Acute liver failure

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Acute liver failure
ICD-10	K72.9
MeSH	D017114

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2], Prashanth Saddala M.B.B.S

Overview

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).

Historical perspective

• 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".
• 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.
• 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.

Classification

1) The 1993 classification defines It reflects the fact that the pace of disease evolution strongly influence prognosis. Underlying aetiology is the other significant determinant of outcome.

• Hyperacute as within 1 week,
• Acute as 8-28 days and
• Subacute as 4-12 weeks

2) Acute liver failure may be fulminant or subfulminant. Both the forms have poor prognosis

• Fulminant hepatic failure - Development of hepatic encephalopathy within 2 months after the onset of acute liver disease.
• Subfulminant hepatic failure - Development of hepatic encephalopathy within 2 months to 6 months after the onset of acute liver disease

Pathophysiology

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.

Causes

Common causes for acute liver failure are:

• Paracetamol (acetaminophen) overdose is the commonest cause. The commonest causes for paracetamol poisoning is suicidal intent. Additionally, the toxic threshold dose of paracetamol decreases in some cases like chronic alcoholics, diabetics, and fasting.
• Idiosyncratic reaction to medication is the second commonest cause. Common culprit drugs are: tetracycline, troglitazone, antituberculosis drugs, and anti-epileptic drugs
• Excessive alcohol intake (severe alcoholic hepatitis)
• Viral hepatitis (hepatitis A or B - it is extremely uncommon in hepatitis C). The incidences of acute liver failure post viral hepatitis has decreased due to the extensive vaccination against these infections.
• Autoimmune hepatitis
• Acute fatty liver of pregnancy
• 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
• Idiopathic (without an obvious cause)
• Diseases of fatty acid oxidation pathways
• Parvovirus B19 infection
• Budd–Chiari syndrome
• Malignancy (lymphomas)
• Shock
• Hyperthermia
• Hypothermia

Differential Diagnosis

• Acute fatty liver of pregnancy
• Autoimmune chronic active hepatitis
• Budd-Chiari Syndrome
• Cytomegalovirus
• Drugs
• Epstein-Barr Virus
• Heatstroke
• Hepatic arterial occlusion or Hepatic venous occlusion
• Hepatitis A - Hepatitis G
• Herpes simplex 1, 2
• Hypotension
• Hypothermia
• Massive malignant infiltration of the liver
• Parainfluenza virus
• Paramyxovirus
• Primary graft nonfunction post liver transplantation
• Reye's Syndrome
• Sepsis
• Shock
• Wilson's Disease

Natural history,Complications and Prognosis

Complications

Cerebral oedema 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 defecit 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 phenomenon. 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 mmHg, cerebral perfusion pressures above 50 mm Hg.

Coagulopathy

Coagulopathy is another cardinal feature of ALF. Liver has 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.

Renal failure

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 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. This often contributes towards multi organ failure. Impaired host defence mechanism due to impaired opsonisation, chemotaxis and intracellular killing substantially increase risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients respectively.

Metabolic derangements

Hyponatraemia is almost universal finding due to water retention and 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 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 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% patients. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury is due to ARDS with or withoutsepsis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty.

Prognosis

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 kings college hospital criteria, MELD score, APACHE II and Clichy criteria.

Diagnosis

History and Symptoms

History taking should include careful review of possible exposures to viral infection and drugs or other toxins.

Physical Examination

From history and clinical examination possibility of underlying chronic disease should be ruled out as it may have different management.

Laboratory tests

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
• Chemistries
  • Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin
  • Creatinine, urea/blood urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
  • glucose
  • Amylase and lipase
• Arterial blood gas, lactate
• Blood type and screen
• Paracetamol (Acetaminophen) level, Toxicology screen
• Viral hepatitis serologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV
• 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)

Liver Biopsy

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.

Treatment

King's College Hospital criteria for liver transplantation in acute liver failure

Patients with paracetamol toxicity pH <7.3 or Prothrombin time >100 seconds and serum creatinine level >3.4 mg/dL (>300 μmol/l) if in grade III or IV encephalopathy

Other patients Prothrombin time >100 seconds or Three of the following variables: Age <10 yr or >40 yr Cause: non-A, non-B hepatitis halothane hepatitis idiosyncratic drug reaction Duration of jaundice before encephalopathy >7 days prothrombin time >50 seconds Serum bilirubin level >17.6 mg/dL (>300 μmol/l)

Aim of therapy is to correct

• Metabolic abnormalities
• Coagulation defects
• Electrolyte and acid-base disturbances
• Advanced chronic kidney disease
• Hypoglycemia
• Encephalopathy

Treatment strategies

General measures

• Treatment involves admission to hospital; often intensive care unit admission or very close observation are required.
• Supportive treatment with adequate nutrition and, optimization of the fluid balance should be done
• Mechanical ventilation, intubation is indicated for stage 3 or 4 encephalopathy
• Sepsis and infections are common with fulminant liver failure. Though prophylactic antibiotic decreases the risk of infection, but is not routinely recommended as no survival benefits have been proved. Nevertheless, broad coverage with antibiotics is recommended for suspected cases of sepsis.
• Routine administration of steroids for adrenal insufficiency is not recommended.
• H2 receptor blocker and proton pump inhibitors are indicated to prevent and treat stress gastropathy.
• Early transfer to a liver transplantation center should be decided based on patient's clinical status.

Management of increased intracranial pressure

• Intracranial pressure monitoring in severe encephalopathy and impending cerebral edema should be done with extradural sensors

• The goal should be to maintain the intracranial pressure below 20 mm Hg and the cerebral perfusion pressure above 70 mm Hg.
• Lactulose is indicated in cases of encephalopathy.
• Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by intravenous infusion over 10 minutes for reducing cerebral edema
• Mannitol should be avoided in patients with advanced chronic kidney diseases.
• Hypernatremia (145-155 mEq/L) through intravenous hypertonic saline infusion to induce hypernatremia may be used to reduce intracranial hypertension.
• Hypothermia (32–34 °C) may reduce intracranial pressure in refractory cases can be tried.
• Other measures like elevation of head end to 30 degrees, hyperventilation and intravenous prostaglandin E1can also be used.
• Short-acting barbiturate, propofol, or i/v indomethacin for refractory intracranial hypertension.

Treatment for specific underlying cause

Acetaminophen or Paracetamol poisoning

• • Acetylcysteine for paracetamol poisoning up to 72 hours after ingestion
  • It improves cerebral blood flow and increases transplant-free survival in patients with stage 1 or 2 encephalopathy due to hepatic failure of any cause.
  • Its treatment can increase prothrombin time giving a false alarm of worsening liver failure.
    • 140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses or
    • 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours

Mushroom poisoning

• Penicillin G - 300,000 to 1 million units/kg/day or
• Silibinin/silymarin/milk thistle (not licensed in the United States)

Chronic viral hepatitis

• Nucleoside analogs - Fulminant hepatitis B

Herpes simplex hepatitis

• Intravenous acyclovir

Wilson disease

• Plasmapheresis + D-penicillamine

Other supportive measures

• 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.

References

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