- Acute liver failure
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 encephalopathyand impaired protein synthesis(as measured by the levels of serum albuminand the prothrombin timein the blood). The 1993 classification defines "hyperacute" as within 1 week, "acute" as 8-28 days and "subacute" as 4-12 weeks. [cite journal |author=O'Grady JG, Schalm SW, Williams R |title=Acute liver failure: redefining the syndromes |journal=Lancet |volume=342 |issue=8866 |pages=273–5 |year=1993 |pmid=8101303 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0140-6736(93)91818-7] It reflects the fact that the pace of disease evolution strongly influences prognosis. Underlying aetiologyis the other significant determinant of outcome.cite journal |author=O'Grady JG |title=Acute liver failure |journal=Postgraduate medical journal |volume=81 |issue=953 |pages=148–54 |year=2005 |pmid=15749789 |doi=10.1136/pgmj.2004.026005]
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 Aor B - it is extremely uncommon in hepatitis C), acute fatty liver of pregnancy, and idiopathic (without an obvious cause). Reye syndromeis acute liver failure in a child with a viral infection (e.g. chickenpox); it appears that aspirinuse 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 parenchymalinflammation is variable and is proportional to duration of disease. [cite journal |author=Boyer JL, Klatskin G |title=Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis) |journal=N. Engl. J. Med. |volume=283 |issue=20 |pages=1063–71 |year=1970 |pmid=4319402 |doi=]
Cerebral oedema and encephalopathy
cerebral oedemaleads to hepatic encephalopathy, coma, brain herniationand 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 pathogenesisremains unclear but is likely to be a consequence of several phenomena. There is a build up of toxic substances like ammonia, mercaptan, endogenous benzodiazepinesand serotonin/ tryptophanin the brain. This affects neurotransmitterlevel and neuroreceptoractivation. Autoregulation of cerebral blood flow is impaired and is associated with anaerobic glycolysisand 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. [cite journal |author=Hazell, Alan S.; Butterworth, Roger F. |title=Hepatic encephalopathy: An update of pathophysiologic mechanisms |journal=Proc. Soc. Exp. Biol. Med. |volume=222 |issue=2 |pages=99–112 |year=1999 |pmid=10564534 |doi=10.1046/j.1525-1373.1999.d01-120.x] [cite journal |author=Larsen FS, Wendon J |title=Brain edema in liver failure: basic physiologic principles and management |journal=Liver Transpl. |volume=8 |issue=11 |pages=983–9 |year=2002 |pmid=12424710 |doi=10.1053/jlts.2002.35779]
Unfortunately, signs of elevated
intracranial pressuresuch as papilloedemaand loss of pupillaryreflexes 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 possiblebenefit (1% fatal haemorrhage). [cite journal |author=Armstrong IR, Pollok A, Lee A |title=Complications of intracranial pressure monitoring in fulminant hepatic failure |journal=Lancet |volume=341 |issue=8846 |pages=690–1 |year=1993 |pmid=8095592 |doi=10.1016/0140-6736(93)90458-S] The aim is to maintain intracranial pressures below 25 mmHg, cerebral perfusion pressures above 50 mm Hg.
Coagulopathyis another cardinal feature of ALF. Liver has central role in synthesis of almost all coagulation factors and some inhibitors of coagulationand fibrinolysis. Hepatocellular necrosisleads to impaired synthesisof many coagulation factorsand their inhibitors. the former produces a prolongation in Prothrombin timewhich is widely used to monitor severity of hepaticinjury.There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopeniawith loss of larger and more active plateletis almost universal. Thrombocytopenia with or without DIC increases risk of intracerebral bleeding.
Renal failureis common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosisor from hyperdynamic circulationleading to hepatorenal syndromeor functional renal failure. Because of impaired production of urea, blood urea do 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. [cite journal |author=Schmidt LE, Larsen FS |title=Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure |journal=Crit. Care Med. |volume=34 |issue=2 |pages=337–43 |year=2006 |pmid=16424712 |doi=10.1097/01.CCM.0000194724.70031.B6] This often contributes towards multi organ failure. Impaired host defence mechanism due to impaired
opsonisation, chemotaxisand intracellular killing substantially increase risk of sepsis. Bacterial sepsis mostly due to gram positiveorganisms and fungal sepsis are observed in up to 80% and 30% patients respectively.cite journal |author=Gimson AE |title=Fulminant and late onset hepatic failure |journal=British journal of anaesthesia |volume=77 |issue=1 |pages=90–8 |year=1996 |pmid=8703634 |doi=]
Hyponatraemiais almost universal finding due to water retention and shift in intracellularsodium transport from inhibition of Na/K ATPaseFact|date=June 2008. Hypoglycaemia(due to depleted hepatic glycogenstore and hyperinsulinaemia), hypokalaemia, hypophosphataemiaand Metabolic alkalosisare often present independent of renal function. Lactic acidosisoccurs predominantly in paracetamol overdose.
Haemodynamic and cardio-respiratory compromise
Hyperdynamic circulationwith peripheral vasodilatation from low systemic vascular resistanceleads to hypotension. There is a compensatory increase in cardiac output. Adrenal insufficiencyhas been documented in 60% of ALF and is likely to contribute in haemodynamic compromise. [cite journal |author=Harry R, Auzinger G, Wendon J |title=The clinical importance of adrenal insufficiency in acute hepatic dysfunction |journal=Hepatology |volume=36 |issue=2 |pages=395–402 |year=2002 |pmid=12143048 |doi=10.1053/jhep.2002.34514] There is also abnormal oxygentransport 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. [cite journal |author=Bihari D, Gimson AE, Waterson M, Williams R |title=Tissue hypoxia during fulminant hepatic failure |journal=Crit. Care Med. |volume=13 |issue=12 |pages=1034–9 |year=1985 |pmid=3933911 |doi=10.1097/00003246-198512000-00010] Pulmonarycomplications occur in up to 50% patients. [cite journal |author=Trewby PN, Warren R, Contini S, "et al" |title=Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure |journal=Gastroenterology |volume=74 |issue=5 Pt 1 |pages=859–65 |year=1978 |pmid=346431 |doi=] Severe lung injury and hypoxemiaresult in high mortality. Most cases of severe lung injury is due to ARDSwith or without sepsis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty.
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.cite journal |author=Polson J, Lee WM |title=AASLD position paper: the management of acute liver failure |journal=Hepatology |volume=41 |issue=5 |pages=1179–97 |year=2005 |pmid=15841455 |doi=10.1002/hep.20703] Initial laboratory examination must be extensive in order to evaluate both the aetiology and severity.
;Initial laboratory analysis
Prothrombin time/ INR
Complete blood count
**Liver function test: AST, ALT,
alkaline phosphatase, GGT, total bilirubin, albumin
Creatinine, urea/ blood urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
Arterial blood gas, lactate
*Blood type and screen
Paracetamol(Acetaminophen) level, Toxicology screen
Viral hepatitisserologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV
Autoimmunemarkers: ANA, ASMA, LKMA, Immunoglobulin levels
CeruloplasminLevel ( when Wilson's disease suspected)
Ammonia(arterial if possible)
HIVstatus (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 have different management.
liver biopsydone via the transjugular route because of coagulopathyis 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.
Treatment involves admission to hospital; often
intensive care unitadmission or very close observation are required. Supportive treatment is with adequate nutrition, optimalisation of the fluid balance, mechanical ventilationand intracranial pressuremonitoring (in severe encephalopathy), and treatment aimed at removing the underlying cause (such as acetylcysteinefor 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.
Historically mortality has been unacceptably high, being in excess of 80%. [cite journal |author=Rakela J, Lange SM, Ludwig J, Baldus WP |title=Fulminant hepatitis: Mayo Clinic experience with 34 cases |journal=Mayo Clin. Proc. |volume=60 |issue=5 |pages=289–92 |year=1985 |pmid=3921780 |doi=] 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%. [cite journal |author=Ostapowicz G, Fontana RJ, Schiødt FV, "et al" |title=Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States |journal=Ann. Intern. Med. |volume=137 |issue=12 |pages=947–54 |year=2002 |pmid=12484709 |doi=]
Several prognostic scoring systems have been devised to predict mortality and to identify who will require early liver transplant. These include kings college hospital criteria, MELD score,
APACHE IIand Clichy criteria.
To date no universally accepted nomenclature has been adopted. Trey and Davidson introduced the term "fulminant hepatic failure" in 1970 to describe "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". [cite journal |author=Trey C, Davidson CS |title=The management of fulminant hepatic failure |journal=Progress in liver diseases |volume=3 |issue= |pages=282–98 |year=1970 |pmid=4908702 |doi=] 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. [cite journal |author=Bernuau J, Goudeau A, Poynard T, "et al" |title=Multivariate analysis of prognostic factors in fulminant hepatitis B |journal=Hepatology |volume=6 |issue=4 |pages=648–51 |year=1986 |pmid=3732998 |doi=10.1002/hep.1840060417] [cite journal |author=Gimson AE, O'Grady J, Ede RJ, Portmann B, Williams R |title=Late onset hepatic failure: clinical, serological and histological features |journal=Hepatology |volume=6 |issue=2 |pages=288–94 |year=1986 |pmid=3082735 |doi=10.1002/hep.1840060222] The umbrella term of "acute liver failure" was proposed by Kings college group which has been adopted in this article. Paradoxically in this classification the best prognosis is in the "hyperacute" group. [cite journal |author=Sass DA, Shakil AO |title=Fulminant hepatic failure |journal=Liver Transpl. |volume=11 |issue=6 |pages=594–605 |year=2005 |pmid=15915484 |doi=10.1002/lt.20435]
*eMedicine|ped|808|Fulminant Hepatic Failure
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