Dysphagia Management

• Formal swallowing screen before any oral intake is strongly recommended for all AIS patients
• Early speech therapy involvement for aspiration prevention
• The 2026 neuroprognostication guidelines (PMID 41942818) include recovery of swallow function as a prognostically important parameter in critically ill stroke patients

9. Neuroprognostication in Critically Ill AIS (New 2026 Guidelines)

• Avoid premature neuroprognostication - a key good-practice statement
• Early neurological improvement within 24 hours of revascularization is a moderately reliable predictor of good functional outcome
• No single clinical variable reliably predicts poor outcome - multimodal assessment is required
• Special guidance for counseling families of patients with large hemispheric infarction before neurological decline

Summary: What's Most Clinically Impactful

1. Tenecteplase is now a first-line choice - simplifies delivery, equivalent efficacy to alteplase
2. Extended IVT window to 9 hours in wake-up/late-window strokes with penumbral imaging - more patients eligible
3. EVT up to 24 hours with imaging selection - significantly more patients eligible for clot removal
4. Posterior circulation and large cores are no longer automatic exclusions from EVT
5. Don't aggressively lower BP post-IVT (< 140 mmHg target abandoned)
6. Mobile stroke units endorsed as a system-of-care standard
7. First pediatric AIS guidelines - a long-awaited addition
8. DAPT for 21 days in minor stroke/high-risk TIA remains strong evidence-based practice