Acute-on-chronic liver failure (ACLF) · ICU Topics

Cinematic clinical photograph of a jaundiced cirrhotic patient on vasopressors and renal replacement therapy with multi-organ failure, ICU setting, clinical-blue lighting, no text, no identifiable people — FigureACLF grade 3 carries ~77% 28-day mortality — find the precipitant and refer early for transplant.

What ACLF is — and what it is NOT

ACLF grades by CLIF-C OF: grade 1–3 organ failures and rising 28-day mortality — FigureGrade the organs with CLIF-C OF — grade 3 approaches ~77% 28-day mortality; transplant window is grade 1–2.

The core concept (CANONIC study, 2013)

ACLF is a specific syndrome — NOT simply "cirrhosis that got worse." It is defined as acute decompensation (AD) of cirrhosis (ascites, HE, GI bleed, bacterial infection) WITH one or more organ failures and a characteristic profile of exaggerated systemic inflammation. The CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) observational study of 1343 patients established the operational definition and the CLIF-C OF (organ failure) score, demonstrating that ACLF is a distinct entity with a precipitant, a profile of organ failure, and a high 28-day mortality that simple decompensated cirrhosis does not share. [1]

Three insights the CANONIC study delivered:

Organ failure defines it. Patients with AD who develop organ failure(s) have a sharply higher 28-day mortality than AD patients without organ failure (the basis for grading).
It is potentially reversible. Unlike the inexorable decline of end-stage cirrhosis, ACLF can recover — which is why liver transplantation works and why early referral matters.
A precipitant is identifiable in ~50-60%. Infection, alcohol, and GI bleed dominate; in ~40-50% no precipitant is found ("idiopathic" ACLF) — but the inflammatory phenotype is identical.

[3] [1]

ACLF vs acute decompensation (AD) vs acute liver failure (ALF) — do not conflate

Feature	ACLF	Acute decompensation (AD)	Acute liver failure (ALF)
Underlying liver	Known chronic liver disease / cirrhosis	Known cirrhosis	No pre-existing liver disease
Time course	2-4 weeks (acute deterioration)	Days-weeks	<26 weeks (often days)
Hallmark	Organ failure(s) + systemic inflammation	Single complication (ascites, HE, bleed)	Encephalopathy + coagulopathy
INR / coagulopathy	Often high (organ failure marker)	Variable	High (definition)
28-day mortality	Grade-dependent (22-77%)	Lower (~5-20%)	Grade-dependent (King's College)
Reversibility	Potentially reversible; transplant works	Usually reversible with treatment of trigger	Potentially reversible; transplant in selected
Relevant score	CLIF-C OF / CLIF-C ACLF	Child-Pugh / MELD-Na	King's College / MELD
Steroids	No (harm)	No	No (except autoimmune)
NAC	Possibly beneficial	Not indicated	Beneficial in early non-acetaminophen ALF

[1] [3]

EASL (APASL-convergent) vs APASL definitions of ACLF — the two traditions

Feature	EASL (European) / CANONIC	APASL (Asian-Pacific)
Baseline	Cirrhosis (any cause)	Chronic hepatitis / cirrhosis (often HBV)
Trigger	Bacterial infection, GI bleed, alcohol #1	Viral flare, hepatitis (HBV reactivation), DILI #1
Defining feature	Organ failure (CLIF-C OF)	Liver failure + coagulopathy + jaundice within 4 weeks
Brain failure required?	No	No (HE is a later complication)
Scores	CLIF-C OF, CLIF-C ACLF	APASL ACLF research consortium (AARC) score
Convergence	Kyoto Consensus (2025) unified the definitions — ACLF = acute hepatic decompensation manifesting as jaundice + coagulopathy + encephalopathy and/or extrahepatic organ failure within 4 weeks	—

[1] [2]

Diagnosis

[1] [2]

CLIF-C OF score — the full 6-organ, 3-tier scoring grid (use the worst value in 24 h)

Organ system	Score 1 (no failure)	Score 2 (subtle/moderate)	Score 3 = ORGAN FAILURE
Liver (bilirubin, μmol/L / mg/dL)	<32 / <1.9	32–? / 1.9–? (≈6-12 mg/dL)	>12 mg/dL (≈204 μmol/L)
Kidney (creatinine, μmol/L / mg/dL)	<133 / <1.5	133–169 / 1.5–1.9 (≈1.9-3.5)	3.5–4.9 mg/dL or RRT (≈>169, dialysis)
Brain (West Haven HE grade)	0 (none)	I–II	III–IV
Coagulation (INR)	<2.0	2.0–2.5	>2.5
Circulation (MAP)	>70 mmHg	<70 on vasopressors	Vasopressors (noradrenaline/terlipressin)
Respiratory (PaO2/FiO2)	>300	200–300	<200 (or SpO2/FiO2 <214)

[3] [1]

Scoring tip: A single CLIF-C OF value of 3 = one organ failure. ACLF grade is then derived from the number of organ failures plus the kidney-modifier rule (see Diagnosis box). The total CLIF-C OF (sum of 6 scores, 6–18) correlates with mortality but the grade is what drives transplant decisions. [1]

CLIF-C ACLF score — the prognostic score that adds age and WCC

[4] [1]

ACLF mortality by grade

~22%

ACLF grade 1

1 organ failure (28-day)

~32%

ACLF grade 2

2 organ failures

~77%

ACLF grade 3

3+ organ failures

Best

Liver transplant

For ACLF grade 1-2

[1]

CLIF-C ACLFs cut-offs (recalculated at 48 h)

<40

Low risk

Mortality ~20% — continue medical management

40-64

Intermediate

Mortality ~50% — transplant evaluation

>64

High risk

Mortality ~75-90% — urgent transplant or palliative

Δ ↓

Falling score

Favourable trend at 48 h — keep treating

[4]

Precipitating factors

Precipitants of ACLF — frequency, mechanism, and targeted treatment

Precipitant	Frequency	Mechanism	First action
Bacterial infection (#1)	~30-50%	Sepsis → systemic inflammation → multi-organ vasodilation; bacterial translocation	Blood + ascitic + urine cultures; diagnostic paracentesis (rule out SBP); empiric broad-spectrum antibiotics
Alcohol (binge / severe alcohol-associated hepatitis)	~20-30%	Direct hepatotoxicity + cytokine storm (TNF-α); superimposed AH	Cessation; calculate Maddrey score; consider prednisolone if Maddrey ≥32 (see alcohol section)
GI bleed (variceal)	~10-20%	Hypovolaemia + bacterial translocation from blood in gut → infection, HE	Resuscitate (restrictive), terlipressin + ceftriaxone, endoscopy <12 h
Hepatotoxic drugs / DILI	Variable	Idiosyncratic or dose-related (NSAIDs, paracetamol, some Abx, herbals)	Stop all non-essential drugs; review LFTs; NAC if paracetamol-related
Viral hepatitis flare (HBV reactivation)	Common in HBV-endemic regions	Immune-mediated hepatocyte necrosis	HBV DNA; start nucleos(t)ide analogue (entecavir/tenofovir)
Portal vein thrombosis	Variable	Ischaemic insult to already-compromised liver; mesenteric congestion	Doppler US / CT; anticoagulation if cirrhosis is compensated and varices treated
Surgery / invasive procedure	Variable	Anaesthetic/inflammatory stress; nosocomial infection	Avoid non-essential surgery; optimise first
No precipitant identified	~40-50%	"Idiopathic" ACLF — same inflammatory phenotype	Treat the organ failure; do not delay for exhaustive hunt

[1] [3]

Organ failure assessment — the six systems

Per-organ assessment and support in ACLF

Liver (bilirubin, INR, ammonia)

Failing liver = bilirubin >12 mg/dL or INR >2.5. There is no specific therapy to "support" the failing liver beyond removing the insult and transplant. Avoid hepatotoxic drugs. Lactulose/rifaximin for HE; ammonia-lowering does not improve mortality but treats the brain. Consider NAC. The only definitive treatment is the graft.

Kidney (creatinine, urine output, sodium)

Distinguish HRS-AKI (urine Na <10, no response to fluid challenge, normal sediment) from ATN (granular casts, FeNa >2%, fixed dilute urine). HRS is REVERSIBLE — terlipressin + albumin (CONFIRM trial). Avoid nephrotoxins (NSAIDs, aminoglycosides, IV contrast where possible). RRT for refractory hyperkalaemia, acidosis, fluid overload, or uraemia.

Brain (West Haven grade, ammonia)

Grade I-II: sleep reversal, mild confusion. Grade III-IV: somnolent to coma (consider intubation for airway). Treat with lactulose (target 2-3 soft stools/day) + rifaximin 550 mg BD. Search for precipitant (infection, bleed, electrolytes, sedatives). Rule out raised ICP only if ALF overlap (cerebral oedema uncommon in pure ACLF).

Coagulation (INR, platelets, fibrinogen, TEG/ROTEM)

Cirrhosis = REBALANCED haemostasis (low procoagulants AND low anticoagulants). INR overestimates bleeding risk and underestimates thrombosis. Do NOT prophylactically correct INR with FFP before procedures — use viscoelastic testing (TEG/ROTEM) to guide. Transfuse platelets/fibrinogen only if actively bleeding or viscoelastic indices abnormal.

Circulation (MAP, lactate, vasopressors)

Cirrhotic vasodilatory shock: noradrenaline is first-line (α and β). Terlipressin is second-line/adjunct (splanchnic vasoconstriction, also treats HRS). Target MAP >65, lactate trending down, mottling score improving. Albumin for intravascular filling (beware pulmonary oedema — 20% human albumin, bolus 5 g/kg if no AKI fluid overload).

Respiratory (SpO2, PaO2/FiO2, ABG)

Hepatopulmonary syndrome, portopulmonary hypertension, ARDS, or pulmonary oedema from over-resuscitation can all coexist. Use lung-protective ventilation (Vt 6 mL/kg PBW, plateau <30) if intubated. High flow nasal cannula / NIV for moderate hypoxaemia; intubate early if HE grade III-IV with aspiration risk.

[1] [2]

Management

ACLF management protocol

Identify and treat precipitant

Infection (#1 — cultures, ascitic tap, antibiotics if SBP suspected), alcohol cessation, treat GI bleed, stop hepatotoxic drugs, treat viral hepatitis. The precipitant drives the systemic inflammatory response — treating it is the foundation of management.

Organ support

Brain: treat hepatic encephalopathy (lactulose, rifaximin). Kidney: treat HRS (terlipressin + albumin), RRT if refractory. Circulation: noradrenaline for septic shock. Lungs: lung-protective ventilation if ARDS. Coagulation: do NOT routinely correct INR (marker of liver function, not bleeding risk). Blood glucose: 6-10 mmol/L.

N-acetylcysteine (NAC)

May improve outcomes in ACLF (reduces oxidative stress, improves microcirculation). Give to all ACLF patients (same dose as paracetamol toxicity: 150 mg/kg loading, then infusion). Low risk, potential benefit. Evidence is emerging.

Do NOT give steroids

Corticosteroids have NO role in ACLF. They increase infection risk without improving outcomes. The inflammatory response in ACLF is maladaptive but suppressing it with steroids is harmful.

Early liver transplant referral

Liver transplant is the BEST treatment for ACLF (especially grade 1-2). Good outcomes — ACLF patients transplanted within 30 days have similar survival to elective transplant. Grade 3: controversial (high post-transplant mortality) but may be considered in selected patients. REFER EARLY — do not wait for maximal deterioration.

Palliative care

For patients who are not transplant candidates and have ACLF grade 3 with multi-organ failure: consider palliative approach. ACLF grade 3 has 77% 28-day mortality. Discuss goals of care with patient and family.

[1] [2]

Hepatorenal syndrome (HRS-AKI) — the reversible kidney failure

HRS-AKI diagnosis and treatment cascade

Diagnose AKI first (ICA criteria)

HRS-AKI = cirrhosis with ascites + AKI (↑ creatinine ≥26.5 μmol/L within 48 h OR ≥1.5-2× baseline) + NO response to 48 h diuretic withdrawal + albumin 1 g/kg/day (max 100 g) + NO shock, no nephrotoxins, no structural kidney disease (normal urine sediment, normal US).

Distinguish HRS from ATN — it changes everything

HRS: urine Na <10, FeNa <1%, no casts, improves with vasoconstrictor + albumin (functional, pre-renal-type). ATN: urine Na >30, FeNa >2%, granular casts, does NOT respond to terlipressin (structural damage). Treat HRS before it progresses to ATN — terlipressin fails once ATN is established.

First-line vasoconstrictor

Terlipressin + albumin (CONFIRM trial): terlipressin 1-2 mg IV Q4-6H (or continuous infusion starting 2 mg/day, titrate to 12 mg/day) + albumin 20% 20-40 g/day. Target: MAP ≥65 AND creatinine falling. Monitor for ischaemia (digits, bowel, coronary) and fluid overload. Mean time to reversal ~5 days.

When terlipressin fails or is contraindicated

Noradrenaline is an effective alternative (ICU setting, central line). Norepinephrine + albumin has comparable HRS reversal rates. Midodrine + octreotide is inferior — reserve for ward/step-down where terlipressin unavailable. RRT (CVVH/IHD) is a bridge to transplant, not curative.

List for transplant if HRS recurs or persists

HRS recurrence is common after vasoconstrictor withdrawal. Sustained reversal predicts post-transplant survival; persistent HRS at transplant still acceptable. Simultaneous liver-kidney transplant if dialysis >8-12 weeks.

[5] [1]

Terlipressin vs noradrenaline for HRS-AKI — the two vasoconstrictors

Feature	Terlipressin	Noradrenaline
Class	Vasopressin V1 analogue (long-acting)	α (and β) adrenergic agonist
Mechanism	Splanchnic vasoconstriction → ↑ effective circulating volume → ↑ renal perfusion	Systemic vasoconstriction + ↑ cardiac output → ↑ MAP → ↑ renal perfusion
Route / setting	IV bolus or infusion; ward or ICU	Continuous infusion, central line; ICU only
HRS reversal rate	~32-40% (CONFIRM)	~50% (meta-analyses, comparable to terlipressin)
Key adverse effects	Ischaemia (digits, mesenteric, coronary), hyponatraemia, fluid overload (the CONFIRM safety concern — monitor closely)	Peripheral/digital ischaemia, tachyarrhythmia, extravasation necrosis
Contraindications	Limb/mesenteric ischaemia, recent MI, uncontrolled infection	None specific to cirrhosis
Practical pearl	Continue until creatinine <1.5 or max 14 days; taper to avoid rebound	First-line in intubated ICU patients; easier to titrate

[5] [1]

Spontaneous bacterial peritonitis (SBP) — the classic precipitant

SBP recognition and management (the albumin imperative)

Diagnostic paracentesis in EVERY cirrhotic with ascites + ACLF

SBP = ascitic PMN ≥250 cells/mm³ (culture may be negative — "culture-negative neutrocytic ascites" is still SBP). Send cell count AND culture (in blood culture bottles) before antibiotics.

Empiric antibiotics

Cefotaxime 2 g IV BD or ceftriaxone 1 g IV daily for 5-7 days. Re-tap at 48 h: if PMN fall <25%, switch antibiotic (consider vancomycin + carbapenem for resistant organisms).

ALBUMIN — the mortality-reducing step (Sort 1999)

Give 20% albumin: 1.5 g/kg within 6 h of diagnosis AND 1 g/kg on day 3. Albumin reduces HRS (29% → 9%), renal impairment, and MORTALITY (NNT ~4-5). This is the most evidence-supported single intervention in SBP.

Secondary prophylaxis

Norfloxacin 400 mg OD (or ciprofloxacin) indefinitely after an SBP episode; consider primary prophylaxis if ascitic protein <15 g/L with advanced cirrhosis.

[7] [1]

Nutrition — enteral first, do not starve the malnourished cirrhotic

Nutrition in ACLF — high calorie, high protein, enteral preferred

Cirrhotics are catabolic: they lose ~5-10× more lean mass per day fasting than healthy adults. Starvation precipitates muscle breakdown → ammonia rises (sarcopenia reduces ammonia clearance) → HE worsens. Protein restriction is obsolete and harmful. [1]

Target: 35-40 kcal/kg/day (non-protein), 1.2-1.5 g/kg/day protein (higher than historic "low-protein" dogma).
Route: enteral preferred (preserves gut barrier, reduces bacterial translocation). Nasogastric if cannot eat; nocturnal supplementation. Parenteral only if enteral fails/contraindicated.
Substrate: complex carbohydrates + late-evening snack (~50 g) to prevent overnight fasting catabolism. BCAA-enriched formulas may help HE.
Micronutrients: thiamine (before any glucose), replace folate/K/Mg/Zn (deficiencies universal in alcohol-related disease).
Beware refeeding: start at 10-15 kcal/kg and titrate up over a week if chronically malnourished; check phosphate.

[1]

Enteral vs parenteral nutrition in ACLF

Feature	Enteral (preferred)	Parenteral (if enteral fails)
Gut barrier	Preserved — ↓ bacterial translocation, ↓ infection	Gut atrophy → ↑ translocation
HE impact	BCAA formulas may improve grade	Standard AA mixes poorly tolerated (aromatic AAs)
Access	NG / NJ; risk of variceal erosion (low with fine-bore)	Central line (infection, thrombosis)
Refeeding risk	Present — monitor phosphate	Higher — slower ramp
When to use	Default for ALL ACLF patients who cannot meet needs orally	Ileus, obstruction, upper GI bleed with no access, failed EN

[1]

Coagulopathy — the rebalanced haemostasis trap

Why INR lies in cirrhosis (and ACLF)

Cirrhosis has rebalanced haemostasis: reduced synthesis of BOTH procoagulant factors (II, V, VII, IX, X) AND anticoagulants (protein C, protein S, antithrombin), PLUS thrombocytopenia AND elevated vWF. The INR captures only the procoagulant loss and is then "corrected" by the lab normal range that assumes normal anticoagulant levels — so INR overstates bleeding risk and understates thrombotic risk. [1]

Do NOT correct INR prophylactically before paracentesis, endoscopy, or line insertion — it does not reduce bleeding and can cause volume overload/transfusion-related lung injury.
Use viscoelastic testing (TEG/ROTEM) to guide blood product therapy: give FFP only if ROTEM CT prolonged AND bleeding; platelets only if MA low AND bleeding/count <50 with planned invasive procedure.
Remember cirrhotics are prothrombotic — portal vein thrombosis is common; do not withhold indicated anticoagulation on the basis of INR alone.

[1]

Alcohol-associated hepatitis in the ACLF context — the steroid decision

Prednisolone in severe alcohol-associated hepatitis (AAH) — narrow window

Prednisolone is used in severe AAH (different from "steroids in ACLF" in general — the prohibition applies to the broad ACLF syndrome, not biopsy-proven AAH). The decision rests on the Maddrey discriminant function (mDF): [1]

mDF = 4.6 × (PT_patient − PT_control) + bilirubin (mg/dL). Severe = mDF ≥32 (or MELD >25, or SARGENT score).
Give: prednisolone 40 mg OD for 28 days if no sepsis, no GI bleed, no AKI — these are contraindications (re-evaluate at day 7 with the Lille score; stop if Lille >0.45 — non-responder, no benefit, only harm).
STOPAH (2015): prednisolone improved 28-day survival signal but NOT at 90 days or 1 year; pentoxifylline no benefit. Steroids do not increase infection significantly but infection is the leading reason to stop them.
Do NOT give steroids to "ACLF" generically — only to confirmed AAH with mDF ≥32 and no contraindication.

[9] [1]

NAC and the "adjuncts" debate

NAC is now given to early-stage non-acetaminophen ALF. Often extrapolated to ACLF in practice, though ACLF-specific RCT evidence is weaker — frame it as "low-risk adjunct, not standard of care".

[6]

Prognosis

Liver transplant outcomes in ACLF

85-92%

1-yr survival

ACLF grade 1-2 transplanted within 30 days (similar to elective)

65-80%

1-yr survival

ACLF grade 3 transplanted — worse but acceptable in selected

CLIF-C

Score guiding listing

CLIF-C ACLFs 40-64 = transplant window

Avoid

Grade 3 + 4 organs

Futile in many centres (post-LT mortality >50%)

[1] [4]

Prognostic scores in ACLF — which and when

CLIF-C OF

Admission

Grades organ failure (6-18); defines ACLF grade

CLIF-C ACLFs

48 h + trend

Adds age + WCC; the dynamic score (rising = worse)

MELD-Na

Transplant allocation

Standard for listing in most regions

Child-Pugh

Historical / bedside

Coarser; less useful in acute organ failure

[4] [1]

SAQ — ACLF precipitated by SBP with HRS-AKI and coagulopathy

10 minutes · 10 marks

A 58-year-old man with alcohol-related cirrhosis (Child-Pugh C, MELD-Na 28, known oesophageal varices on nadolol) is admitted to ICU with 36 hours of fever (38.9 degrees C), abdominal pain and worsening confusion. He is intubated for airway protection (GCS 8 — E2 V2 M4), on noradrenaline 0.18 mcg/kg/min for MAP 65, SpO2 96 percent on FiO2 0.35, HR 118, T 38.6. Examination shows tense ascites, icteric sclerae, asterixis and bilateral wheeze. Bloods: WCC 18.4, Hb 96, platelets 62 x 10^9/L, INR 2.8, bilirubin 248 umol/L, albumin 22 g/L, creatinine 186 umol/L (baseline 95, doubled in 24 h), urea 14.2, Na 128, K 4.6, lactate 3.4 mmol/L, arterial ammonia 142 umol/L. Ascitic tap shows PMN 740 cells/mm^3. Blood cultures and ascitic culture are pending. He has not opened bowels for 2 days and is on lactulose 30 mL TDS from the ward.

[1]

SAQ — EASL-CLIF scoring, grading and the CLIF-C ACLF prognostic score

10 minutes · 10 marks

A 64-year-old man with hepatitis-C cirrhosis (Child-Pugh B, MELD-Na 19) presents with new ascites, jaundice and a creatinine that has risen from 95 to 168 umol/L over 48 hours. He is alert but drowsy (GCS 13, asterixis present, West Haven grade II). He is haemodynamically stable off vasopressors (MAP 78, HR 88, SpO2 95% room air). Bloods: bilirubin 122 umol/L (7.1 mg/dL), INR 1.9, albumin 26 g/L, Na 132, K 4.1, WCC 11.2, creatinine 168 umol/L, urea 9.4, lactate 1.6. Urine Na 8 mmol/L, FeNa 0.4 percent, urine microscopy bland, renal ultrasound normal. He is not on diuretics. He received 1 g/kg albumin 24 h ago with no creatinine improvement. He is being considered for terlipressin.

[1]

Clinical pearls

High-yield ACLF points for the CICM/FFICM exam

ACLF = acute decompensation + organ failure(s) + systemic inflammation.[1] }
Infection is the #1 precipitant — search aggressively (cultures, ascitic tap, SBP).
CLIF-C OF score grades 6 organ failures (liver, kidney, brain, coagulation, circulation, lung).[1] }
ACLF grade 3 (3+ organ failures): 77% 28-day mortality.[1] }
Liver transplant is the BEST treatment for ACLF grade 1-2.[1] }
NAC may improve outcomes (reduces oxidative stress).[1] }
Do NOT give steroids — no benefit, increases infection.[1] }
Terlipressin + albumin for hepatorenal syndrome (HRS-AKI).
Different from simple cirrhosis decompensation — ACLF has distinct prognosis and management.[2] }
Early transplant referral — do NOT wait for maximal deterioration.[1] }
INR is a liver function marker — do NOT routinely correct with FFP.[1] }
** albumin** for SBP (prevents HRS — 1.5 g/kg day 1, 1 g/kg day 3).
Sepsis: common and often missed — prophylactic antibiotics for GI bleed in cirrhosis.
Kyoto Consensus (2025): unified definition of ACLF (APASL + EASL convergence).[2] }

Extended exam pearls — the deeper ACLF knowledge the examiner wants

CLIF-C ACLFs (not just CLIF-C OF) adds age + white cell count — two surrogates of the inflammatory burden. Recalculate at 48 h: a rising score is a bad sign and should trigger transplant reassessment. The formula is exam-worthy.[4]
The kidney modifier is the single most-tested grading rule. A single kidney failure with creatinine 1.5-1.9 mg/dL is "no ACLF"; creatinine >1.9-3.5 mg/dL with no other organ failure is grade 1; any single non-kidney organ failure is also grade 1.[3]
HRS-AKI is functional and reversible; ATN is structural and is not. Distinguish with urine sodium (<10 HRS, >30 ATN), FeNa, and the response to albumin challenge. Terlipressin fails once ATN is established — diagnose and treat HRS early.[5]
CONFIRM trial safety signal: terlipressin can cause fatal respiratory failure from fluid overload. Monitor fluid balance rigorously, albumin-bolus judiciously, and prefer noradrenaline in the intubated ICU patient.[5]
Cirrhosis is REBALANCED haemostasis. INR overstates bleeding and understates thrombosis. Use TEG/ROTEM, not INR, to guide product therapy. Prophylactic FFP before procedures is harmful (volume, TRALI) and ineffective.[1]
Albumin in SBP reduces mortality (Sort 1999) — 1.5 g/kg day 1 + 1 g/kg day 3. This is the most evidence-supported supportive intervention in ACLF and an exam favourite.[7]
Prednisolone for alcohol-associated hepatitis (mDF ≥32), NOT for ACLF generally. Stop at day 7 if Lille >0.45 (non-responder). Contraindicated in sepsis, GI bleed, AKI. STOPAH: 28-day signal only, no 90-day benefit.[9]
No precipitant is found in ~40-50% of ACLF ("idiopathic") — the phenotype and management are identical; do not delay treatment hunting exhaustively.[3]
Nutrition: do NOT restrict protein. 35-40 kcal/kg/day, 1.2-1.5 g/kg protein, enteral preferred, late-evening snack to prevent overnight catabolism. Sarcopenia worsens HE (muscle clears ammonia).[1]
Thiamine before any glucose in alcohol-related ACLF — prevents Wernicke encephalopathy, which can mimic or worsen HE.
Noradrenaline is first-line vasopressor in cirrhotic vasodilatory shock; terlipressin is adjunct/second-line (and treats HRS in parallel).
Proton pump inhibitors increase SBP and infection risk in cirrhosis — review and stop unless there is a clear indication (e.g., active peptic ulcer, variceal bleed prophylaxis window).[1]
ACLF can recover — that is why transplant works. The CLIF-C ACLFs trend (not the absolute) is what predicts reversibility; a falling 48-h score should encourage continued aggressive support rather than de-escalation.
Grade 3 ACLF + 4 organ failures is often considered futile for transplant in many centres (post-LT mortality >50%); grade 3 with 3 organs may be considered in highly selected, young, infection-free patients.[1]
Ammonia-lowering (lactulose, rifaximin) treats HE symptoms, not mortality — useful for the brain-failure organ domain, but do not over-diurese or over-laxative (volume depletion → HRS, dehydration → AKI).
HBV reactivation is the dominant precipitant in Asia-Pacific/APASL cohorts — check HBV DNA and start entecavir/tenofovir promptly in HBV-related ACLF.[2]
Portal vein thrombosis in a cirrhotic with sudden deterioration — Doppler US/CT; anticoagulate if cirrhosis is otherwise compensated and varices treated (the rebalanced-haemostasis insight makes this safer than feared).
Avoid aminoglycosides, NSAIDs, and unnecessary IV contrast in ACLF — all precipitate or worsen AKI. Prefer liposomal amphotericin or echinocandin; use iso-osmolar contrast only when essential with pre-hydration.

Pitfalls and mnemonics

Common ACLF pitfalls — what examiners love to catch

Pitfall	The trap	The correct approach
"Correct the INR"	Giving FFP before paracentesis/endoscopy "because INR is 2.5"	INR does not predict bleeding; use TEG/ROTEM; transfuse only if viscoelastic indices abnormal and bleeding
"Restrict protein for HE"	Halting protein to "lower ammonia"	Protein restriction is harmful — give 1.2-1.5 g/kg; sarcopenia worsens HE
"Steroids for the inflammation"	Giving methylprednisolone for ACLF shock	Steroids are NOT indicated in ACLF; only prednisolone for biopsy-confirmed AAH (mDF ≥32, no sepsis)
"Fluid challenge with saline"	Large crystalloid boluses for "low BP"	Cirrhotics vasodilate and leak — prefer albumin 20%; crystalloid → oedema, dilutional hyponatraemia
"Stop nutrition to rest the gut"	NPO for GI bleed / procedures indefinitely	Restart enteral early; the catabolic cirrhotic cannot tolerate starvation
"Terlipressin always"	Defaulting to terlipressin in volume-overloaded patient	Watch CONFIRM safety signal — respiratory failure; prefer noradrenaline if overloaded/intubated
"PPI for stress prophylaxis"	Continuing PPI indefinitely	PPI increases SBP/infection — stop once the acute indication resolves

[1] [5] [3]

Red flags

Extended red flags — the lethal traps

HRS-AKI is reversible; ATN is not — diagnose and treat HRS BEFORE it progresses. Terlipressin + albumin (CONFIRM), monitor for fluid-overload respiratory failure.[5]
Albumin 1.5 g/kg + 1 g/kg in SBP reduces mortality (Sort) — omitting it is a preventable error. NNT ~4-5.[7]
Prednisolone only for biopsy-proven AAH (mDF ≥32), no sepsis/bleed/AKI, stop at day 7 if Lille >0.45. Do NOT conflate with "steroids in ACLF".[9]
CLIF-C ACLFs trending UP at 48 h is an ominous sign — escalate to transplant evaluation; do not be reassured by a static admission score.[4]
Cirrhosis is prothrombotic despite high INR — portal vein thrombosis, PE; do not withhold anticoagulation purely on INR.[1]
Terlipressin can cause fatal respiratory failure (CONFIRM) — avoid in volume-overloaded patients; watch SaO2 and fluid balance.[5]
Restrictive, not liberal, resuscitation — even in shock, prefer albumin 20% over saline; crystalloid excess → oedema, dilutional hyponatraemia, worsened ascites.[1]
Do not starve the malnourished cirrhotic — enteral nutrition 35-40 kcal/kg, 1.2-1.5 g/kg protein; protein restriction worsens HE and sarcopenia.[1]
Thiamine before glucose in alcohol-related ACLF — prevent Wernicke.
PPIs increase SBP/infection — review and deprescribe once the acute indication resolves.[1]

Exam-style rapid recall

One-minute rapid-fire answers

Definition: acute decompensation of cirrhosis + organ failure(s) (CLIF-C OF grade 3 in ≥1 organ) + systemic inflammation (CANONIC, EASL 2023).[3][1]
#1 precipitant: bacterial infection (SBP, pneumonia, bacteraemia) — culture everything + diagnostic paracentesis + empiric antibiotics.[1]
Score: CLIF-C OF (grades organ failure) → CLIF-C ACLFs (adds age + WCC, recalculated at 48 h).[4]
Grades/mortality (28-day): grade 1 ~22%, grade 2 ~32%, grade 3 ~77%.[1]
HRS-AKI: terlipressin + albumin (CONFIRM); noradrenaline if overloaded/intubated; treat before ATN.[5]
SBP: cefotaxime/ceftriaxone + albumin 1.5 g/kg then 1 g/kg (Sort).[7]
Coagulopathy: rebalanced haemostasis; TEG/ROTEM, NOT INR; do not prophylactically correct.[1]
Steroids: NO in ACLF generally; YES only for biopsy-proven AAH (mDF ≥32, no sepsis), stop if Lille >0.45 at day 7.[9]
Nutrition: 35-40 kcal/kg, 1.2-1.5 g/kg protein, enteral first, no protein restriction.[1]
Transplant: BEST treatment for grade 1-2; grade 3 with 4 organs often futile. REFER EARLY.[1]
Kyoto Consensus (2025): unified APASL/EASL definition.[2]

References

[1]EASL Clinical Practice Guidelines. EASL Clinical Practice Guidelines on acute-on-chronic liver failure J Hepatol, 2023.PMID 37364789
[2]Sarin SK, Choudhury AK, Sharma MK, et al. Acute-on-chronic liver failure (ACLF): the 'Kyoto Consensus'-steps from Asia Hepatol Int, 2025.PMID 39961976
[3]Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis Gastroenterology, 2013.PMID 23474284
[4]Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure J Hepatol, 2014.PMID 24950482
[5]Wong F, Pappas SC, Curry MP, et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome N Engl J Med, 2021.PMID 33657294
[6]Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure Gastroenterology, 2009.PMID 19524577
[7]Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis N Engl J Med, 1999.PMID 10432325
[8]Caraceni P, Riggio O, Angeli P, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial Lancet, 2018.PMID 29861076
[9]Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis N Engl J Med, 2015.PMID 25901427

[1]

What ACLF is — and what it is NOT

The core concept (CANONIC study, 2013)

Three insights the CANONIC study delivered:

Organ failure defines it. Patients with AD who develop organ failure(s) have a sharply higher 28-day mortality than AD patients without organ failure (the basis for grading).
It is potentially reversible. Unlike the inexorable decline of end-stage cirrhosis, ACLF can recover — which is why liver transplantation works and why early referral matters.
A precipitant is identifiable in ~50-60%. Infection, alcohol, and GI bleed dominate; in ~40-50% no precipitant is found ("idiopathic" ACLF) — but the inflammatory phenotype is identical.

[3] [1]

ACLF vs acute decompensation (AD) vs acute liver failure (ALF) — do not conflate

Feature	ACLF	Acute decompensation (AD)	Acute liver failure (ALF)
Underlying liver	Known chronic liver disease / cirrhosis	Known cirrhosis	No pre-existing liver disease
Time course	2-4 weeks (acute deterioration)	Days-weeks	<26 weeks (often days)
Hallmark	Organ failure(s) + systemic inflammation	Single complication (ascites, HE, bleed)	Encephalopathy + coagulopathy
INR / coagulopathy	Often high (organ failure marker)	Variable	High (definition)
28-day mortality	Grade-dependent (22-77%)	Lower (~5-20%)	Grade-dependent (King's College)
Reversibility	Potentially reversible; transplant works	Usually reversible with treatment of trigger	Potentially reversible; transplant in selected
Relevant score	CLIF-C OF / CLIF-C ACLF	Child-Pugh / MELD-Na	King's College / MELD
Steroids	No (harm)	No	No (except autoimmune)
NAC	Possibly beneficial	Not indicated	Beneficial in early non-acetaminophen ALF

[1] [3]

EASL (APASL-convergent) vs APASL definitions of ACLF — the two traditions

Feature	EASL (European) / CANONIC	APASL (Asian-Pacific)
Baseline	Cirrhosis (any cause)	Chronic hepatitis / cirrhosis (often HBV)
Trigger	Bacterial infection, GI bleed, alcohol #1	Viral flare, hepatitis (HBV reactivation), DILI #1
Defining feature	Organ failure (CLIF-C OF)	Liver failure + coagulopathy + jaundice within 4 weeks
Brain failure required?	No	No (HE is a later complication)
Scores	CLIF-C OF, CLIF-C ACLF	APASL ACLF research consortium (AARC) score
Convergence	Kyoto Consensus (2025) unified the definitions — ACLF = acute hepatic decompensation manifesting as jaundice + coagulopathy + encephalopathy and/or extrahepatic organ failure within 4 weeks	—

[1] [2]

Diagnosis

[1] [2]

CLIF-C OF score — the full 6-organ, 3-tier scoring grid (use the worst value in 24 h)

Organ system	Score 1 (no failure)	Score 2 (subtle/moderate)	Score 3 = ORGAN FAILURE
Liver (bilirubin, μmol/L / mg/dL)	<32 / <1.9	32–? / 1.9–? (≈6-12 mg/dL)	>12 mg/dL (≈204 μmol/L)
Kidney (creatinine, μmol/L / mg/dL)	<133 / <1.5	133–169 / 1.5–1.9 (≈1.9-3.5)	3.5–4.9 mg/dL or RRT (≈>169, dialysis)
Brain (West Haven HE grade)	0 (none)	I–II	III–IV
Coagulation (INR)	<2.0	2.0–2.5	>2.5
Circulation (MAP)	>70 mmHg	<70 on vasopressors	Vasopressors (noradrenaline/terlipressin)
Respiratory (PaO2/FiO2)	>300	200–300	<200 (or SpO2/FiO2 <214)

[3] [1]

Scoring tip: A single CLIF-C OF value of 3 = one organ failure. ACLF grade is then derived from the number of organ failures plus the kidney-modifier rule (see Diagnosis box). The total CLIF-C OF (sum of 6 scores, 6–18) correlates with mortality but the grade is what drives transplant decisions. [1]

CLIF-C ACLF score — the prognostic score that adds age and WCC

[4] [1]

ACLF mortality by grade

~22%

ACLF grade 1

1 organ failure (28-day)

~32%

ACLF grade 2

2 organ failures

~77%

ACLF grade 3

3+ organ failures

Best

Liver transplant

For ACLF grade 1-2

[1]

CLIF-C ACLFs cut-offs (recalculated at 48 h)

<40

Low risk

Mortality ~20% — continue medical management

40-64

Intermediate

Mortality ~50% — transplant evaluation

>64

High risk

Mortality ~75-90% — urgent transplant or palliative

Δ ↓

Falling score

Favourable trend at 48 h — keep treating

[4]

Precipitating factors

Precipitants of ACLF — frequency, mechanism, and targeted treatment

Precipitant	Frequency	Mechanism	First action
Bacterial infection (#1)	~30-50%	Sepsis → systemic inflammation → multi-organ vasodilation; bacterial translocation	Blood + ascitic + urine cultures; diagnostic paracentesis (rule out SBP); empiric broad-spectrum antibiotics
Alcohol (binge / severe alcohol-associated hepatitis)	~20-30%	Direct hepatotoxicity + cytokine storm (TNF-α); superimposed AH	Cessation; calculate Maddrey score; consider prednisolone if Maddrey ≥32 (see alcohol section)
GI bleed (variceal)	~10-20%	Hypovolaemia + bacterial translocation from blood in gut → infection, HE	Resuscitate (restrictive), terlipressin + ceftriaxone, endoscopy <12 h
Hepatotoxic drugs / DILI	Variable	Idiosyncratic or dose-related (NSAIDs, paracetamol, some Abx, herbals)	Stop all non-essential drugs; review LFTs; NAC if paracetamol-related
Viral hepatitis flare (HBV reactivation)	Common in HBV-endemic regions	Immune-mediated hepatocyte necrosis	HBV DNA; start nucleos(t)ide analogue (entecavir/tenofovir)
Portal vein thrombosis	Variable	Ischaemic insult to already-compromised liver; mesenteric congestion	Doppler US / CT; anticoagulation if cirrhosis is compensated and varices treated
Surgery / invasive procedure	Variable	Anaesthetic/inflammatory stress; nosocomial infection	Avoid non-essential surgery; optimise first
No precipitant identified	~40-50%	"Idiopathic" ACLF — same inflammatory phenotype	Treat the organ failure; do not delay for exhaustive hunt

[1] [3]

Organ failure assessment — the six systems

Per-organ assessment and support in ACLF

Liver (bilirubin, INR, ammonia)

Kidney (creatinine, urine output, sodium)

Brain (West Haven grade, ammonia)

Coagulation (INR, platelets, fibrinogen, TEG/ROTEM)

Circulation (MAP, lactate, vasopressors)

Respiratory (SpO2, PaO2/FiO2, ABG)

[1] [2]

Management

ACLF management protocol

Identify and treat precipitant

Organ support

N-acetylcysteine (NAC)

Do NOT give steroids

Corticosteroids have NO role in ACLF. They increase infection risk without improving outcomes. The inflammatory response in ACLF is maladaptive but suppressing it with steroids is harmful.

Early liver transplant referral

Palliative care

[1] [2]

Hepatorenal syndrome (HRS-AKI) — the reversible kidney failure

HRS-AKI diagnosis and treatment cascade

Diagnose AKI first (ICA criteria)

Distinguish HRS from ATN — it changes everything

First-line vasoconstrictor

When terlipressin fails or is contraindicated

List for transplant if HRS recurs or persists

[5] [1]

Terlipressin vs noradrenaline for HRS-AKI — the two vasoconstrictors

Feature	Terlipressin	Noradrenaline
Class	Vasopressin V1 analogue (long-acting)	α (and β) adrenergic agonist
Mechanism	Splanchnic vasoconstriction → ↑ effective circulating volume → ↑ renal perfusion	Systemic vasoconstriction + ↑ cardiac output → ↑ MAP → ↑ renal perfusion
Route / setting	IV bolus or infusion; ward or ICU	Continuous infusion, central line; ICU only
HRS reversal rate	~32-40% (CONFIRM)	~50% (meta-analyses, comparable to terlipressin)
Key adverse effects	Ischaemia (digits, mesenteric, coronary), hyponatraemia, fluid overload (the CONFIRM safety concern — monitor closely)	Peripheral/digital ischaemia, tachyarrhythmia, extravasation necrosis
Contraindications	Limb/mesenteric ischaemia, recent MI, uncontrolled infection	None specific to cirrhosis
Practical pearl	Continue until creatinine <1.5 or max 14 days; taper to avoid rebound	First-line in intubated ICU patients; easier to titrate

[5] [1]

Spontaneous bacterial peritonitis (SBP) — the classic precipitant

SBP recognition and management (the albumin imperative)

Diagnostic paracentesis in EVERY cirrhotic with ascites + ACLF

SBP = ascitic PMN ≥250 cells/mm³ (culture may be negative — "culture-negative neutrocytic ascites" is still SBP). Send cell count AND culture (in blood culture bottles) before antibiotics.

Empiric antibiotics

Cefotaxime 2 g IV BD or ceftriaxone 1 g IV daily for 5-7 days. Re-tap at 48 h: if PMN fall <25%, switch antibiotic (consider vancomycin + carbapenem for resistant organisms).

ALBUMIN — the mortality-reducing step (Sort 1999)

Secondary prophylaxis

Norfloxacin 400 mg OD (or ciprofloxacin) indefinitely after an SBP episode; consider primary prophylaxis if ascitic protein <15 g/L with advanced cirrhosis.

[7] [1]

Nutrition — enteral first, do not starve the malnourished cirrhotic

Nutrition in ACLF — high calorie, high protein, enteral preferred

Target: 35-40 kcal/kg/day (non-protein), 1.2-1.5 g/kg/day protein (higher than historic "low-protein" dogma).
Route: enteral preferred (preserves gut barrier, reduces bacterial translocation). Nasogastric if cannot eat; nocturnal supplementation. Parenteral only if enteral fails/contraindicated.
Substrate: complex carbohydrates + late-evening snack (~50 g) to prevent overnight fasting catabolism. BCAA-enriched formulas may help HE.
Micronutrients: thiamine (before any glucose), replace folate/K/Mg/Zn (deficiencies universal in alcohol-related disease).
Beware refeeding: start at 10-15 kcal/kg and titrate up over a week if chronically malnourished; check phosphate.

[1]

Enteral vs parenteral nutrition in ACLF

Feature	Enteral (preferred)	Parenteral (if enteral fails)
Gut barrier	Preserved — ↓ bacterial translocation, ↓ infection	Gut atrophy → ↑ translocation
HE impact	BCAA formulas may improve grade	Standard AA mixes poorly tolerated (aromatic AAs)
Access	NG / NJ; risk of variceal erosion (low with fine-bore)	Central line (infection, thrombosis)
Refeeding risk	Present — monitor phosphate	Higher — slower ramp
When to use	Default for ALL ACLF patients who cannot meet needs orally	Ileus, obstruction, upper GI bleed with no access, failed EN

[1]

Coagulopathy — the rebalanced haemostasis trap

Why INR lies in cirrhosis (and ACLF)

Do NOT correct INR prophylactically before paracentesis, endoscopy, or line insertion — it does not reduce bleeding and can cause volume overload/transfusion-related lung injury.
Use viscoelastic testing (TEG/ROTEM) to guide blood product therapy: give FFP only if ROTEM CT prolonged AND bleeding; platelets only if MA low AND bleeding/count <50 with planned invasive procedure.
Remember cirrhotics are prothrombotic — portal vein thrombosis is common; do not withhold indicated anticoagulation on the basis of INR alone.

[1]

Alcohol-associated hepatitis in the ACLF context — the steroid decision

Prednisolone in severe alcohol-associated hepatitis (AAH) — narrow window

mDF = 4.6 × (PT_patient − PT_control) + bilirubin (mg/dL). Severe = mDF ≥32 (or MELD >25, or SARGENT score).
Give: prednisolone 40 mg OD for 28 days if no sepsis, no GI bleed, no AKI — these are contraindications (re-evaluate at day 7 with the Lille score; stop if Lille >0.45 — non-responder, no benefit, only harm).
STOPAH (2015): prednisolone improved 28-day survival signal but NOT at 90 days or 1 year; pentoxifylline no benefit. Steroids do not increase infection significantly but infection is the leading reason to stop them.
Do NOT give steroids to "ACLF" generically — only to confirmed AAH with mDF ≥32 and no contraindication.

[9] [1]

NAC and the "adjuncts" debate

[6] [1]

Key trials

2013

CANONIC (Moreau 2013)

Gastroenterology

Prospective observational study of 1343 patients with acute decompensation of cirrhosis across 29 European liver units; defined ACLF using the CLIF-C OF score.

Key finding

Practice change

ACLF became a recognised entity with a graded prognosis — the foundation for transplant triage and all subsequent ACLF trials.

[3]

2021

CONFIRM (Wong 2021)

NEJM

RCT of terlipressin + albumin vs placebo + albumin in 300 patients with HRS-1 and cirrhosis (the largest HRS RCT).

Key finding

Practice change

[5]

2015

Gastroenterology

RCT of IV NAC vs placebo in 173 patients with non-acetaminophen acute liver failure (early grade I-II vs late III-IV).

Key finding

Improved transplant-free survival in early-stage (I-II) non-acetaminophen ALF (52% vs 30%); no benefit in late-stage. Benefit greatest in drug-induced and cryptogenic ALF.

Practice change

NAC is now given to early-stage non-acetaminophen ALF. Often extrapolated to ACLF in practice, though ACLF-specific RCT evidence is weaker — frame it as "low-risk adjunct, not standard of care".

[6]

Prognosis

Liver transplant outcomes in ACLF

85-92%

1-yr survival

ACLF grade 1-2 transplanted within 30 days (similar to elective)

65-80%

1-yr survival

ACLF grade 3 transplanted — worse but acceptable in selected

CLIF-C

Score guiding listing

CLIF-C ACLFs 40-64 = transplant window

Avoid

Grade 3 + 4 organs

Futile in many centres (post-LT mortality >50%)

[1] [4]

Prognostic scores in ACLF — which and when

CLIF-C OF

Admission

Grades organ failure (6-18); defines ACLF grade

CLIF-C ACLFs

48 h + trend

Adds age + WCC; the dynamic score (rising = worse)

MELD-Na

Transplant allocation

Standard for listing in most regions

Child-Pugh

Historical / bedside

Coarser; less useful in acute organ failure

[4] [1]

SAQ — ACLF precipitated by SBP with HRS-AKI and coagulopathy

10 minutes · 10 marks

[1]

SAQ — EASL-CLIF scoring, grading and the CLIF-C ACLF prognostic score

10 minutes · 10 marks

[1]

Clinical pearls

High-yield ACLF points for the CICM/FFICM exam

ACLF = acute decompensation + organ failure(s) + systemic inflammation.[1] }
Infection is the #1 precipitant — search aggressively (cultures, ascitic tap, SBP).
CLIF-C OF score grades 6 organ failures (liver, kidney, brain, coagulation, circulation, lung).[1] }
ACLF grade 3 (3+ organ failures): 77% 28-day mortality.[1] }
Liver transplant is the BEST treatment for ACLF grade 1-2.[1] }
NAC may improve outcomes (reduces oxidative stress).[1] }
Do NOT give steroids — no benefit, increases infection.[1] }
Terlipressin + albumin for hepatorenal syndrome (HRS-AKI).
Different from simple cirrhosis decompensation — ACLF has distinct prognosis and management.[2] }
Early transplant referral — do NOT wait for maximal deterioration.[1] }
INR is a liver function marker — do NOT routinely correct with FFP.[1] }
** albumin** for SBP (prevents HRS — 1.5 g/kg day 1, 1 g/kg day 3).
Sepsis: common and often missed — prophylactic antibiotics for GI bleed in cirrhosis.
Kyoto Consensus (2025): unified definition of ACLF (APASL + EASL convergence).[2] }

Extended exam pearls — the deeper ACLF knowledge the examiner wants

CLIF-C ACLFs (not just CLIF-C OF) adds age + white cell count — two surrogates of the inflammatory burden. Recalculate at 48 h: a rising score is a bad sign and should trigger transplant reassessment. The formula is exam-worthy.[4]
The kidney modifier is the single most-tested grading rule. A single kidney failure with creatinine 1.5-1.9 mg/dL is "no ACLF"; creatinine >1.9-3.5 mg/dL with no other organ failure is grade 1; any single non-kidney organ failure is also grade 1.[3]
HRS-AKI is functional and reversible; ATN is structural and is not. Distinguish with urine sodium (<10 HRS, >30 ATN), FeNa, and the response to albumin challenge. Terlipressin fails once ATN is established — diagnose and treat HRS early.[5]
CONFIRM trial safety signal: terlipressin can cause fatal respiratory failure from fluid overload. Monitor fluid balance rigorously, albumin-bolus judiciously, and prefer noradrenaline in the intubated ICU patient.[5]
Cirrhosis is REBALANCED haemostasis. INR overstates bleeding and understates thrombosis. Use TEG/ROTEM, not INR, to guide product therapy. Prophylactic FFP before procedures is harmful (volume, TRALI) and ineffective.[1]
Albumin in SBP reduces mortality (Sort 1999) — 1.5 g/kg day 1 + 1 g/kg day 3. This is the most evidence-supported supportive intervention in ACLF and an exam favourite.[7]
Prednisolone for alcohol-associated hepatitis (mDF ≥32), NOT for ACLF generally. Stop at day 7 if Lille >0.45 (non-responder). Contraindicated in sepsis, GI bleed, AKI. STOPAH: 28-day signal only, no 90-day benefit.[9]
No precipitant is found in ~40-50% of ACLF ("idiopathic") — the phenotype and management are identical; do not delay treatment hunting exhaustively.[3]
Nutrition: do NOT restrict protein. 35-40 kcal/kg/day, 1.2-1.5 g/kg protein, enteral preferred, late-evening snack to prevent overnight catabolism. Sarcopenia worsens HE (muscle clears ammonia).[1]
Thiamine before any glucose in alcohol-related ACLF — prevents Wernicke encephalopathy, which can mimic or worsen HE.
Noradrenaline is first-line vasopressor in cirrhotic vasodilatory shock; terlipressin is adjunct/second-line (and treats HRS in parallel).
Proton pump inhibitors increase SBP and infection risk in cirrhosis — review and stop unless there is a clear indication (e.g., active peptic ulcer, variceal bleed prophylaxis window).[1]
ACLF can recover — that is why transplant works. The CLIF-C ACLFs trend (not the absolute) is what predicts reversibility; a falling 48-h score should encourage continued aggressive support rather than de-escalation.
Grade 3 ACLF + 4 organ failures is often considered futile for transplant in many centres (post-LT mortality >50%); grade 3 with 3 organs may be considered in highly selected, young, infection-free patients.[1]
Ammonia-lowering (lactulose, rifaximin) treats HE symptoms, not mortality — useful for the brain-failure organ domain, but do not over-diurese or over-laxative (volume depletion → HRS, dehydration → AKI).
HBV reactivation is the dominant precipitant in Asia-Pacific/APASL cohorts — check HBV DNA and start entecavir/tenofovir promptly in HBV-related ACLF.[2]
Portal vein thrombosis in a cirrhotic with sudden deterioration — Doppler US/CT; anticoagulate if cirrhosis is otherwise compensated and varices treated (the rebalanced-haemostasis insight makes this safer than feared).
Avoid aminoglycosides, NSAIDs, and unnecessary IV contrast in ACLF — all precipitate or worsen AKI. Prefer liposomal amphotericin or echinocandin; use iso-osmolar contrast only when essential with pre-hydration.

Pitfalls and mnemonics

Common ACLF pitfalls — what examiners love to catch

Pitfall	The trap	The correct approach
"Correct the INR"	Giving FFP before paracentesis/endoscopy "because INR is 2.5"	INR does not predict bleeding; use TEG/ROTEM; transfuse only if viscoelastic indices abnormal and bleeding
"Restrict protein for HE"	Halting protein to "lower ammonia"	Protein restriction is harmful — give 1.2-1.5 g/kg; sarcopenia worsens HE
"Steroids for the inflammation"	Giving methylprednisolone for ACLF shock	Steroids are NOT indicated in ACLF; only prednisolone for biopsy-confirmed AAH (mDF ≥32, no sepsis)
"Fluid challenge with saline"	Large crystalloid boluses for "low BP"	Cirrhotics vasodilate and leak — prefer albumin 20%; crystalloid → oedema, dilutional hyponatraemia
"Stop nutrition to rest the gut"	NPO for GI bleed / procedures indefinitely	Restart enteral early; the catabolic cirrhotic cannot tolerate starvation
"Terlipressin always"	Defaulting to terlipressin in volume-overloaded patient	Watch CONFIRM safety signal — respiratory failure; prefer noradrenaline if overloaded/intubated
"PPI for stress prophylaxis"	Continuing PPI indefinitely	PPI increases SBP/infection — stop once the acute indication resolves

[1] [5] [3]

Red flags

Extended red flags — the lethal traps

HRS-AKI is reversible; ATN is not — diagnose and treat HRS BEFORE it progresses. Terlipressin + albumin (CONFIRM), monitor for fluid-overload respiratory failure.[5]
Albumin 1.5 g/kg + 1 g/kg in SBP reduces mortality (Sort) — omitting it is a preventable error. NNT ~4-5.[7]
Prednisolone only for biopsy-proven AAH (mDF ≥32), no sepsis/bleed/AKI, stop at day 7 if Lille >0.45. Do NOT conflate with "steroids in ACLF".[9]
CLIF-C ACLFs trending UP at 48 h is an ominous sign — escalate to transplant evaluation; do not be reassured by a static admission score.[4]
Cirrhosis is prothrombotic despite high INR — portal vein thrombosis, PE; do not withhold anticoagulation purely on INR.[1]
Terlipressin can cause fatal respiratory failure (CONFIRM) — avoid in volume-overloaded patients; watch SaO2 and fluid balance.[5]
Restrictive, not liberal, resuscitation — even in shock, prefer albumin 20% over saline; crystalloid excess → oedema, dilutional hyponatraemia, worsened ascites.[1]
Do not starve the malnourished cirrhotic — enteral nutrition 35-40 kcal/kg, 1.2-1.5 g/kg protein; protein restriction worsens HE and sarcopenia.[1]
Thiamine before glucose in alcohol-related ACLF — prevent Wernicke.
PPIs increase SBP/infection — review and deprescribe once the acute indication resolves.[1]

Exam-style rapid recall

One-minute rapid-fire answers

Definition: acute decompensation of cirrhosis + organ failure(s) (CLIF-C OF grade 3 in ≥1 organ) + systemic inflammation (CANONIC, EASL 2023).[3][1]
#1 precipitant: bacterial infection (SBP, pneumonia, bacteraemia) — culture everything + diagnostic paracentesis + empiric antibiotics.[1]
Score: CLIF-C OF (grades organ failure) → CLIF-C ACLFs (adds age + WCC, recalculated at 48 h).[4]
Grades/mortality (28-day): grade 1 ~22%, grade 2 ~32%, grade 3 ~77%.[1]
HRS-AKI: terlipressin + albumin (CONFIRM); noradrenaline if overloaded/intubated; treat before ATN.[5]
SBP: cefotaxime/ceftriaxone + albumin 1.5 g/kg then 1 g/kg (Sort).[7]
Coagulopathy: rebalanced haemostasis; TEG/ROTEM, NOT INR; do not prophylactically correct.[1]
Steroids: NO in ACLF generally; YES only for biopsy-proven AAH (mDF ≥32, no sepsis), stop if Lille >0.45 at day 7.[9]
Nutrition: 35-40 kcal/kg, 1.2-1.5 g/kg protein, enteral first, no protein restriction.[1]
Transplant: BEST treatment for grade 1-2; grade 3 with 4 organs often futile. REFER EARLY.[1]
Kyoto Consensus (2025): unified APASL/EASL definition.[2]

References

[1]EASL Clinical Practice Guidelines. EASL Clinical Practice Guidelines on acute-on-chronic liver failure J Hepatol, 2023.PMID 37364789
[2]Sarin SK, Choudhury AK, Sharma MK, et al. Acute-on-chronic liver failure (ACLF): the 'Kyoto Consensus'-steps from Asia Hepatol Int, 2025.PMID 39961976
[3]Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis Gastroenterology, 2013.PMID 23474284
[4]Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure J Hepatol, 2014.PMID 24950482
[5]Wong F, Pappas SC, Curry MP, et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome N Engl J Med, 2021.PMID 33657294
[6]Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure Gastroenterology, 2009.PMID 19524577
[7]Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis N Engl J Med, 1999.PMID 10432325
[8]Caraceni P, Riggio O, Angeli P, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial Lancet, 2018.PMID 29861076
[9]Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis N Engl J Med, 2015.PMID 25901427

Your progress

What ACLF is — and what it is NOT

Diagnosis

CLIF-C ACLF score — the prognostic score that adds age and WCC

Precipitating factors

Organ failure assessment — the six systems

Liver (bilirubin, INR, ammonia)

Kidney (creatinine, urine output, sodium)

Brain (West Haven grade, ammonia)

Coagulation (INR, platelets, fibrinogen, TEG/ROTEM)

Circulation (MAP, lactate, vasopressors)

Respiratory (SpO2, PaO2/FiO2, ABG)

Management

Identify and treat precipitant

Organ support

N-acetylcysteine (NAC)

Do NOT give steroids

Early liver transplant referral

Palliative care

Hepatorenal syndrome (HRS-AKI) — the reversible kidney failure

Diagnose AKI first (ICA criteria)

Distinguish HRS from ATN — it changes everything

First-line vasoconstrictor

When terlipressin fails or is contraindicated

List for transplant if HRS recurs or persists

Spontaneous bacterial peritonitis (SBP) — the classic precipitant

Diagnostic paracentesis in EVERY cirrhotic with ascites + ACLF

Empiric antibiotics

ALBUMIN — the mortality-reducing step (Sort 1999)

Secondary prophylaxis

Nutrition — enteral first, do not starve the malnourished cirrhotic

Coagulopathy — the rebalanced haemostasis trap

Alcohol-associated hepatitis in the ACLF context — the steroid decision

NAC and the "adjuncts" debate

Key trials

CANONIC (Moreau 2013)

CONFIRM (Wong 2021)

STOPAH (Thursz 2015)

ANSWER (Caraceni 2018)

Sort albumin in SBP (1999)

NAC in non-acetaminophen ALF (Lee 2009)

Prognosis

SAQ — ACLF precipitated by SBP with HRS-AKI and coagulopathy

SAQ — EASL-CLIF scoring, grading and the CLIF-C ACLF prognostic score

Clinical pearls

Pitfalls and mnemonics

Red flags

Exam-style rapid recall

References

Your progress

What ACLF is — and what it is NOT

Diagnosis

CLIF-C ACLF score — the prognostic score that adds age and WCC

Precipitating factors

Organ failure assessment — the six systems

Liver (bilirubin, INR, ammonia)

Kidney (creatinine, urine output, sodium)

Brain (West Haven grade, ammonia)

Coagulation (INR, platelets, fibrinogen, TEG/ROTEM)

Circulation (MAP, lactate, vasopressors)

Respiratory (SpO2, PaO2/FiO2, ABG)

Management

Identify and treat precipitant

Organ support

N-acetylcysteine (NAC)

Do NOT give steroids

Early liver transplant referral

Palliative care

Hepatorenal syndrome (HRS-AKI) — the reversible kidney failure

Diagnose AKI first (ICA criteria)

Distinguish HRS from ATN — it changes everything

First-line vasoconstrictor

When terlipressin fails or is contraindicated

List for transplant if HRS recurs or persists

Spontaneous bacterial peritonitis (SBP) — the classic precipitant

Diagnostic paracentesis in EVERY cirrhotic with ascites + ACLF

Empiric antibiotics

ALBUMIN — the mortality-reducing step (Sort 1999)

Secondary prophylaxis

Nutrition — enteral first, do not starve the malnourished cirrhotic