Measurable Neurocognitive Impairment Persists after Episodes of Hepatic Encephalopathy in People with Liver Cirrhosis

		SUMMARY: Changes in working memory, psychomotor speed, and other neurocognitive measures persist in patients with hepatic encephalopathy due to decompensated liver cirrhosis, according to research presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. A related study presented at the Digestive Disease Week conference (DDW 2010) last week in New Orleans found that more than half of people with compensated cirrhosis (mostly due to hepatitis C) showed signs of neurocognitive impairment, indicating that mild hepatic encephalopathy is common even among individuals without severe liver disease.

By Liz Highleyman

Hepatic encephalopathy is a form of brain disease caused by the build-up of toxins such as ammonia in people whose livers are so damaged they cannot perform their normal filtering function (a condition known as decompensated cirrhosis). Over years or decades, chronic hepatitis B and C can progress to decompensated liver disease and ultimately end-stage liver failure.

Jasmohan Bajaj and colleagues from Virginia Commonwealth University designed a cross-sectional study to evaluate whether recurrent episodes of hepatic encephalopathy lead to persistent or progressive cognitive impairment.

Hepatic encephalopathy is associated with physiological changes and evidence of injury to neurons (the primary nervous system cells that carry electrical signals) and astrocytes (a type of support cell in the brain). Obvious mental status changes due to hepatic encephalopathy can usually be reversed with treatment, but some level of chronic cognitive impairment may persist, the investigators noted as background.

This analysis included 64 patients with cirrhosis who had experienced at least 1 prior episode of hepatic encephalopathy but were currently in remission due to treatment with lactulose and/or rifaximin.

A majority of participants (about 60%) were men, the average was 56 years, and the most common cause of cirrhosis was hepatitis C (78%). With regard to therapy, 53 patients were treated with lactulose only, 5 received rifaximin only, and 6 received both.

Participants underwent a battery of standard neurocognitive measurements including the number connection test, digit symbol test, block design test, and 2 inhibitory control tests. The number of hepatic encephalopathy episodes and hospitalizations, and the duration between the first hospitalization and current testing, were then correlated with psychometric tests scores.

Results

	Over an average follow-up period of 13 months, participants experienced a median of 2 episodes of hepatic encephalopathy (range 1-13).
	About half the patients were hospitalized at least once due to hepatic encephalopathy, with a median of 1 hospitalization (range 1-7).
	Psychometric test scores were "highly abnormal" in all patients.
	Worse scores on all 4 tests were strongly correlated with a greater number of hepatic encephalopathy episodes.
	Psychometric test performance and number of hospitalizations were also significantly correlated, as was the time from the first hepatic encephalopathy episode to testing.

Based on these findings, the researchers concluded that among patients with liver cirrhosis, "deficits in working memory, psychomotor speed, attention and response inhibition increase with number and severity of episodes of overt hepatic encephalopathy."

In the study presented at DDW, Christopher Randolph and a team of colleagues including Bajaj used a series of tests known as the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess hepatic encephalopathy among more than 300 people with compensated cirrhosis.

Though typically not debilitating, mild hepatic encephalopathy is associated with reduced quality of life and increased risk of negative outcomes such as job loss and motor vehicle accidents, the researchers noted. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) recommends the RBANS as the tool of choice for detecting mild encephalopathy because it has well-established population norms and correlates with impaired daily functioning and job loss.

This analysis included 301 participants screened for the ASTUTE trial, a Phase 2b study to evaluate whether AST-120 (spherical adsorbent carbon) is an effective therapy for mild hepatic encephalopathy. Again, a majority were men, the average age was 55 years, and hepatitis C was the most common cause of liver disease. About 80% were high school graduates and just over half attended college (factors known to affect neurocognitive test scores).

This group of patients was considerably healthier than those in the previous study, however. They had MELD scores < 25, had not received surgical shunts to re-route blood flow due to portal hypertension, had not had an episode of overt hepatic encephalopathy during the prior 3 months, and had not taken lactulose, rifaximin, or neomycin during the past week.

Study participants had an average RBANS score of 74, compared with 100 for the general population. Of the screened patients, 54% had a score below the tenth percentile after adjusting for age and education, thus meeting the eligibility criteria for randomization in the ASTUTE trial. The RBANS score could not be predicted on the basis of age, sex, education level, or measures of liver disease severity including platelet count, bilirubin level, MELD score, or history of esophageal varices.

"The RBANS is a very useful tool for assessing neurocognitive impairment in cirrhotic patients," the researchers concluded. Using the RBANS, we found a neurocognitive impairment rate of [54%] in a population of healthy appearing, well-compensated cirrhotics, suggesting that mild hepatic encephalopathy is highly prevalent in these patients. Mild hepatic encephalopathy was not predicted by age, education, MELD score, or indicators of portal hypertension."

EASL study: Departments of Gastroenterology, Hepatology, Nutrition, and Biostatistics, Virginia Commonwealth University, Richmond, VA; McGuire VA Medical Center, Richmond, VA.

DDW Study: Neurology, Loyola University Medical Center, Chicago, IL; McGuire VA Medical Center, Richmond, VA; University of California San Francisco Fresno Medical Education Program, Fresno, CA; Permian Research Foundation, Odessa, TX; University of Florida, Gainesville, FL; Tulane University, New Orleans, LA; Veterans Medical Center San Deigo, San Diego, CA; Case Western Reserve University, Cleveland, OH; Ocera Therapeutics, San Diego, CA.

5/11/10

References

J Bajaj, C Schubert, AJ Sanyal, and others. Severity of chronic cognitive impairment in cirrhosis increases with number of episodes of overt hepatic encephalopathy. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

C Randolph, J Bajaj, M Sheikh, and others. Mild Hepatic Encephalopathy (HE) Assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (Rbans) Is Highly Prevalent in Ambulatory Patients With Cirrhosis and Is Unrelated to Severity of Cirrhosis. Digestive Disease Week (DDW 2010). New Orleans, May 1-5, 2010. (Abstract M1272).