What are the causes and management of hepatic insufficiency?

Causes of Hepatic Insufficiency

Hepatic insufficiency results from extreme derangement of liver cell function and can be classified into acute liver failure (ALF) and chronic hepatic insufficiency, with the most common causes being alcohol abuse, viral hepatitis, and metabolic dysfunction-associated fatty liver disease. 1, 2

Acute Liver Failure (ALF)

Definition and Epidemiology

• ALF is defined by severe liver injury with hepatic encephalopathy in a previously healthy person without pre-existing liver disease 3
• Estimated 2,000 cases annually in the United States, representing 0.1% of all deaths and approximately 6% of liver-related deaths 3

Common Causes of ALF

• Drug-induced hepatotoxicity

  • Acetaminophen overdose (most common cause of ALF in many Western countries) 1
  • Other medications (antimicrobials, antiepileptics, statins) 1
  • Herbal supplements and nutritional products 1

• Viral hepatitis

  • Hepatitis A and B (approximately 12% of ALF cases in the US) 1
  • Hepatitis E (particularly severe in pregnant women) 1
  • Herpes simplex virus (especially in immunocompromised patients and pregnant women) 1

• Toxin exposure

  • Mushroom poisoning (Amanita phalloides) 1
  • Recreational drugs (cocaine, ecstasy, amphetamines) 1

• Vascular causes

  • Ischemic hepatitis ("shock liver") from cardiac arrest, hypotension, or severe heart failure 1
  • Budd-Chiari syndrome (hepatic vein thrombosis) 1

• Other causes

  • Autoimmune hepatitis 1
  • Wilson's disease 1
  • Acute fatty liver of pregnancy 1
  • HELLP syndrome 1
  • Malignant infiltration (breast cancer, small cell lung cancer, lymphoma, melanoma) 1

Chronic Hepatic Insufficiency/Cirrhosis

Epidemiology

• Affects approximately 2.2 million adults in the US 4
• Annual age-adjusted mortality increased from 14.9 to 21.9 per 100,000 people between 2010 and 2021 4

Common Causes

• Alcohol use disorder (approximately 45% of all cirrhosis cases) 1, 4
• Viral hepatitis
  • Hepatitis B and C (hepatitis C accounts for 41% of cases) 1, 4
• Metabolic dysfunction-associated fatty liver disease (MAFLD) (26% of cases) 1, 4
• Genetic disorders
  • Alpha-1 antitrypsin deficiency 1
  • Hemochromatosis
  • Wilson's disease

Acute-on-Chronic Liver Failure (ACLF)

• Defined as acute decompensation of cirrhosis with one or more extrahepatic organ failures and high short-term mortality 1
• Can occur in patients with or without prior history of acute decompensation 1
• Severity classified based on number of organs failing using CLIF SOFA score 1

Clinical Manifestations of Hepatic Insufficiency

Acute Liver Failure

• Hepatic encephalopathy (from mild confusion to coma) 3
• Coagulopathy (elevated prothrombin time/INR) 2
• Jaundice 1
• Hypoglycemia 1
• Metabolic acidosis 1
• Renal dysfunction 1
• Hemodynamic instability 1

Chronic Hepatic Insufficiency/Cirrhosis

• Portal hypertension complications:
  • Ascites 1, 4
  • Variceal hemorrhage 1
  • Spontaneous bacterial peritonitis (annual incidence 11% in patients with ascites) 4
  • Hepatorenal syndrome (annual incidence 8% in patients with ascites) 4
• Hepatic encephalopathy (median survival following onset is 0.92 years) 4
• Muscle cramps (approximately 64% prevalence) 4
• Pruritus (39% prevalence) 4
• Poor-quality sleep (63% prevalence) 4
• Sexual dysfunction (53% prevalence) 4
• Hepatocellular carcinoma (develops in 1-4% of cirrhotic patients annually) 4

Diagnostic Approach

Acute Liver Failure

• Laboratory tests:

  • Liver function tests (markedly elevated transaminases) 1
  • Coagulation studies (PT/INR, factor V) 1
  • Blood glucose and arterial lactate levels 1
  • Arterial ammonia 1
  • Acetaminophen levels 1
  • Viral hepatitis serologies (IgM VHA, HBsAg, anti-HBc IgM) 1
  • Toxicology screen 1

• Imaging:

  • Hepatic Doppler ultrasound 1
  • Echocardiography 1

Chronic Hepatic Insufficiency/Cirrhosis

• Non-invasive assessment:
  • Elastography (cirrhosis typically confirmed at levels ≥15 kPa) 4
• Liver biopsy (gold standard but not always necessary) 4

Management Considerations

Acute Liver Failure

• General measures:

  • Early contact with transplant unit 1
  • Systematic administration of N-acetylcysteine regardless of suspected etiology 1
  • Empirical broad-spectrum antibiotics for signs of sepsis or worsening encephalopathy 5
  • Maintain serum sodium between 140-145 mmol/L 1
  • Monitor and correct electrolyte disturbances 1
  • Stress ulcer prophylaxis 1

• Specific treatments based on etiology:

  • Acyclovir for suspected herpes simplex virus hepatitis 1
  • Penicillin G and silymarin for mushroom poisoning 1

• Management of complications:

  • Tracheal intubation and sedation for progressive hepatic encephalopathy (Glasgow <8) 1
  • Standard lung-protective ventilation strategy 1
  • Norepinephrine for refractory hypotension 1
  • Renal replacement therapy as needed 1

Chronic Hepatic Insufficiency/Cirrhosis

• Portal hypertension management:

  • Nonselective β-blockers (carvedilol or propranolol) to reduce risk of decompensation 4

• Ascites management:

  • Combination aldosterone antagonist and loop diuretics 4

• Hepatic encephalopathy treatment:

  • Lactulose (reduces mortality and risk of recurrent overt hepatic encephalopathy) 4
  • Rifaximin (not recommended in ALF but used in chronic hepatic encephalopathy) 1, 4

• Hepatorenal syndrome:

  • Terlipressin improves rate of reversal 4

• Symptom management:

  • Hydroxyzine for sleep dysfunction 4
  • Pickle brine and taurine for muscle cramps 4
  • Tadalafil for sexual dysfunction in men 4

Important Considerations in Hepatic Insufficiency

• Medication dosing:

  • Liver dysfunction may reduce plasma clearance of drugs eliminated by biotransformation and/or biliary excretion 6
  • Reduced liver blood flow can decrease systemic clearance of high-extraction drugs 6
  • Dosage reduction necessary for many drugs in patients with chronic liver disease 6
  • Safest antibiotics include third-generation cephalosporins and piperacillin-tazobactam 5
  • Avoid or use reduced doses of rifampicin, isoniazid, and macrolides 5

• Transplantation considerations:

  • Liver transplantation recommended when spontaneous recovery appears unlikely 3
  • Approximately 7% of all liver transplants are done for ALF 3
  • One-year patient survival rates average 63% for ALF transplants 3