Acute-on-Chronic Liver Failure

Acute-on-chronic liver failure is acute decompensation of cirrhosis (or advanced chronic liver disease) with failure of one or more organs and high short term mortality (28-day mortality of 15% or more). It is usually triggered by an insult such as infection, alcoholic hepatitis, variceal bleeding or drug injury.

Epidemiology. It is found in about 20 to 35% of hospitalised patients with cirrhosis and decompensation. Grade 1 has 28-day mortality of about 20%, grade 2 about 30%, and grade 3 about 70 to 80%.

Grading by organ failure.

• Grade 1: single kidney failure (creatinine 177 micromol/L or more), or single non-kidney organ failure with creatinine 133 to 176 micromol/L or hepatic encephalopathy grade 1 to 2 with a cerebral failure.
• Grade 2: two organ failures.
• Grade 3: three or more organ failures.
• Organs: liver (bilirubin 205 micromol/L or more), kidney, brain (encephalopathy grade 3 to 4), coagulation (INR 2.5 or more), circulation (vasopressors) and respiration (PaO2/FiO2 200 or less).

Precipitants. Bacterial infection (spontaneous bacterial peritonitis, pneumonia, urinary sepsis), alcoholic hepatitis, gastrointestinal bleeding, hepatitis B reactivation or flare, drug induced liver injury, surgery, portal vein thrombosis and unknown (about 40%).

Pathophysiology. Systemic inflammation, bacterial translocation and oxidative stress overwhelm the cirrhotic liver. Circulatory dysfunction, immune paralysis and impaired regeneration lead to multi-organ failure.

Presentation is jaundice, ascites, encephalopathy, bleeding, hypotension, oliguria, fever, abdominal pain and respiratory failure, with signs of chronic liver disease (spider naevi, splenomegaly, caput medusae).

Red flags.

• Encephalopathy grade 3 to 4, shock or rising creatinine.
• Gastrointestinal bleeding or fever with ascites.
• Hypoxia, bilirubin over 205 micromol/L or INR over 2.5.

Full blood count, coagulation, liver tests, creatinine, electrolytes, lactate, glucose, ammonia (interpretation limited), arterial gas, CRP and procalcitonin. Diagnostic paracentesis in every patient with ascites (neutrophil count over 250/mm3 indicates spontaneous bacterial peritonitis), blood, urine and ascitic cultures, chest radiograph, abdominal ultrasound with Doppler (portal vein thrombosis, hepatocellular carcinoma), and tests for viral hepatitis, alcohol, drugs and autoimmune disease. Upper endoscopy for bleeding.

Differential diagnosis. Acute liver failure on a normal liver, hepatorenal syndrome alone, sepsis without liver failure, hepatocellular carcinoma progression and acute alcoholic hepatitis.

Admit to intensive care or high dependency for organ failure.

Infection. Start broad spectrum antibiotics within 1 hour for suspected sepsis or spontaneous bacterial peritonitis: ceftriaxone 2 g IV daily, or piperacillin-tazobactam 4.5 g IV every 6 hours for nosocomial infection, or meropenem 1 g IV every 8 hours for resistant organisms, adjusted to renal function.

Albumin. For spontaneous bacterial peritonitis, albumin 1.5 g/kg IV on day 1 and 1 g/kg on day 3. For large volume paracentesis (over 5 L) give albumin 6 to 8 g for each litre removed.

Hepatorenal syndrome acute kidney injury. Stop diuretics and nephrotoxins. Give albumin 1 g/kg (maximum 100 g) on day 1 then 20 to 40 g daily.

Terlipressin 0.85 mg IV every 6 hours (or 2 mg daily as continuous infusion), increasing to 1.7 mg every 6 hours if creatinine has not fallen by 25% at day 3, and stopping at day 14 or when there is no response. Contraindicated or used with caution in hypoxia (oxygen saturation under 90%), ischaemic disease and volume overload.

Noradrenaline 0.5 to 3 mg/h IV is an alternative in intensive care. Renal replacement as a bridge to transplantation.

Hepatic encephalopathy. Search for and treat the precipitant. Lactulose 30 to 45 mL orally every 1 to 2 hours until bowel movement then 15 to 30 mL twice or three times daily (titrated to 2 to 3 soft stools daily), or 300 mL in 700 mL water as an enema. Add rifaximin 550 mg orally twice daily. Intubate for grade 3 to 4 encephalopathy.

Alcoholic hepatitis. If discriminant function is 32 or more with no infection or bleeding: prednisolone 40 mg orally daily for 28 days, with early assessment of response at day 7. Stop if no response. N-acetylcysteine 150 mg/kg IV over 1 hour then 12.5 mg/kg/h for 4 hours then 6.25 mg/kg/h for 67 hours may be added.

Hepatitis B flare. Entecavir 0.5 mg orally daily (reduced in renal impairment) or tenofovir alafenamide 25 mg daily, started promptly.

Variceal bleeding. Terlipressin, antibiotics and endoscopic band ligation.

Circulation and respiration. Noradrenaline to mean arterial pressure of 65 mmHg after albumin based fluid, lung protective ventilation, and judicious fluid.

Coagulopathy. Do not correct INR routinely. Give vitamin K 10 mg IV once, and replace products only for bleeding or procedures.

Nutrition. Enteral feeding with 35 to 40 kcal/kg/day and protein 1.2 to 1.5 g/kg/day, a late evening snack, and avoid protein restriction.

Transplantation. Early assessment for liver transplantation in patients with grade 2 to 3 failure and no contraindication, since survival without it is poor.

Monitoring. Organ failure scores daily, creatinine, lactate, glucose every 4 to 6 hours, mental state, infection markers and bleeding.

Referral and escalation. Hepatology and liver transplant centre early, with intensive care.

Special groups. In pregnancy, involve hepatology and obstetrics. In renal impairment, adjust antibiotic and entecavir doses.