What is the pathophysiology and treatment approach for a patient with acute on chronic liver failure?

Acute-on-Chronic Liver Failure: Pathophysiology and Treatment

Pathophysiology

ACLF is fundamentally driven by excessive systemic inflammation triggered by acute precipitants, leading to multi-organ failure in patients with underlying cirrhosis. 1

The core pathophysiological mechanism involves:

• Deregulated inflammatory cascade: An initial cytokine storm presents as Systemic Inflammatory Response Syndrome (SIRS), which progresses to Compensatory Anti-inflammatory Response Syndrome (CARS) with associated immunoparalysis, ultimately leading to sepsis and multi-organ failure 2
• Acute precipitants (present in ~60% of cases): Bacterial infections with sepsis, severe alcohol-related hepatitis, viral hepatitis, drug-induced liver injury, or surgery 1
• Organ system failures: Involves six major systems—liver, kidney, brain, coagulation, circulation, and respiration—with failure defined by specific thresholds 1
• Critical "Golden Window": The first 7 days represent a crucial period where the cascade of SIRS/sepsis and extrahepatic organ failure develops; intervention during this window is essential 3

Immediate Recognition and Triage

Verify three diagnostic criteria: (1) liver failure with elevated bilirubin AND INR, (2) acute clinical deterioration, and (3) at least one extrahepatic organ failure. 4

Initial Assessment

• ICU transfer is mandatory for patients with ACLF Grade 2-3 or declining mental status 4
• Calculate severity scores: MELD-Na, CLIF-C ACLF score, or NACSELD ACLF score (do NOT rely on MELD alone as it underestimates mortality by ignoring extrahepatic organ failures) 4
• Assess ACLF grade and volume status before initiating any vasoactive therapy 5
• Obtain baseline oxygen saturation (SpO2) before any treatment—do not initiate therapy in hypoxic patients (SpO2 <90%) 5

Laboratory Workup

• Complete metabolic panel: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose 4
• Liver function: AST, ALT, alkaline phosphatase, total/direct bilirubin, albumin 4
• Coagulation: PT/INR 4
• Renal function: creatinine (>132-170 mmol/L indicates compromise), BUN, eGFR 4
• Inflammatory markers: C-reactive protein, WBC count 4
• Arterial blood gas, arterial lactate 1
• Infection workup: blood cultures, diagnostic paracentesis for spontaneous bacterial peritonitis 1

Treatment Algorithm

1. Identify and Treat Precipitants (First Priority)

Early identification and aggressive treatment of the acute insult within the first 7 days is crucial for survival. 3

• Bacterial infections: Obtain cultures immediately, start empiric broad-spectrum antibiotics without delay in high-risk patients 1
• Severe alcoholic hepatitis: Consider corticosteroids if appropriate 1
• HBV-related ACLF: Initiate nucleoside analogues immediately 2
• Autoimmune hepatitis flare: Consider corticosteroids 2
• GI bleeding: Investigate and treat promptly 1

2. Organ System Support

Hepatic Encephalopathy Management

• Lactulose: Start empirically if no alternative cause is apparent; titrate to 2-3 soft bowel movements daily 1
• For Grade 3-4 HE: Consider lactulose enema (300 mL lactulose in 700 mL water) 1
• Insert nasogastric tube if needed for administration (use caution if recent variceal banding) 1
• Identify and treat precipitants: infections, GI bleeding, electrolyte disorders, AKI, alkalosis, dehydration, constipation 1
• Do NOT use benzodiazepines in patients with altered mental status 1

Circulatory Support

• Target mean arterial pressure 50-60 mm Hg 4
• Fluid resuscitation: Use balanced crystalloids (lactated Ringer's) or albumin as first-line; avoid normal saline 1
• Assess volume status with bedside transthoracic echocardiography (cardiac function, IVC preload, stroke volume) 1
• Monitor dynamic changes: stroke volume variation, pulse pressure variation, or passive leg raise to guide resuscitation 1
• Vasopressors: If fluid replacement fails, use norepinephrine, epinephrine, or dopamine 4
• Albumin administration: 1 g/kg on Day 1 (maximum 100 g), then 20-40 g/day as clinically indicated 5
• Avoid volume overload: Patients with fluid overload are at increased risk of respiratory failure; use judicious diuretics and reduce albumin if needed 5

Renal Support (Hepatorenal Syndrome)

• Terlipressin (Terlivaz): For HRS with rapid reduction in kidney function 5
  • Contraindications: Hypoxia (SpO2 <90%), ongoing coronary/peripheral/mesenteric ischemia, ACLF Grade 3 (high respiratory failure risk) 5
  • Dosing: 0.85 mg IV every 6 hours on Days 1-3; adjust on Day 4 based on creatinine response 5
  • Monitoring: Continuous pulse oximetry; discontinue if SpO2 drops below 90% 5
  • Limitation: Patients with creatinine >5 mg/dL unlikely to benefit 5
• Renal replacement therapy: Use continuous modes (NOT intermittent hemodialysis) 4
• Do NOT use prophylactic FFP—reserve for active bleeding or procedures 4

Respiratory Support

• Monitor continuously with pulse oximetry 5
• Assess for hepatopulmonary syndrome, portopulmonary hypertension, or volume overload 1
• Consider low tidal volume and low PEEP strategies if mechanical ventilation required 1
• Avoid ACLF Grade 3 patients for terlipressin due to significant respiratory failure risk 5

Infection Prevention

• Prophylaxis for stress ulceration: H2 blockers or proton pump inhibitors 4
• Early empiric antibiotics for suspected infections 1
• Culture-directed therapy when organisms identified 1

3. Serial Monitoring

ACLF is dynamic—monitor organ function frequently as patients can rapidly develop new organ failures. 4

• Mental status: Frequent assessments for hepatic encephalopathy progression 4
• Continuous pulse oximetry 5
• Serial creatinine, bilirubin, INR, lactate 4
• Hemodynamic monitoring with bedside echocardiography 1

4. Liver Transplantation Evaluation

Early referral to a liver transplant center for immediate evaluation is strongly recommended for ACLF Grade 2-3. 4

• Expedited transplantation may be indicated in selected patients, though specific predictors of acceptable outcomes remain under investigation 1
• High MELD scores (≥35): Benefits of treatment may not outweigh risks, as ACLF-related complications (respiratory failure, ischemia) can make patients ineligible for transplantation 5
• Multidisciplinary teams with critical care and transplant expertise should manage these patients 6

5. Futility Assessment

Four or more organ failures after one week of adequate intensive treatment suggests futility. 4

• 28-day mortality ranges from 30-50% overall 4
• ACLF Grade 3 carries particularly high mortality 1
• Decisions about futility should be based on: candidacy for expedited transplant, available resources, and potential reversibility of ACLF 1

6. Palliative Care Integration

All patients with ACLF should receive palliative care consultation to define prognosis, determine goals of care, and document advance directives, regardless of transplant listing status. 1

• Identify surrogate decision-maker within 48 hours of admission 1
• Goals of care discussion required for: mechanical ventilation >48 hours, ICU stay >48 hours, hemodialysis initiation, or pacemaker placement 1
• Disease-directed care (including transplant evaluation) does not preclude palliative care 1
• Non-transplant candidates with HRS-AKI unresponsive to pharmacotherapy should be offered palliative care or hospice 1

Critical Pitfalls to Avoid

• Do NOT delay ICU transfer—patients with declining mental status require immediate ICU admission 4
• Do NOT use MELD or MELD-Na alone for prognostication—they underestimate mortality by not accounting for extrahepatic organ failures 4
• Do NOT administer FFP prophylactically—reserve for active bleeding or procedures 4
• Do NOT use intermittent hemodialysis—continuous modes are preferred 4
• Do NOT initiate terlipressin in hypoxic patients or those with ACLF Grade 3 5
• Do NOT use benzodiazepines in patients with altered mental status 1
• Exclude Gilbert's syndrome before attributing hyperbilirubinemia to ACLF (unconjugated bilirubin >70-80% of total, typically <4-5 mg/dL) 4

Emerging Therapies (Not Routine)

• Plasma exchange: EASL recommends against routine use outside research trials; AASLD suggests only for acute liver failure with hyperammonemia (ammonia >150 μmol/L), NOT for ACLF 7
• May be considered in highly selected critically ill patients as bridge to transplantation when standard therapies fail, ideally within research protocols 7