What are the causes and management strategies for a patient with Acute-on-Chronic Liver Failure (ACLF)?

Causes and Management of Acute-on-Chronic Liver Failure (ACLF)

Causes of ACLF

Infection is the most common precipitant of ACLF worldwide, occurring in 48% of cases, followed by active alcohol use and hepatitis B flares. 1

Primary Precipitating Events

• Bacterial infections are the leading cause, with spontaneous bacterial peritonitis (SBP), urinary tract infections, and skin/soft-tissue infections being most common 1
• Active alcoholism with superimposed alcoholic hepatitis represents a major precipitant, particularly in Western populations 1, 2
• Hepatitis B virus reactivation causes massive hepatic necrosis and is especially common in untreated HBV-associated cirrhosis 3
• Gastrointestinal bleeding can trigger ACLF through hemodynamic instability and increased infection risk 4
• Drug toxicity including acetaminophen and other hepatotoxic medications 1, 4
• No identifiable precipitant is found in approximately 40% of ACLF cases despite thorough investigation 3

High-Risk Patient Populations

• Younger male patients with alcohol-associated cirrhosis and high MELD scores are at greatest risk 1
• Patients with invasive procedures, indwelling lines, and catheters face increased infection risk 1
• Multi-drug-resistant (MDR) organisms substantially increase both ACLF risk and mortality 1

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Management of ACLF

Immediate transfer to an intensive care or enhanced care unit with early transplant center referral is mandatory, as ACLF carries 28-day mortality rates of 30-40% and requires aggressive organ support as a bridge to transplantation or spontaneous recovery. 3, 4

Initial Assessment and Stabilization

• Diagnose and treat precipitating factors immediately, particularly bacterial infections with empirical broad-spectrum antibiotics for patients with worsening hepatic encephalopathy or signs of systemic inflammatory response syndrome (SIRS) 1
• Assess ACLF grade and volume status before initiating any vasoactive therapy 5
• Monitor oxygen saturation continuously using pulse oximetry, as respiratory failure is a critical complication 1, 5
• Obtain baseline serum creatinine, electrolytes, and coagulation parameters to guide organ support decisions 1

Infection Management

Empirical broad-spectrum antibiotics should be administered immediately to patients with worsening hepatic encephalopathy or SIRS criteria, as infection-related ACLF has higher mortality than non-infectious ACLF. 1

• Start antibiotics before culture results in patients with new decompensation (worsening mental status, hyponatremia, AKI, relative WBC increase, hemodynamic changes) 1
• Maintain high suspicion for sepsis even without fever, as fever is often absent in cirrhotic patients with infection 1
• Biomarkers (C-reactive protein, procalcitonin, lactate) are frequently elevated in cirrhosis regardless of infection, but persistent elevation indicates poor prognosis 1
• Adjust antibiotic coverage based on local resistance patterns and culture results, with particular attention to MDR organisms 1

Hepatorenal Syndrome and Acute Kidney Injury

For Stage 2 or greater HRS-AKI, initiate vasoconstrictors (terlipressin 0.5-2.0 mg IV q6h or norepinephrine) plus albumin (20-40 g/day) after withdrawing diuretics and volume resuscitation with IV albumin 1 g/kg (maximum 100 g/day) for 48 hours. 1

Stepwise Approach to AKI in ACLF:

1. Withdraw diuretics and treat precipitating factors (infection, bleeding) 1
2. Volume challenge with IV albumin at 1 g/kg body weight (maximum 100 g/day) for 48 hours 1
3. Initiate vasoconstrictors for Stage 2+ HRS-AKI:
   • Terlipressin (0.5-2.0 mg IV q6h or continuous infusion 2 g/24h IV) is indicated for hospitalized patients without ACLF-3 or major cardiopulmonary/vascular disease 1
   • Critical contraindication: Do NOT use terlipressin in patients with hypoxia (SpO2 <90%) or ACLF Grade 3, as it causes serious or fatal respiratory failure 5
   • Norepinephrine is the alternative to terlipressin and may be preferred in patients with shock 1
4. Renal replacement therapy (RRT) is recommended for patients who fail pharmacotherapy and are listed or being considered for liver transplantation 1

Respiratory Management

For acute hypoxemic respiratory failure, consider high-flow nasal cannula (HFNC) with close monitoring for escalation to mechanical ventilation if tachypnea or refractory hypoxemia develops. 1

Mechanical Ventilation Strategy:

• Lung protective ventilation with tidal volume 6 mL/kg predicted body weight (PBW) and plateau pressure <30 cm H2O for acute lung injury (ALI)/ARDS 1
• Low PEEP strategy (<10 cm H2O) for mild ALI (PaO2/FiO2 200-300 mm Hg) to avoid impairing venous return in vasodilated patients 1
• High PEEP may be required for moderate-severe ALI (PaO2/FiO2 <200 mm Hg) despite hemodynamic risks 1
• Treat coexisting pulmonary complications: therapeutic thoracentesis for hydrothorax or paracentesis for tense ascites causing respiratory compromise 1

Hemodynamic Support

Norepinephrine is the first-line vasopressor for persistent hypotension after fluid resuscitation, with crystalloids as the initial fluid of choice. 4

• Monitor hemodynamic function continuously and avoid excessive volume expansion that worsens organ function 4
• Vasopressin can be added when hypotension persists despite norepinephrine 4
• Maintain mean arterial pressure adequate for organ perfusion while recognizing baseline vasodilation from portal hypertension 1

Hepatic Encephalopathy Management

Treat hepatic encephalopathy with lactulose (oral or rectal) or polyethylene glycol if ileus/abdominal distention is a concern, and consider ICU admission for Grade 3-4 encephalopathy. 4

• Maintain serum sodium 140-145 mmol/L to prevent cerebral edema 1
• Monitor blood glucose at least every 2 hours due to impaired hepatic gluconeogenesis 1
• Intubate for progressive encephalopathy (Glasgow Coma Scale <8) with minimal sedation depth 1
• Do NOT use benzodiazepines or metoclopramide as they worsen encephalopathy 1
• Rifaximin as adjunctive therapy is recommended 4

Coagulation Management

Do NOT routinely correct coagulation abnormalities unless active bleeding is present, as clotting factor administration can worsen outcomes. 1

• Restrict fresh frozen plasma and platelet transfusions to cases of active hemorrhage 1
• Avoid prophylactic correction of INR or platelet count for procedures in stable patients 1

Liver Transplantation

Early referral to a liver transplant center for immediate evaluation is mandatory for all ACLF patients, as transplantation is the definitive treatment but must be weighed against multiorgan failure severity. 1, 4

• ACLF-2 or ACLF-3 patients require urgent transplant assessment 4
• Patients with 4 or more organ failures after one week of adequate intensive treatment who are not transplant candidates should have withdrawal of care discussions 4
• Vasoconstrictors for HRS-AKI improve post-transplant outcomes with fewer patients requiring RRT and developing chronic kidney disease at 1 year 1

Plasma Exchange

Plasma exchange is NOT recommended for routine ACLF management outside research trials, despite emerging data showing potential benefit. 6, 7

• The European Association for the Study of the Liver (EASL) explicitly recommends against routine plasma exchange for ACLF 6
• The American Association for the Study of Liver Diseases (AASLD) suggests plasma exchange only for acute liver failure (ALF) with hyperammonemia (>150 μmol/L), not for ACLF 6, 7
• Consider plasma exchange only in highly selected cases: listed for transplant, deteriorating despite standard therapy, at centers with expertise, ideally within research protocols 6, 7

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Critical Pitfalls to Avoid

• Do NOT delay transfer to transplant centers when ACLF is diagnosed 4
• Do NOT use terlipressin in ACLF Grade 3 or hypoxic patients (SpO2 <90%) due to fatal respiratory failure risk 5
• Do NOT use lactulose to lower ammonia in acute liver failure, though it remains standard for hepatic encephalopathy in chronic liver disease 4
• Do NOT perform routine ammonia level measurements for hepatic encephalopathy diagnosis 4
• Do NOT provide excessive volume expansion as it worsens organ function 4
• Do NOT use nephrotoxic drugs including NSAIDs in patients with or at risk for AKI 1