Hepatic failure is when the liver loses the ability to regenerate or repair, so that decompensation occurs.
It is marked by:

• Encephalopathy
• Haemorrhagic diathesis
• Ascites
• Jaundice

Classification

• Fulminant hepatic failure (FHF) is when the failure occurs within eight weeks of the onset of the underlying illness.
• Late onset hepatic failure (also called subacute FHF) is when there has been a gap of 8 to 26 weeks. The difference may not immediately be obvious, as the underlying disease may have been present for a long time but undiagnosed.
• Chronic decompensated hepatic failure is when the latent period is over six months.

Epidemiology

• There is no predilection for gender.
• In the UK, over 600 liver transplants a year are performed but that figure is said to be low compared with the rest of Europe.¹ 60 people a year die waiting.

Aetiology

There are many causes of hepatic failure and the following represent just a few.

Toxins

• Chronic alcohol abuse.
• Paracetamol overdose. This can occur at a lower level than expected in chronic alcohol users
• Drug toxicity associated with co-amoxiclav, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, halothane, statins, cyclophosphamide, methotrexate, disulfiram, flutamide, gold and propylthiouracil.² NB: list is NOT comprehensive
• Poisoning by various substances, including mushrooms or chemicals containing carbon tetrachloride and other organic solvents and phosphorus
• Herbal remedies including ginseng, pennyroyal oil, Teucrium polium, chaparral or germander tea³
• Illicit drugs including ecstasy and cocaine
• Reye's syndrome

Infections

• Viral hepatitis, particularly if one strain is accompanied by co-infection with hepatitis B. Hepatitis D requires pre-existing hepatitis B to permit infection.
  Hepatitis E is similar to Hepatitis A in that it occurs mainly by contamination of food and water. It is common in India, Asia, Africa, the Middle East and Central America. It may cause acute hepatitis but not normally severe, long-term disease. The exception is in pregnancy when it may cause miscarriage at any stage and, if caught in the last trimester, is fatal in 20% of cases.
• Adenovirus, Epstein-Barr virus, cytomegalovirus and viral haemorrhagic fevers

Neoplastic

• Hepatocellular carcinoma or metastatic carcinoma

Metabolic

• Wilson's disease
• Others, e.g. alpha-1-antitrypsin deficiency, fructose intolerance, galactosaemia and tyrosinaemia

Pregnancy-related

• Acute fatty liver of pregnancy - about half develop severe pre-eclampsia

Vascular

• Ischaemia or veno-occlusive disease
• Budd-Chiari syndrome

Others

• Autoimmune liver disease
• Unknown cause - 15%

History

Mental faculties may be so impaired that history from someone close may be required. There may be hallucinations. Haematemesis or melaena may complicate gastrointestinal bleeding.

Ask about:

• Date of onset of jaundice and encephalopathy
• Alcohol use
• Medication including prescription medicines, illicit drugs and alternative medicines
• Family history of liver disease (Wilson's disease or haemochromatosis)
• Exposure risk factors for viral hepatitis (travel, transfusions, sexual contacts, occupation, body piercing)
• Toxin ingestion (mushrooms, organic solvents, phosphorus contained in fireworks)
• Past medical history

Examination

• Mental state shows drowsiness and possibly confusion
• Jaundice
• Hyperdynamic circulation with multiple organ failure may mimic septic shock
• Abdominal distension and abdominal masses, including:
  • Possible massive ascites and anasarca due to fluid redistribution and hypoalbuminaemia
  • A dehydrated patient may not show much ascites
  • Hepatomegaly and splenomegaly but not invariably
• Cerebral oedema with increased intracranial pressure (ICP), may produce papilloedema, hypertension, and bradycardia
• Liver palms are red and an hepatic flap, also called asterixis, may be present
  • Hyperextend the fingers and wrist, gently pushing back and a slow clonic movement is the liver flap

Differential diagnosis

• Structural lesions or space-occupying lesions in the brain
• Cerebral infection, bacterial or viral
• Drug or alcohol intoxication
• Delirium tremens or Wernicke's encephalopathy
• Metabolic upset such as hypoglycaemia, ketoacidosis, electrolyte imbalance, hypoxia, hypercapnia

Investigations

Blood

• FBC may show thrombocytopenia.
• INR will be raised. Although these are sensitive tests they may indicate other causes, such as vitamin K deficiency or disseminated intravascular coagulation.
• Transaminases are very markedly raised but alkaline phosphatase may be slightly high or normal.
• Bilirubin is raised.
• Pseudocholinesterase is low.
• Ammonia levels are high. This should preferably be estimated on arterial blood.
• Glucose can be dangerously low and must be monitored.
• There may be elevated lactate, hypoxia and raised creatinine, especially if there is hepatorenal syndrome or acute renal failure.
• Blood cultures. They are very susceptible to infection.
• Viral serology may indicate the infection that precipitated the hepatic failure.
• Tests for specific conditions include free copper for Wilson's disease and paracetamol levels in case of poisoning.

Imaging

• Doppler ultrasound may establish whether or not the hepatic vein is patent (Budd-Chiari syndrome) as well as looking for primary or secondary carcinoma and checking for ascites.
• CT or MRI scanning may demonstrate the hepatic anatomy and can exclude other pathology, particularly if there are massive ascites, obesity, or transplantation is considered. Avoid contrast in case it damages the kidneys.
• Imaging of the head may demonstrate cerebral oedema.
• EEG may help define level of encephalopathy.
• Liver biopsy should be avoided with compromised coagulation, although a transjugular approach is sometimes used.

Management

Early recognition of the diagnosis and transfer to a specialist unit is required. The possibility of liver transplant should be considered at an early stage.⁴

• Poisoning with drugs such as paracetamol or mushrooms may require specific interventions.
• Lactulose, often with neomycin, is given to reduce ammonia production.
• Protein restriction may not be as important as is traditionally taught.⁵
• Mannitol may reduce intracranial pressure. Try to avoid sedatives, as they make assessment difficult. Intracranial pressure monitoring is sometimes required.
• Cerebral oedema often leads to brain herniation and death. A possible treatment that is being assessed is hypothermia.⁶
• Renal failure may require haemodialysis or continuous arteriovenous haemofiltration, as the former can drop blood pressure to a dangerous level.
• Coagulation deficits require fresh frozen plasma and platelets, often in large amounts.⁷
• Monitor glucose and other biochemical parameters. Large amounts of IV glucose may be required.
• Liver transplantation may be life-saving if a graft becomes available.⁸ Various artificial liver devices have been developed and they may bridge the gap until transplant or spontaneous recovery.⁹ They include a bio-artificial liver.¹⁰

Complications

• Infection is a great problem. Spontaneous peritonitis is common as is infection of one of the access lines. Opportunistic infection and pneumonia may occur.
• Cerebral oedema may require intervention including intubation to permit hyperventilation to lower ICP.¹¹
• Haemorrhage can be a considerable problem. Oesophageal varices may require attention. If large transfusion requirements exceed apparent blood loss consider retroperitoneal haemorrhage.
• The major complications that cause death, even after transplantation are bleeding, sepsis, cerebral oedema, renal failure, and respiratory failure.¹²

Prognosis

Prognosis depends on the cause of the hepatic failure:

• Hepatitis A has a good prognosis with a 50% to 60% survival rate. It accounts for around 20% of paediatric liver transplants.
• Features indicating poor prognosis include arterial pH under 7.3, prothrombin time above 100 seconds, bilirubin above 300μmol/L, more than 7 days' jaundice before encephalopathy and age under 11 or over 40.¹²
• When Wilson's disease presents as FHF it is almost invariably fatal unless transplantation can be performed.
• In the USA in 1995 it was reported that 7% of all liver transplants were for FHF and that the survival rate at one year was 63% compared with 78% for non-fulminant hepatic disease.¹³
• Figures from England suggest a 75% survival rate at one year compared with a 90% mortality rate for liver failure without transplantation.¹⁴
• When comparing figures for survival, it is important to compare like with like in terms of case mix. It seems that three and twelve months' survival rates are similar,¹⁵ suggesting that most deaths occur in the first three months.

Document references

1. NHS. Blood and Transplant. Transplant activity in the UK.
2. Chang CY, Schiano TD; Review article: drug hepatotoxicity. Aliment Pharmacol Ther. 2007 May 15;25(10):1135-51. [abstract]
3. Stickel F, Seitz HK, Hahn EG, et al; Liver toxicity of drugs of plant origin. Z Gastroenterol. 2001 Mar;39(3):225-32, 234-7. [abstract]
4. Hirschfield GM, Gibbs P, Griffiths WJ; Adult liver transplantation: what non-specialists need to know. BMJ. 2009 May 22;338:b1670. doi: 10.1136/bmj.b1670.
5. Shawcross D, Jalan R; Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005 Jan 29-Feb 4;365(9457):431-3. [abstract]
6. Jalan R, Rose C; Hypothermia in acute liver failure. Metab Brain Dis. 2004 Dec;19(3-4):215-21. [abstract]
7. Pereira SP, Langley PG, Williams R; The management of abnormalities of hemostasis in acute liver failure. Semin Liver Dis. 1996 Nov;16(4):403-14. [abstract]
8. Lidofsky SD; Liver transplantation for fulminant hepatic failure. Gastroenterol Clin North Am. 1993 Jun;22(2):257-69. [abstract]
9. Hughes RD, Williams R; Use of bioartificial and artificial liver support devices. Semin Liver Dis. 1996 Nov;16(4):435-44. [abstract]
10. Demetriou AA, Brown RS Jr, Busuttil RW, et al; Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg. 2004 May;239(5):660-7; discussion 667-70. [abstract]
11. Lidofsky SD, Bass NM, Prager MC, et al; Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology. 1992 Jul;16(1):1-7. [abstract]
12. O'Grady JG, Alexander GJ, Hayllar KM, et al; Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. [abstract]
13. Hoofnagle JH, Carithers RL Jr, Shapiro C, et al; Fulminant hepatic failure: summary of a workshop. Hepatology. 1995 Jan;21(1):240-52. [abstract]
14. Bernal W, Wendon J; Acute liver failure; clinical features and management. Eur J Gastroenterol Hepatol. 1999 Sep;11(9):977-84. [abstract]
15. Burroughs AK, Sabin CA, Rolles K, et al; 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome. Lancet. 2006 Jan 21;367(9506):225-32. [abstract]

Internet and further reading

• British Liver Trust
• Sood GK; Acute Liver Failure; emedicine June 2009
• Liver disease. Consultant hepatologist Mark Wright on the questions to ask and how not drinking alcohol can help. A short video from NHS Choices. (October 2007)

Acknowledgements