Hepatic Encephalopathy (HE)

📋 Key Information Summary

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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver dysfunction or portosystemic shunting, resulting in accumulation of neurotoxins — principally ammonia — that cross a compromised blood–brain barrier.
West Haven grading classifies HE into covert (minimal HE + Grade I, detected only by testing) and overt (Grades II–IV, clinically apparent).
Every new episode of overt HE mandates systematic search for a precipitant — most commonly infection (especially SBP), GI bleeding, electrolyte disturbance, constipation, and sedative use.
First-line treatment of acute HE is lactulose (oral or rectal enema if obtunded), titrated to 2–3 soft bowel motions per day.
Rifaximin 550 mg PO BD is added to lactulose for secondary prophylaxis after ≥1 episode of overt HE (NNT 4 to prevent one additional episode).
Do NOT restrict protein intake — maintain 1.2–1.5 g/kg/day; protein restriction worsens sarcopenia and outcomes.
Screen for large spontaneous portosystemic shunts in recurrent/refractory HE; consider coil embolisation or BATO.
After TIPS, if HE is refractory despite medical therapy, consider TIPS reduction or closure.
Refer early for liver transplant assessment if HE is refractory to combined lactulose + rifaximin ± shunt embolisation.
Driving must cease during overt HE; the treating physician has a legal duty to notify the relevant state/territory licensing authority.
Aboriginal and Torres Strait Islander patients experience higher cirrhosis burden; culturally safe care, AMS engagement, and addressing barriers to specialist access are essential.

Precipitants & Grading

Pathophysiology

HE results from the accumulation of neurotoxins — principally ammonia (NH₃) — in the setting of impaired hepatic clearance and/or portosystemic shunting. Ammonia, generated predominantly by gut urease-producing bacteria (Enterobacteriaceae, Streptococcaceae), is normally cleared by hepatic urea-cycle conversion to urea. In cirrhosis, reduced hepatocyte mass and portosystemic collaterals allow ammonia to reach the systemic circulation and cross the blood–brain barrier. Astrocyte swelling from glutamine accumulation, neuroinflammation (TNF-α, IL-1β, IL-6), manganese deposition, and alterations in GABAergic/benzodiazepine receptor signalling collectively produce the neuropsychiatric manifestations. The gut–liver–brain axis is central, explaining why therapies targeting gut ammonia production (lactulose, rifaximin) are effective.

West Haven Grading System

The West Haven Criteria remain the standard bedside classification for HE severity:

Classification	Grade	Clinical Features
Covert HE	Minimal HE	No clinical abnormality on standard exam; detected only by psychometric or neurophysiological testing (impaired attention, working memory, psychomotor speed)
Covert HE	Grade I	Lack of awareness, shortened attention span, impaired addition/subtraction, sleep disturbance, euphoria or anxiety; may be detected only by careful questioning
Overt HE	Grade II	Lethargy, disorientation to time, personality change, inappropriate behaviour, asterixis (flapping tremor)
	Grade III	Somnolence but rousable, gross disorientation, bizarre behaviour, muscular rigidity, hyperreflexia, upgoing plantars
	Grade IV	Coma — unresponsive to verbal or noxious stimuli; decerebrate or decorticate posturing possible

Minimal (Covert) HE — Diagnostic Testing

Minimal HE affects 20–80% of patients with cirrhosis and is associated with impaired quality of life, increased fall risk, poor driving performance, and progression to overt HE. It is not detectable by standard neurological examination. Recommended screening tools in Australia include:

Available Psychometric Hepatic Encephalopathy Score (PHES) Battery of five paper-and-pencil tests (number connection A & B, digit symbol, line tracing, serial dotting). Score ≤ −4 defines minimal HE. Gold standard in Australasia.

Available EncephalApp Stroop Smartphone/tablet-based test measuring cognitive flexibility. OffTime + OnTime > 190 seconds suggests minimal HE. Validated in Australian cohorts; practical for outpatient screening.

Available Animal Naming Test (ANT) Patient names as many animals as possible in 1 minute. ≤ 15 animals suggests cognitive impairment. Quick bedside test; sensitivity 70%.

Referral Critical Flicker Frequency (CFF) Neurophysiological test measuring the threshold at which a flickering light appears continuous. < 39 Hz suggests minimal HE. Limited availability; requires dedicated equipment.

Screen with PHES or EncephalApp Stroop in all patients with cirrhosis — particularly those with driving or occupational safety concerns, prior episodes of overt HE, or TIPS.

Precipitants of Overt HE

Always search for and treat reversible precipitants before or concurrently with HE-specific therapy. More than one precipitant is present in up to 60% of episodes.

Infection

Spontaneous Bacterial Peritonitis & Other Sepsis

Most common precipitant in Australia. SBP, UTI, pneumonia, cellulitis, and Clostridioides difficile all trigger HE via systemic inflammation and cytokine release. Perform diagnostic paracentesis in all cirrhotics with ascites presenting with HE.

Action: Diagnostic paracentesis, blood cultures, urine MCS, CXR if respiratory symptoms

GI Bleed

Variceal / Peptic Ulcer Haemorrhage

Digestion of blood in the GI tract provides a large nitrogen load. HE commonly develops 24–72 hours after variceal haemorrhage.

Action: Urgent endoscopy, IV terlipressin or octreotide, bowel lavage with lactulose/PegLyte

Electrolyte

Hypokalaemia, Hyponatraemia, Metabolic Alkalosis

Hypokalaemia promotes renal ammoniagenesis. Metabolic alkalosis favours conversion of NH₄⁺ → NH₃ (membrane-permeable). Hyponatraemia directly impairs astrocyte function.

Action: Correct K⁺ to > 3.5 mmol/L, address alkalosis, cautiously correct Na⁺

Constipation

Increased Gut Ammonia Absorption

Prolonged colonic transit time increases contact between gut bacteria and nitrogenous substrates, increasing ammonia production and absorption.

Action: Lactulose, adequate hydration, review opioids/anticholinergics

Medications

Sedatives, Opioids, Psychoactive Drugs

Benzodiazepines (GABAergic potentiation), opioids (constipation + CNS depression), and antipsychotics worsen or unmask HE. Avoid benzodiazepines in cirrhosis; use oxazepam if anxiolysis essential (short-acting, no hepatic metabolism).

Action: Discontinue offending agents; avoid diazepam, nitrazepam, temazepam

Dehydration

Over-diuresis / Volume Depletion

Pre-renal AKI from over-diuresis reduces renal ammonia excretion. Aim for ≤ 0.5 kg/day weight loss on diuretics.

Action: Temporarily withhold diuretics, IV normal saline if hypovolaemic, monitor creatinine

TIPS

Transjugular Intrahepatic Portosystemic Shunt

TIPS creates a direct portosystemic shunt; 25–50% of patients develop new or worsened HE within 3 months. Risk factors: age > 65, prior HE, low MELD with preserved hepatic reserve, large shunt diameter.

Action: Pre-TIPS HE assessment, prophylactic lactulose ± rifaximin, consider TIPS reduction if refractory

Metabolic

Hypoglycaemia, Hypoxia, Alkalaemia

Hypoglycaemia and hypoxia impair cerebral metabolism. Alkalaemia (respiratory or metabolic) shifts NH₄⁺ equilibrium toward NH₃.

Action: BGL monitoring, ABG, correct acid–base disturbance

Treatment

General Principles

Identify and treat precipitants first — HE-specific therapy alone is insufficient if an untreated precipitant persists.
Do NOT restrict protein — malnutrition and sarcopenia are near-universal in decompensated cirrhosis and independently worsen prognosis.
Aim for caloric intake 35 kcal/kg/day and protein 1.2–1.5 g/kg/day with small, frequent meals and a late-evening snack.
Review and stop all non-essential sedatives, opioids, and psychoactive medications.

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Do NOT restrict protein. Historical protein restriction is harmful. Maintaining protein intake of 1.2–1.5 g/kg/day improves HE outcomes and prevents sarcopenia. A late-evening snack (predominantly complex carbohydrate) reduces overnight protein catabolism.

Pharmacotherapy — Acute Overt HE

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Lactulose

Duphalac® · Generic · Osmotic laxative / acidifier

Adult dose (oral) 30–45 mL PO every 1–2 hours until bowel motion, then 15–30 mL PO TDS–QID

Adult dose (rectal) 300 mL in 700 mL water as retention enema × 30–60 min; repeat every 4–6 h if needed

Target 2–3 soft bowel motions per day; titrate to effect

Paediatric dose 1–3 mL/kg/day PO in divided doses; rectal: 1–2 mL/kg in 3 volumes water

Route Oral or rectal enema

Key precautions Avoid in galactosaemia; caution with bowel obstruction; excessive use → dehydration and electrolyte disturbance

Renal adjustment No dose adjustment required; monitor electrolytes

PBS status ✔ PBS General Benefit

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Rifaximin

Xifaxan® · Non-absorbable gut-selective antibiotic

Adult dose 550 mg PO BD — continuous long-term therapy

Indication Secondary prophylaxis of recurrent OHE (add-on to lactulose)

Route Oral

Renal adjustment No adjustment required

Hepatic adjustment No adjustment; non-absorbed drug

PBS status ⚠ PBS Restricted Benefit — Authority Required

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L-Ornithine L-Aspartate (LOLA)

Hepa-Merz® · Amino acid combination

Adult dose (IV) 20 g/day IV infusion in 250–500 mL 5% glucose over 4 hours

Adult dose (oral) 6 g (3 sachets) PO TDS with meals

Route IV or oral granules

Evidence Meta-analyses show benefit in acute HE (reduces ammonia, improves grading); not yet standard of care in Australia but used adjunctively

PBS status ✘ Not PBS-listed

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Branched-Chain Amino Acids (BCAAs)

Various · Leucine, isoleucine, valine supplements

Adult dose 12–24 g/day PO in divided doses

Indication Selected patients with protein intolerance or recurrent HE unresponsive to standard therapy

Evidence Cochrane 2017: uncertain benefit for HE; some trials show improvement in minimal HE and nutritional status

PBS status ✘ Not PBS-listed

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Flumazenil

Anexate® · GABA-A receptor antagonist

Adult dose 0.2 mg IV over 15 seconds; may repeat every 1 min to max 1–2 mg total

Use Diagnostic and short-term therapeutic for suspected benzodiazepine-induced HE. Response confirms BZD involvement.

Duration Effect lasts 1–2 hours; not for long-term use

PBS status ✔ PBS General Benefit (hospital)

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Avoid benzodiazepines in cirrhosis. If anxiolysis is essential, use oxazepam or lorazepam (short-acting, no hepatic oxidative metabolism) at reduced doses. Avoid diazepam, nitrazepam, and temazepam.

Nutritional Management

Historical advice to restrict protein is outdated and harmful. Evidence demonstrates that protein restriction worsens sarcopenia, increases infection risk, and does not improve HE outcomes.

Target 1.2–1.5 g/kg/day protein (adjusted body weight in obesity).
Provide 35 kcal/kg/day total energy.
Small, frequent meals (4–6 per day) plus a late-evening snack (complex carbohydrate-rich) to reduce overnight protein catabolism.
Vegetable and dairy protein may be better tolerated than meat-based protein in some patients (lower ammonia generation).
Consider dietitian referral for all hospitalised cirrhotics.

Supportive Care

Nursing observation every 1–2 hours for Grade II–III HE; continuous monitoring in Grade IV.
Aspiration precautions — head of bed ≥ 30°; consider NG tube for enteral lactulose if unable to swallow safely.
Pressure area care; DVT prophylaxis with LMWH if no active bleeding.
Minimise sedation; avoid antipsychotics (haloperidol contraindicated in hepatic disease).

Recurrent & Refractory HE

Recurrent HE is defined as ≥2 episodes of overt HE within 6 months despite treatment of precipitants. Refractory HE is persistent or rapidly recurring HE despite optimal medical therapy (lactulose + rifaximin). These patients require a systematic escalation strategy.

1. Optimise Long-Term Medical Therapy

Lactulose — ensure ongoing adherence; titrate to 2–3 soft bowel motions/day. Review compliance (palatability is a common issue).
Rifaximin 550 mg PO BD — continuous therapy; requires PBS Authority approval. Reduces HE recurrence by 58% (NNT = 4) based on the Bass et al. 2010 RCT.
Confirm absence of ongoing precipitants (recurrent SBP prophylaxis with norfloxacin 400 mg daily or ciprofloxacin 500 mg daily if indicated).

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Rifaximin (maintenance)

Xifaxan® · Long-term secondary prophylaxis

Adult dose 550 mg PO BD — continuous, indefinite

Evidence Bass et al. NEJM 2010: lactulose + rifaximin vs lactulose alone → HE recurrence 22.1% vs 45.9% (p < 0.001)

Cost note Significant PBS co-payment; discuss with patient

PBS status ⚠ PBS Restricted Benefit — Authority Required

2. Screen for Large Spontaneous Portosystemic Shunts

Large spontaneous portosystemic shunts (SPSS) — particularly splenorenal, gastrorenal, and paraumbilical shunts — allow ammonia-rich portal blood to bypass the liver, perpetuating HE despite adequate hepatic reserve. They are present in 25–40% of cirrhotics and are increasingly recognised as a treatable cause of recurrent/refractory HE.

Investigation: Multiphase CT abdomen or MRI with portal venous phase; interventional radiology assessment for shunt calibre and anatomy.
Intervention: Balloon-occluded retrograde transvenous obliteration (BATO) or coil embolisation of large SPSS.
Evidence: Case series show 50–80% reduction in HE episodes after SPSS embolisation in selected patients. Australian tertiary centres (RPA, Austin, Alfred) perform this procedure.
Risk: Re-bleeding of varices, procedure-related portal hypertension — requires multidisciplinary hepatology–interventional radiology discussion.

3. TIPS-Related Refractory HE

If HE develops or worsens after TIPS placement (25–50% within 3 months):

Optimise lactulose + rifaximin as above.
Exclude other precipitants.
Consider TIPS reduction (using stent-graft reduction or parallel stent placement to decrease shunt diameter from 10–12 mm to 5–8 mm) — reduces portal flow diversion while maintaining some portal decompression.
In severe cases, TIPS occlusion/closure may be necessary, but this risks recurrent variceal bleeding or refractory ascites — transplant referral should accompany this decision.

4. Liver Transplant Referral

Refractory HE is an indication for liver transplant evaluation. Key points:

Refer early — before irreversible neurocognitive damage (hepatocerebral degeneration).
Persistent HE accounts for 10–20% of liver transplant indications in Australia.
Repeat episodes cause cumulative neurocognitive impairment that may not fully reverse post-transplant.
Discuss with a transplant hepatologist at the nearest liver transplant centre (RPA/Concord NSW, Austin VIC, PAH QLD, Sir Charles Gairdner WA, Royal Adelaide SA).
Include MELD score and HE frequency in referral documentation.

5. Driving & Occupational Counselling

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Driving — Legal Obligations

Patients with overt HE (any grade) must cease all driving immediately — this includes private and commercial licences.
Minimal HE / covert HE — assess formally (PHES, EncephalApp Stroop); impaired patients must not drive.
The treating physician has a duty to notify the relevant state/territory licensing authority (e.g., Transport for NSW, VicRoads, TMR QLD).
Fitness to drive may be reassessed after ≥3 months of sustained freedom from overt HE on stable therapy, with normal cognitive testing.
Commercial/heavy vehicle licence holders: stricter criteria; may require formal neuropsychological assessment.

Occupational counselling: Patients with HE should avoid occupations involving heavy machinery, working at heights, or safety-critical decision-making until formally assessed. Occupational therapy and neuropsychological assessment may be useful for return-to-work planning. Centrelink/NDIS referral may be appropriate for refractory cases.

Aboriginal and Torres Strait Islander Health

Aboriginal and Torres Strait Islander peoples experience a significantly higher burden of liver disease and its complications compared with non-Indigenous Australians. HE management must be embedded in culturally safe, community-centred care.

Disease Burden

Liver disease is the 6th leading cause of death for Indigenous Australians. Cirrhosis mortality is 3–7 times higher than in non-Indigenous Australians, particularly in remote communities. AIHW 2023 data show viral hepatitis (B & C), alcohol-related liver disease, and NAFLD as the leading aetiologies.

Aetiology Considerations

Chronic hepatitis B is endemic in some Aboriginal communities (prevalence up to 5% in the NT); hepatitis C prevalence is also higher. Consider earlier screening for cirrhosis complications including HE. Wilson disease should be considered in young Indigenous patients with unexplained liver disease and neurological features.

Remote Access

Gastroenterology and hepatology specialist services are limited in remote and very remote Australia. Telehealth for HE assessment, specialist hepatology review (e.g., via Royal Darwin Hospital, Alice Springs Hospital outreach), and medication management via remote prescribing are essential. Retrieval services for Grade III–IV HE to tertiary centres.

AMS Engagement

Involve the local Aboriginal Medical Service (AMS) or Aboriginal Community Controlled Health Organisation (ACCHO) in ongoing HE management. Aboriginal Health Workers and Aboriginal Liaison Officers can provide medication support (lactulose adherence), education, and culturally appropriate follow-up.

Stigma & Mental Health

Liver disease in Indigenous communities is often associated with stigma (alcohol, hepatitis B/C). Non-judgemental, trauma-informed care is essential. Co-existing mental health conditions (depression, anxiety, substance use) may complicate HE assessment and management.

Medication & PBS Access

Lactulose (PBS General Benefit) is widely available. Rifaximin requires Authority PBS approval — ensure remote pharmacy access and consider closing-the-gap PBS co-payment for eligible Indigenous patients (no co-payment for PBS medicines for Indigenous Australians enrolled through CTG).

Language & Health Literacy

Provide patient education in plain English and, where possible, in the patient's first language. Use Aboriginal Interpreter Service (NT), visual aids, and culturally appropriate health education materials. Explain the link between liver disease and HE in accessible terms.

📚 References

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2. Rose CF, Amodio P, Bajaj JS, et al. Hepatic encephalopathy: novel insights into classification, pathophysiology and therapy. J Hepatol. 2020;73(6):1526–1547.
3. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–1081.
4. Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458–1463.
5. Gluud LL, Dam G, Borre M, et al. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: a meta-analysis. BMJ Open Gastroenterol. 2016;3(1):e000099.
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8. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of clinical trials in hepatic encephalopathy — an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011;33(7):739–747.
9. Latt N, Bhat S, Patel P, et al. Australian burden of liver disease study: cirrhosis mortality in Aboriginal and Torres Strait Islander peoples. Med J Aust. 2022;216(6):299–304.
10. Australian Institute of Health and Welfare (AIHW). Aboriginal and Torres Strait Islander Health Performance Framework 2020 summary report. Canberra: AIHW; 2020.
11. RHDAustralia (Northern Territory Department of Health and Menzies School of Health Research). 2022 Australian national guidelines for the management of hepatitis B in Aboriginal and Torres Strait Islander peoples. Darwin: RHDAustralia; 2022.
12. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. J Hepatol. 2022;77(3):807–824.