Hepatic encephalopathy

Characterized by neuropsychiatric changes caused by nitrogenous products and bacterial toxins released by colon bacteria that are incompletely metabolized by the damaged liver or bypass the liver because of portal hypertension and portosystemic shunting.

HE define as the symptomatic loss of normal brain function caused by hepatic insufficiency and/or portosystemic shunting.

Hospitalizations due to HE are increasing and it is a common cause for hospital readmissions and risk of mortality.

Neuropsychiatric changes include personality changes, intellectual impairment, impaired consciousness as a result of accumulation of neurotoxins with liver failure.

Classified into several grades, from minimal to overt according to symptom severity.

Patients with minimal hepatic encephalopathy and have mild cognitive impairment often clinically undetectable except through specific psychometric testing.

Patients with overt hepatic encephalopathy have clinical symptoms with pronounced degrees of cognitive impairment, behavior, personality, mood, psychomotor dysfunction, altered sleep patterns and consciousness impairment.

Ammonia is the most critical neurotoxin in its development but other toxins are involved.

Alterations in gut microbiome, inflammation, and changes in expression and activation of neural transmitters also occur.

Accounted for about 50,000 hospitalizations in 2004 (Leevy CB).

Bacteria in the colon produce ammonia that is absorbed into the blood stream and goes to the liver where it normally is detoxified, resulting in only small quantities to entering the general circulation and exposure to the brain.

With advanced hepatic disease detoxification of ammonia and other toxins are inadequate and their accumulation results in impaired brain function.

Impaired ability of the liver to detoxify toxins due to inadequate functioning liver cells and to the presence of vascular shunting around the liver which occurs with cirrhosis and other advanced liver diseases.

As liver disease progresses portosystemic shunting occurs and the liver is less able able to remove neurotoxins, resulting in increased levels of systemic gut derived neurotoxins.

Pathophysiology of HE multifactorial with accumulation of gut derived microbial toxins, inflammation, oxidative stress causing brain alterations such as cerebral edema which underlie the pathogenesis of the process.

HE is generally a reversible neurologic complication presents with a wide range of symptoms, from personality changes and lethargy to confusion disorientation and the most extreme presentation being comer.

Presents with sleep problems, euphoria, or depression and followed by disorientation, slurred speech, somnolence, inappropriate behavior, asterixis, unconsciousness, or coma.

Chronic cognitive impairment may result from prior episodes of hepatic encephalopathy.

It is estimated that 44% of patients with cirrhosis developed HE within a five year period.

Type A HE refers to HE. secondary to acute liver failure.

Type B HE refers to enteric hyperammonemia without liver disease.

Type C HE is associated with chronic liver disease.

Clinical diagnosis based on 2 symptoms: impaired mental status and impaired neuromotor function.

Clinical diagnosis based on Conn score-a scale of 0-4, with higher score reflecting more severe illness.

Neuropsychiatric alterations are reversible with therapy.

Overall poor prognosis.

Symptoms may be subtle CNS changes to coma.

Episodic HE develops over short timeframe and may fluctuate.

Chronic HE is persistent and impairs day today executive function.

Most patients with episodic disease requires hospitalization.

Advanced encephalopathy in the presence of acute liver failure is a harbinger of cerebral edema, which is rare in chronic liver disease.

Eventually occurs in up to 50% of patients with cirrhosis.

Portends a worse survival in cirrhosis compared with patients without HE, even accounting for MELD score.

HE in cirrhosis is a consideration for liver transplantation.

Treatment involves medical stabilization and possible hospitalization, limitation of precipitating factors such as dehydration and hypokalemia, and correction of glucose and electrolyte abnormalities, and reduction in systemic levels of gut derived neurotoxins.

Treatment of HE may not alter survival.

Precipitated by infection, real insufficiency, gastrointestinal hemorrhage, hypokalemia, use of sedatives, increased dietary protein, constipation, portal vein thrombosis, increasing hepatic disease, development of hepatocellular carcinoma, and recent TIPSS placement.

Nighttime insomnia common, as is reversal of day and night.

Common physical finding is asterixis a non-synchronous and coarse tremor, best demonstrated by having the patient outstretch the hands with straight elbow, wrists cocked at 90% and fingers spread.

Fetor hepaticus may be present and is a musty sweet odor that is present on the patient’s breath.

A frequent complication of a transjugular intrahepatic portosystemic shunt (TIPS).

With TIPS placement blood from the portal vein containing relatively high levels of ammonia passes through the shunt placed within the liver rather than going through the liver itself, as it normally does.

Non absorbed disaccharides and non absorbable antibiotics are mainstay of treatment.

Hepatic encephalopathy-may be associated with toxins other than ammonia such as mercaptans.

Lactulose 30-60 gm/day titrated to achieve 3-4 stools per day with a pH of less than 6 is effective in treating more than 90% of patients.

Lactulose is a non-absorbable disaccheride that decreases ammonia absorption through cathartic effects by alteration colonic pH.

Lactulose may be excessively sweet, and cause bloating, flatulence and diarrhea and limit its compliance.

Oral non absorbable antibiotics including metronidazole (Flagyl) 250 mg tid, rifaximin (Xifaxan) 400 mg 2-3 times per day, and oral vancomycin (Vancomycin) 2 gm/day can help when Lactulose is inadequate.

In severe disease oral intake should be withheld.

Dietary protein should be limited to 20-80g/day depending on individual tolerance, while avoiding negative nitrogen balance.

Dextrose infusions help decrease protein catabolism.

Develops in about 28% of cirrhotic patients within 10 years of diagnosis.

Advanced age and severity of cirrhosis are the only factors that predict for its development.

Increase in frequency and severity of episodes associated with increased risk of death.

Rifaximin at 550 mg BID over 6 months in hepatic encephalopathy maintains remission and reduces the risk of hosptilaization compared to placebo (Bass NM).

Rifaximin may improve the long-term prognosis of patients cirrhosis with increased five-year probability of remaining free of hepatic encephalopathy in patients with alcohol-related decompensated cirrhosis and ascites.

Treatment was with rifaximin and lactulose reduce hospitalization rates and improve survival.

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