Acute liver failure
|Acute liver failure|
|Classification and external resources|
Acute liver failure from Marburg virus, a rare cause. Note hepatocellular necrosis and sinusoidal bleeding.
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days and subacute as 4–12 weeks. It reflects the fact that the pace of disease evolution strongly influences prognosis. Underlying etiology is the other significant determinant of outcome.
- 1 Definition
- 2 Signs and symptoms
- 3 Causes
- 4 Pathophysiology
- 5 Evaluation
- 6 Treatment
- 7 Prognosis
- 8 Terminology
- 9 References
- 10 External links
Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease".:1557
The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively.:1557
The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks.:1557
Signs and symptoms
Cerebral edema and encephalopathy
In ALF, cerebral oedema leads to hepatic encephalopathy, coma, brain herniation and eventually death. Detection of encephalopathy is central to the diagnosis of ALF. It may vary from subtle deficit in higher brain function (e.g. mood, concentration in grade I) to deep coma (grade IV). Patients presenting as acute and hyperacute liver failure are at greater risk of developing cerebral oedema and grade IV encephalopathy. The pathogenesis remains unclear but is likely to be a consequence of several phenomena. There is a build up of toxic substances like ammonia, mercaptan, endogenous benzodiazepines and serotonin/tryptophan in the brain. This affects neurotransmitter level and neuroreceptor activation. Autoregulation of cerebral blood flow is impaired and is associated with anaerobic glycolysis and oxidative stress. Neuronal cell astrocytes are susceptible to these changes and they swell up, resulting in increased intracranial pressure. Inflammatory mediators also play important role.
Unfortunately, signs of elevated intracranial pressure such as papilloedema and loss of pupillary reflexes are not reliable and occur late in the disease process. CT imaging of the brain is also unhelpful in detecting early cerebral oedema but is often performed to rule out intra-cerebral bleeding. Invasive intracranial pressure monitoring via subdural route is often recommended, however the risk of complications must be weighed against the possible benefit (1% fatal haemorrhage). The aim is to maintain intracranial pressures below 25 mm Hg, cerebral perfusion pressures above 50 mm Hg.
Coagulopathy is another cardinal feature of ALF. The liver has the central role in synthesis of almost all coagulation factors and some inhibitors of coagulation and fibrinolysis. Hepatocellular necrosis leads to impaired synthesis of many coagulation factors and their inhibitors. The former produces a prolongation in prothrombin time which is widely used to monitor severity of hepatic injury. There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopenia with loss of larger and more active platelet is almost universal. Thrombocytopenia with or without DIC increases risk of intracerebral bleeding.
|Condition||Prothrombin time||Partial thromboplastin time||Bleeding time||Platelet count|
|Vitamin K deficiency or warfarin||Prolonged||Normal or mildly prolonged||Unaffected||Unaffected|
|Disseminated intravascular coagulation||Prolonged||Prolonged||Prolonged||Decreased|
|Von Willebrand disease||Unaffected||Prolonged or unaffected||Prolonged||Unaffected|
|Liver failure, early||Prolonged||Unaffected||Unaffected||Unaffected|
|Liver failure, end-stage||Prolonged||Prolonged||Prolonged||Decreased|
|Factor V deficiency||Prolonged||Prolonged||Unaffected||Unaffected|
|Factor X deficiency as seen in amyloid purpura||Prolonged||Prolonged||Unaffected||Unaffected|
|Bernard-Soulier syndrome||Unaffected||Unaffected||Prolonged||Decreased or unaffected|
|Factor XII deficiency||Unaffected||Prolonged||Unaffected||Unaffected|
Renal failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional renal failure. Because of impaired production of urea, blood urea does not represent degree of renal impairment.
Inflammation and infection
About 60% of all ALF patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection. This often contributes towards multi organ failure. Impaired host defence mechanism, due to impaired opsonisation, chemotaxis and intracellular killing, substantially increases risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients, respectively.
Hyponatraemia is an almost universal finding due to water retention and a shift in intracellular sodium transport from inhibition of Na/K ATPase. Hypoglycaemia (due to depleted hepatic glycogen store and hyperinsulinaemia), hypokalaemia, hypophosphataemia and Metabolic alkalosis are often present, independent of renal function. Lactic acidosis occurs predominantly in paracetamol (also known as acetaminophen) overdose.
Haemodynamic and cardio-respiratory compromise
Hyperdynamic circulation, with peripheral vasodilatation from low systemic vascular resistance, leads to hypotension. There is a compensatory increase in cardiac output. Adrenal insufficiency has been documented in 60% of ALF cases, and is likely to contribute in haemodynamic compromise.There is also abnormal oxygen transport and utilization. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis.
Pulmonary complications occur in up to 50% of patients. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury are due to ARDS, with or without sepsis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty.
In late pregnancy liver function decreases significantly, which can be easily monitored by blood tests. Early clinical manifestations of ALF in late pregnancy include: hypodynamia, decrease in appetite, dark amber urine, deep jaundice, nausea, vomiting, and abdominal distention. Among patients whose deaths were attributed to ALF in late pregnancy, the majority had experienced vaginal deliveries.
Common causes for acute liver failure are paracetamol (acetaminophen) overdose, idiosyncratic reaction to medication (e.g. tetracycline, troglitazone), excessive alcohol intake (severe alcoholic hepatitis), viral hepatitis (hepatitis A or B — it is extremely uncommon in hepatitis C), acute fatty liver of pregnancy, and idiopathic (without an obvious cause). Reye syndrome is acute liver failure in a child with a viral infection (e.g. chickenpox); it appears that aspirin use may play a significant role. Wilson's disease (hereditary copper accumulation) may infrequently present with acute liver failure.
In the majority of acute liver failure (ALF) there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease.
Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia. Zone 2 (midzonal), although rare, is seen in yellow fever. Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure, or chloroform ingestion. In acute acetaminophen overdose, toxification occurs, mostly in Zone III which has the highest level of P450 micro-enzymes. That fact along with Zone III's decreased oxygen level helps to explain why it is preferentially one of the initial sites of damage.
All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation of mental status. If the prothrombin time is prolonged by ≈ 4–6 seconds or more (INR ≥ 1.5), and there is any evidence of altered sensorium, the diagnosis of ALF should be strongly suspected, and hospital admission is mandatory. Initial laboratory examination must be extensive in order to evaluate both the aetiology and severity.
- Initial laboratory analysis
- Prothrombin time/INR
- Complete blood count
- Arterial blood gas, lactate
- Blood type and screen
- Paracetamol (acetaminophen) level, toxicology screen
- Viral hepatitis serologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HCV
- Autoimmune markers: ANA, ASMA, LKMA, immunoglobulin levels
- Ceruloplasmin level (when Wilson's disease suspected)
- Pregnancy test (females)
- Ammonia (arterial if possible)
- HIV status (has implication for transplantation)
History taking should include careful review of possible exposures to viral infection and drugs or other toxins. From history and clinical examination, possibility of underlying chronic disease should be ruled out as it may require different management.
A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies. As the evaluation continues, several important decisions have to be made; such as whether to admit the patient to an ICU, or whether to transfer the patient to a transplant facility. Consultation with the transplant centre as early as possible is critical due to possibility of rapid progression of ALF.
|King's College Hospital criteria
for liver transplantation in acute liver failure
|Patients with paracetamol toxicity
Prothrombin time > 100 seconds or
Treatment involves admission to hospital. Often, intensive care unit admission or very close observation is required. Supportive treatment is with adequate nutrition, optimalisation of the fluid balance, mechanical ventilation and intracranial pressure monitoring (in severe encephalopathy), and treatment aimed at removing the underlying cause (such as acetylcysteine for paracetamol poisoning). Other supportive measures may include the drainage of ascites.
"Liver dialysis" (various measures to replace normal liver function) is evolving as a treatment modality, and is gradually being introduced in the care of patients with liver failure.
Historically mortality has been unacceptably high, being in excess of 80%. In recent years the advent of liver transplantation and multidisciplinary intensive care support have improved survival significantly. At present overall short term survival with transplant is more than 65%.
Several prognostic scoring systems have been devised to predict mortality and to identify who will require early liver transplant. These include King's College Hospital criteria, MELD score, APACHE II, and Clichy criteria.
To date, no universally accepted nomenclature has been adopted. Trey and Davidson introduced the phrase fulminant hepatic failure in 1970, which they described as a "...potentially reversible condition, the consequence of severe liver injury, with an onset of encephalopathy within 8 weeks of the appearance of the first symptoms and in the absence of pre-existing liver disease". Later, it was suggested that the term fulminant should be confined to patients who develop jaundice to encephalopathy within 2 weeks. Phrases subfulminant hepatic failure and late onset hepatic failure were coined for onset between 2 weeks to 3 months and for 8 weeks to 24 weeks, respectively. The umbrella phrase of acute liver failure was proposed by King's College group, which has been adopted in this article. Paradoxically, in this classification, the best prognosis is in the hyperacute group.
- O'Grady JG, Schalm SW, Williams R (1993). "Acute liver failure: redefining the syndromes". Lancet 342 (8866): 273–5. doi:10.1016/0140-6736(93)91818-7. PMID 8101303.
- O'Grady JG (2005). "Acute liver failure". Postgraduate Medical Journal 81 (953): 148–54. doi:10.1136/pgmj.2004.026005. PMC 1743234. PMID 15749789.
- Sleisenger, edited by Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt; consulting editor, Marvin H. (2009). Sleisenger & Fordtran's gastrointestinal and liver disease pathophysiology, diagnosis, management (9th ed. ed.). St. Louis, Mo.: MD Consult. ISBN 978-1-4160-6189-2.
- Sood, Gagan K. "Acute Liver Failure". Mescape. Retrieved 14 December 2011.
- Hazell, Alan S.; Butterworth, Roger F. (1999). "Hepatic encephalopathy: An update of pathophysiologic mechanisms". Proc. Soc. Exp. Biol. Med. 222 (2): 99–112. doi:10.1046/j.1525-1373.1999.d01-120.x. PMID 10564534.
- Larsen FS, Wendon J (2002). "Brain edema in liver failure: basic physiologic principles and management". Liver Transpl. 8 (11): 983–9. doi:10.1053/jlts.2002.35779. PMID 12424710.
- Armstrong IR, Pollok A, Lee A (1993). "Complications of intracranial pressure monitoring in fulminant hepatic failure". Lancet 341 (8846): 690–1. doi:10.1016/0140-6736(93)90458-S. PMID 8095592.
- Gimson AE (1996). "Fulminant and late onset hepatic failure". British journal of anaesthesia 77 (1): 90–8. doi:10.1093/bja/77.1.90. PMID 8703634.
- Schmidt LE, Larsen FS (2006). "Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure". Crit. Care Med. 34 (2): 337–43. doi:10.1097/01.CCM.0000194724.70031.B6. PMID 16424712.
- Harry R, Auzinger G, Wendon J (2002). "The clinical importance of adrenal insufficiency in acute hepatic dysfunction". Hepatology 36 (2): 395–402. doi:10.1053/jhep.2002.34514. PMID 12143048.
- Bihari D, Gimson AE, Waterson M, Williams R (1985). "Tissue hypoxia during fulminant hepatic failure". Crit. Care Med. 13 (12): 1034–9. doi:10.1097/00003246-198512000-00010. PMID 3933911.
- Trewby PN, Warren R, Contini S,et al. (1978). "Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure". Gastroenterology 74 (5 Pt 1): 859–65. PMID 346431.
- Li XM, Ma L, Yang YB, Shi ZJ, Zhou SS. (2005). "Clinical characteristics of fulminant hepatitis in pregnancy". World J Gastroenterol 11 (29): 4600–3. PMID 16052697.
- Li XM, Ma L, Yang YB, Shi ZJ, Zhou SS. (2005). "Prognostic factors of fulminant hepatitis in pregnancy". Chin Med J (Engl) 118 (20): 1754–7. PMID 16313765.
- Boyer JL, Klatskin G (1970). "Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis)". N. Engl. J. Med. 283 (20): 1063–71. doi:10.1056/NEJM197011122832001. PMID 4319402.
- Polson J, Lee WM (2005). "AASLD position paper: the management of acute liver failure". Hepatology 41 (5): 1179–97. doi:10.1002/hep.20703. PMID 15841455.
- O'Grady JG, Alexander GJ, Hayllar KM, Williams R (1989). "Early indicators of prognosis in fulminant hepatic failure". Gastroenterology 97 (2): 439–45. PMID 2490426.
- Lee WM, Hynan LS, Rossaro L, et al. (September 2009). "Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure". Gastroenterology 137 (3): 856–64, 864.e1. doi:10.1053/j.gastro.2009.06.006. PMID 19524577.
- Rakela J, Lange SM, Ludwig J, Baldus WP (1985). "Fulminant hepatitis: Mayo Clinic experience with 34 cases". Mayo Clin. Proc. 60 (5): 289–92. PMID 3921780.
- Ostapowicz G, Fontana RJ, Schiødt FV, et al. (2002). "Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States". Ann. Intern. Med. 137 (12): 947–54. PMID 12484709.
- Trey C, Davidson CS (1970). "The management of fulminant hepatic failure". Progress in liver diseases 3: 282–98. PMID 4908702.
- Bernuau J, Goudeau A, Poynard T, et al. (1986). "Multivariate analysis of prognostic factors in fulminant hepatitis B". Hepatology 6 (4): 648–51. doi:10.1002/hep.1840060417. PMID 3732998.
- Gimson AE, O'Grady J, Ede RJ, Portmann B, Williams R (1986). "Late onset hepatic failure: clinical, serological and histological features". Hepatology 6 (2): 288–94. doi:10.1002/hep.1840060222. PMID 3082735.
- Sass DA, Shakil AO (2005). "Fulminant hepatic failure". Liver Transpl. 11 (6): 594–605. doi:10.1002/lt.20435. PMID 15915484.