Acute liver failure pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [3] Husnain Shaukat, M.D [4]

Overview

Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without a preexisting liver disease. The consequences of acute liver failure are due to the loss of its metabolic, secretory and regulatory effects. This results in the accumulation of toxic substances and causes deleterious effects. The major pathophysiological mechanisms of morbidity and mortality in patients with acute liver failure are cerebral edema, hypoperfusion to the liver, idiosyncratic drug reactions, depletion of glutathione and viral hepatitis. Cerebral edema in acute liver failure can be due to vasogenic and cytotoxic effects. In cytotoxic type, there is intracellular swelling but blood-brain barrier is intact. In vasogenic type, the blood-brain barrier breaks down and plasma and water accumulate in the extracellular space. The increased ammonia concentration in liver failure in combination with the glutamine produced by the astrocytes causes excess levels of glutamine with the help of enzyme glutamine synthetase. The excess glutamine is cytotoxic and may influence the osmotic gradient which could result in brain edema. In acute liver failure, the increased levels of nitric oxide in the circulation can also disrupt the cerebral autoregulation. Acetaminophen is the leading cause of acute liver failure in the United States. Acetaminophen causes dose-related toxicity. Toxicity is rarely seen at normal therapeutic doses (up to 4 g/day) without underlying liver disease. Viral hepatitis is the leading cause of acute liver failure in the developing world. Hepatitis A, B, D (associated with B), and E (in endemic countries) are commonly associated with acute liver failure.

Pathophysiology

Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without preexisting liver disease.

• The effects of acute liver failure are due to the loss of its metabolic, secretory and regulatory effects. This results in the accumulation of toxic substances and causes deleterious effects.
• The major pathophysiological mechanisms of morbidity and mortality in patients with acute liver failure are cerebral edema, hypoperfusion to the liver, idiosyncratic drug reactions, depletion of glutathione, and viral hepatitis.
• Cerebral edema in acute liver failure can be due to vasogenic and cytotoxic effects.
• In cytotoxic type, there is intracellular swelling but blood-brain barrier is intact.
• In vasogenic type, the blood-brain barrier breaks down and plasma and water accumulate in the extracellular space.
• The increased ammonia concentration in liver failure in combination with the glutamine produced by the astrocytes causes excess levels of glutamine with the help of enzyme glutamine synthetase. The excess glutamine is cytotoxic and can disturb the osmotic gradient which can result in brain edema.
• In acute liver failure, the increased levels of nitric oxide in the circulation can also disrupt the cerebral autoregulation.

Specific Conditions

Acetaminophen Toxicity

• Acetaminophen is the leading cause of acute liver failure in the United States.
• Acetaminophen causes dose-related toxicity.
• Toxicity is rarely seen at normal therapeutic doses (up to 4 g/day) without underlying liver disease.
• Acetaminophen is mainly metabolized (90 %) in the liver and its metabolic end products (sulfate and glucuronide conjugates) are then excreted in the urine.
• Remaining one half unmetabolized acetaminophen is excreted unchanged in the urine and rest is metabolized by cytochrome P450 pathway to N-acetyl-p-benzoquinoneimine (NAPQI).
• NAPQI is hepatotoxic and converted to nontoxic cysteine and mercaptan compounds by hepatic glutathione which are then excreted in the urine.
• At toxic doses, the sulfate and glucuronide conjugation pathway are overwhelmed and led to increased acetaminophen to be metabolized by cytochrome P450.
• At toxic doses, the glutathione stores are depleted and it led to excess unattended NAPQI which causes hepatotoxicity.

Other Drugs

• Drugs other than acetaminophen also cause acute liver failure.
• These constitute 13% of cases of acute liver failure in US.
• They cause idiosyncratic drug hepatotoxicity.
• They usually present within six months of drug initiation.

Mushroom Poisoning

• This is mainly caused by the genus Amanita (Amanita phalloides).
• Presentations may vary from case to case and it constitutes a medical emergency.
• Patients may recover from traditional medical treatment, or may require transplantation in more severe cases.

Viral Hepatitis

• Hepatitis A, B, D (associated with B), and E (in endemic countries) can cause acute liver failure in the developing world.
• Viral hepatitis (Hepatitis A and B) constitute to causing 12% of the cases of acute liver failure in US.
• Hepatitis C alone doesn't seem to cause acute liver failure.
• There is a difference in the survival rate of patients with acute liver failure in hepatitis A and hepatitis B. This may be an inherent feature of infections and does not depend on the severity of dysfunction.

Autoimmune Hepatitis

• Autoimmune hepatitis may be an unrecognized coexistent condition.
• Autoantibodies are helpful in the diagnosis of the condition. In cases of a negative test for autoantibodies, biopsy may be required.
• A few patients may need transplantation along with steroid therapy.

Ischemic Injury

• This condition is called shock liver. It is a common occurrence in the ICU with a prevalence of 10%.
• Shock liver results from severe hypotension due to any causes such as heart failure or vasoconstictive drugs.
• Early recovery frequently occurs, but the long term outcome depends on the underlying cause of the ischemia.

HELLP Syndrome

• Some women near the end of their pregnancy may develop rapidly progressive liver failure.
• HELLP syndrome conisists of the triad of hemolysis, elevated liver enzymes and low platelets.
• Most of the patients will improve spontaneously with delivery.
• Postpartum deterioration may require liver transplantation.

Malignancy

• Malignant infiltration may cause acute liver failure.
• Severe acute infiltrations may occur with a few malignancies like breast cancer, small cell lung cancer, lymphoma, melanoma, and myeloma.
• Transplantation is not advised in these patients.

Gross Pathology

On gross pathology, characteristic findings of acute liver failure include:

Microscopic Pathology

On microscopic pathology, characteristic findings of acute liver failure include:

Drug induced hepatitis
Soource:By Nephron (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

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