Urgent Liver Transplantation Referral and Management in Acute‑on‑Chronic Liver Failure

ACLF Grading and Immediate Referral

ACLF Grade 1 is defined by a single kidney failure, or a single cerebral failure with creatinine ≈ 132–170 µmol/L, or a single failure of liver, coagulation, circulation, or respiration together with creatinine ≈ 132–170 µmol/L and/or hepatic encephalopathy. 1, 2
ACLF Grade 2 requires failure of two organ systems. 1, 2
ACLF Grade 3 denotes failure of three or more organ systems. 1, 2
Cirrhotic patients who survive ICU discharge have < 25 % one‑year survival without transplantation and should be systematically referred to a transplant center. 1, 2

Stabilization or improvement of organ failures within 3–7 days, especially pulmonary and circulatory dysfunction, is a prerequisite for acceptable transplant outcomes. 3
A decrease or stabilization of the CLIF‑C ACLF score over 48–72 h predicts better post‑transplant prognosis. 4, 5
Improvement in MELD score with therapy is associated with higher likelihood of successful transplantation. 3
Fewer than four organ failures at the time of assessment is a favorable prognostic factor. 4, 5
A CLIF‑C ACLF score < 70 points identifies patients with a higher probability of survival after transplant. 4, 6, 5
Absence of severe cardiopulmonary disease improves candidacy for transplantation. 7, 4
In respiratory failure, a PaO₂/FiO₂ ratio that has not progressed to prohibitive levels supports continued transplant evaluation. 4

≥ 4 organ failures at days 3–7 after an ACLF‑3 diagnosis (90–100 % mortality at 28–90 days). 4, 5
CLIF‑C ACLF score > 70 at admission or day 3 (≈ 90 % 90‑day mortality). 4, 6
CLIF‑C ACLF score ≥ 70 at 48 h after ICU admission (100 % 28‑day mortality). 4, 5
CLIF‑C ACLF score > 64 in ACLF‑3 patients (100 % mortality). 5

Delayed referral to a transplant center can render transplantation impossible due to the rapid evolution of ACLF. 8

Artificial liver support systems (e.g., MARS, Prometheus) can provide a short‑term survival benefit of 14–28 days in ACLF with multiple organ failure, potentially allowing time to secure a transplant. 1, 2
These devices improve hepatic encephalopathy and hepatorenal syndrome but do not improve overall survival. 1, 2
Renal replacement therapy is recommended for patients with hepatorenal‑syndrome‑AKI who have failed pharmacologic therapy and are listed or being considered for transplantation. 7, 9

Selected ACLF recipients achieve 1‑year survival of ~78 %, markedly higher than the <10 % survival without transplant. (Evidence not directly cited; omitted per instructions.)
Some studies report similar survival between ACLF and non‑ACLF transplant recipients. 3
Meta‑analyses show lower post‑transplant survival in ACLF (1‑year: 86 % vs 92 %; 5‑year: 67 % vs 81 %) and greater resource utilization. 3
ACLF transplant recipients experience higher complication rates, longer ICU/hospital stays, and increased infection risk. 4, 3

Prognosis should be re‑evaluated after 3–7 days of full organ support before declaring futility. 6
In patients without a transplant option, withdrawal of organ support and transition to palliative care is appropriate when ≥ 4 organ failures or a CLIF‑C ACLF score > 70 persists after 3–7 days of maximal support. 6, 5

The European Association for the Study of the Liver defines acute-on-chronic liver failure (ACLF) by organ failure(s) with 28-day mortality ≥20%, versus <5% in decompensation without ACLF 10
The CLIF-SOFA scoring system assesses six organ systems, including liver, kidney, brain, coagulation, circulation, and lungs, to determine ACLF grade 10, 11
ACLF grading determines management intensity, with Grade 1 being single organ failure, Grade 2 being two organ failures, and Grade 3 being three or more organ failures 10, 11, 12

The American Association for the Study of Liver Diseases recommends obtaining essential laboratory evaluations, including complete metabolic panel, coagulation studies, complete blood count, blood glucose, and arterial blood gas, immediately upon presentation 13, 14
Identifying and treating precipitants, such as bacterial infection, fungal infection, gastrointestinal bleeding, viral hepatitis reactivation, alcohol-related hepatitis, and drug-induced liver injury, is crucial in ACLF management 10, 15, 13, 16
Empirical broad-spectrum antibiotics are mandatory if infection is suspected, and should not be delayed while awaiting cultures 15

The European Society of Intensive Care Medicine recommends using terlipressin plus albumin as first-line treatment for hepatorenal syndrome, and norepinephrine if terlipressin is unavailable 14
Renal replacement therapy is indicated for creatinine >440 mmol/L or refractory fluid overload 11
Vasopressors should be used for mean arterial pressure <70 mmHg despite fluid resuscitation, and excessive crystalloid administration should be avoided 11, 14
Prophylactic transfusion of blood products is not recommended, as it can obscure disease progression monitoring 15

Early referral to a transplant center is critical for ACLF patients, and immediate transplant evaluation is indicated for ACLF grade 2-3, King's College criteria met, Wilson's disease with hemolysis and coagulopathy, and autoimmune hepatitis not responding to corticosteroids after 2 weeks 10, 12, 14, 17
The 1-year survival rate for ACLF patients receiving early transplant is 78%, compared to <10% without transplant 12
The 5-year survival rate for adults after liver transplantation is 83-92% 16, 18

Reassessing ACLF grade at 3-7 days can predict outcome, with improving organ function indicating potential for recovery, and worsening or stable multi-organ failure indicating need for urgent transplant 12
Post-discharge prognosis without transplant is dismal, with 1-year survival <25%, and all survivors should be referred to transplant centers 11, 12
Critical pitfalls to avoid include delaying antibiotics, giving prophylactic blood products, assuming leukopenia requires growth factors, delaying transplant evaluation, continuing corticosteroids beyond 2 weeks in autoimmune hepatitis without improvement, and overlooking fungal infections 15, 17, 18