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Hepatic encephalopathy is a complication of cirrhosis of the liver and its resultant portal hypertension, toxic substances accumulate in the blood and impair the function of brain cells. Signs can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness.
Pathogenesis
Cirrhosis will obstruct the passage of blood through the liver causing portal hypertension. This means it is difficult for blood from the intestines to go through the liver to get back to the heart. Portal-systemic anastamoses ("shunts") develop, and portal blood (from the intestinal veins) will bypass the liver and return to the heart via another route without undergoing first-pass detoxification by the liver. Furthermore, the liver (damaged from the cirrhosis) will not be functioning as well as it should be, so blood that does travel through the liver may not be as detoxified as it otherwise would be.
The toxic substances involved are not well understood, but have been thought to include ammonia (NH3) and mercaptans. Ammonia is normally converted to urea by the liver and, as with mercaptans, is produced by the bacterial breakdown of protein in the intestines.
Ammonia can cross the blood-brain barrier, where it causes the support cells of the brain (astrocytes) to swell. The swelling of the brain tissue increases intracranial pressure, and can lead to coma or death via herniation of the brainstem.
Grading
In the World Congress of Gastroenterology 1998 in Vienna, a proposed classification of hepatic encephalopathy was presented to standardize the subclasses. According to this classification, hepatic encephalopathy is subdivided in type A, B and C. Type A (=acute) describes hepatic encephalopathy associated with acute liver failure; type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease; and type C (=cirrhosis) occurs in patients with cirrhosis Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35: 716-21..
In addition, the duration and characteristics of hepatic encephalopathy were classified into episodic, persistent and minimal. The term minimal encephalopathy is defined by patients with cirrhosis who do not demonstrate clinically overt cognitive dysfunction, but who show a cognitive impairment on neuropsychological studies.
The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; 72: 573-83..
- Grade 1 - Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition
- Grade 2 - Lethargy or apathy; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction
- Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; Confusion; Gross disorientation
- Grade 4 - Coma (unresponsive to verbal or noxious stimuli)
Treatment
It is important to remove excess protein from the lumen of the gut. If there is a gastrointestinal bleed (for instance, ruptured oesophageal varices) this should be stopped, as it serves as a protein supply for bacteria. Dietary intake of protein should be minimised. Special enteral feeding formulations with a high concentration of branched-chain amino acids are sometimes used in therapy, as is parenteral nutrition.
Lactulose is a compound that will cause osmotic diarrhoea, lessening the time bacteria have to metabolise proteins and produce toxic substances. As well as this, it acidifies the bowel, causing ammonia (NH3) to be converted to ammonium (NH4+) which is less readily absorbed. Recent evidence suggests there is little evidence for its use, although it continues to be used in clinical practise. (Als-Nielsen et al 2004).
Antibiotics (such as metronidazole) may be given to kill bacteria present in the gut. Neomycin, a non-absorbable aminoglycoside, is becoming less popular as it has been found that part of it was indeed absorbed due to increased gut permeability, increasing the risk of renal failure and hearing loss.
Notes and reference
- Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev. 2004;(2):CD003044. PMID 15106187
"Hepatic encephalopathy"