| Acute liver failure | |
|---|---|
| Classification and external resources | |
Acute liver failure from Marburg virus, a rare cause. Note hepatocellular necrosis and sinusoidal bleeding |
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| ICD-10 | K72 |
| ICD-9 | 570 |
| eMedicine | med/990 |
| MeSH | D017114 |
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.[1] It reflects the fact that the pace of disease evolution strongly influences prognosis. Underlying etiology is the other significant determinant of outcome.[2]
Contents |
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".[3]: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.[3]: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.[4] 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.[3]:1557
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.[5][6]
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. Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause necrosis on zone 3.
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.[2][7][8]
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).[9] The aim is to maintain intracranial pressures below 25 mmHg, cerebral perfusion pressures above 50 mm Hg.[2]
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.[6]
| 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 | prolonged | unaffected |
| Hemophilia | unaffected | prolonged | unaffected | unaffected |
| Aspirin | unaffected | unaffected | prolonged | unaffected |
| Thrombocytopenia | unaffected | unaffected | prolonged | decreased |
| Liver failure, early | prolonged | unaffected | unaffected | unaffected |
| Liver failure, end-stage | prolonged | prolonged | prolonged | decreased |
| Uremia | unaffected | unaffected | prolonged | unaffected |
| Congenital afibrinogenemia | prolonged | prolonged | prolonged | unaffected |
| Factor V deficiency | prolonged | prolonged | unaffected | unaffected |
| Factor X deficiency as seen in amyloid purpura | prolonged | prolonged | unaffected | unaffected |
| Glanzmann's thrombasthenia | unaffected | unaffected | prolonged | unaffected |
| Bernard-Soulier syndrome | unaffected | unaffected | prolonged | decreased or 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.
About 60% of all ALF patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection.[10] 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.[6]
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.
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.[11] 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.[12]
Pulmonary complications occur in up to 50% of patients.[13] 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.[14] Among patients whose deaths were attributed to ALF in late pregnancy, the majority had experienced vaginal deliveries.[15]
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.[16] Initial laboratory examination must be extensive in order to evaluate both the aetiology and severity.
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[17] |
| Patients with paracetamol toxicity pH <7.3 or |
| Other patients 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.
While many people who develop acute liver failure recover with supportive treatment, liver transplantation is often required in people who continue to deteriorate or have adverse prognostic factors.
"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.
Intravenous N-acetylcysteine has been found to be beneficial in both acetaminophen toxicity and non-acetaminophen-related acute liver failure.[18]
Historically mortality has been unacceptably high, being in excess of 80%.[19] 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%.[20]
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 term 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".[21] Later, it was suggested that the term fulminant should be confined to patients who develop jaundice to encephalopathy within 2 weeks. Terms 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.[22][23] The umbrella term 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.[24]
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