Acute liver failure pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2] Husnain Shaukat, M.D [3]

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 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 and 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 swelling. 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.

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. [1]
  • 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).[2]
  • 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

Autoimmune Hepatitis

Ischemic Injury

  • This condition is called shock liver. It is a common occurrence in the ICU with a prevalence of 10%.[4]
  • 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

Malignancy

Gross Pathology

Microscopic Pathology

[4].

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

References

  1. 1.0 1.1 Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM (2002). "Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States". Annals of Internal Medicine. 137 (12): 947–54. PMID 12484709. Retrieved 2012-10-27. Unknown parameter |month= ignored (help)
  2. Catalina MV, Núñez O, Ponferrada A, Menchén L, Matilla A, Clemente G, Bañares R (2003). "[Liver failure due to mushroom poisoning: clinical course and new treatment perspectives]". Gastroenterología Y Hepatología (in Spanish; Castilian). 26 (7): 417–20. PMID 12887855. Retrieved 2012-10-27.
  3. 3.0 3.1 Schiødt FV, Davern TJ, Shakil AO, McGuire B, Samuel G, Lee WM (2003). "Viral hepatitis-related acute liver failure". The American Journal of Gastroenterology. 98 (2): 448–53. doi:10.1111/j.1572-0241.2003.t01-1-07223.x. PMID 12591067. Retrieved 2012-10-27. Unknown parameter |month= ignored (help)
  4. Fuhrmann V, Jäger B, Zubkova A, Drolz A (2010). "Hypoxic hepatitis - epidemiology, pathophysiology and clinical management". Wiener Klinische Wochenschrift. 122 (5–6): 129–39. doi:10.1007/s00508-010-1357-6. PMID 20361374. Retrieved 2012-10-27. Unknown parameter |month= ignored (help)
  5. Woolf GM, Petrovic LM, Rojter SE, Villamil FG, Makowka L, Podesta LG, Sher LS, Memsic L, Vierling JM (1994). "Acute liver failure due to lymphoma. A diagnostic concern when considering liver transplantation". Digestive Diseases and Sciences. 39 (6): 1351–8. PMID 8200270. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)

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