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Liver Cirrhosis- and Hepatitis C Virus-related Brain Disease

There are scant data on the association between liver disease and brain dysfunction in the medical literature. In 1954, Sherlock et al. [1] described the clinical features of hepatic encephalopathy (HE) associated with liver cirrhosis and portosystemic shunting.

However, new findings have been presented with regard to the neurological complications of acute liver failure, the pathophysiology of HE in cirrhotic patients, and the natural course of hepatic myelopathy (HM).

Here we present excerpts from an article authored by Karin Weissenborn and colleagues at the Hannover Medical School [10] in Hannover, Germany. Published in the October 2005 supplement of AIDS, the article presents the current knowledge on the neuropsychiatric features of acute liver failure and liver cirrhosis, and the characteristic neurological findings in HM.

In addition, the first hints of an involvement of the central nervous system in hepatitis C virus (HCV) infection are reported.

The clinical presentation of acute liver failure and hepatic encephalopathy (HE) in patients with cirrhosis differs significantly. The most serious neurological complication of acute liver failure is the development of devastating brain edema. Therefore, intracranial pressure monitoring is urgently needed in these patients.

Brain edema is amplified by hypoglycemia, hypoxia and seizures, which are also frequent complications of acute liver failure. Therefore, these parameters must also be monitored.

In contrast to acute liver failure in which cerebral dysfunction progresses rapidly, cognitive decline may be clinically undetectable for a long time in cirrhotic patients, until clinically overt symptoms such as psychomotor slowing, disorientation, confusion, extrapyramidal and cerebellar symptoms or a decrease in consciousness occur.

Clinically, overt HE is preceded by minimal alterations of cerebral function that can only be detected by neuropsychological or neurophysiological measures, but which nevertheless interfere with the patient's daily living.

Hepatic Encephalopathy in Cirrhotic Patients

HE is one of the most frequent complications of liver cirrhosis. It is assumed that approximately 60-80% of cirrhotic patients suffer from HE of various extent in the course of the disease [2]. Although cirrhotic patients do not die as a result of HE, HE is a severe prognostic sign. According to the results of a recent study [3], the survival probability after the first episode of overt encephalopathy in patients with chronic liver disease is 42% at one year of follow-up and 23% at 3 years.

The clinical features of HE in cirrhosis are manifold. In most patients, HE occurs episodically and resolves after adequate treatment, either to a normal neurological status or to minor grades of encephalopathy such as minimal or grade I HE. Some patients, however, develop chronic persistent HE, which may persist even after ammonia-lowering therapy.

Cognitive dysfunction has recently been detected in hepatitis C virus (HCV)-infected patients with normal liver function. The patients presented with severe fatigue, cognitive dysfunction and mood disorders. Alterations in brain metabolites, as detected by magnetic resonance spectroscopy, indicated central nervous system alteration in these patients.

In contrast to patients with HE, HCV-infected patients did not show motor symptoms or deficits in visual perception, but considerable deficits in attention and concentration ability.

Hepatitis C Virus Infection-associated Encephalopathy

Chronic liver disease has been associated with chronic fatigue. Patients' complaints about disabling fatigue, however, are usually not taken seriously if there is only mild liver dysfunction. Several groups recently reported that approximately two-thirds of patients with chronic hepatitis C infection suffer from mild to severe chronic fatigue even in the absence of considerable liver disease [4,5].

In addition to fatigue, musculoskeletal pain, right upper abdominal discomfort, depression, mental clouding and the perception of an inability to function effectively are frequent complaints of HCV-infected patients with normal liver function. These so-called extrahepatic manifestations of chronic HCV infection have been shown to interfere severely with the health-related quality of life [6].

Somewhat astonishing was the observation that the extent of the extrahepatic manifestations does not depend on the degree of hepatitis. Even after successful treatment of the HCV infection, disabling fatigue was present in approximately 30% of the responders [7]. Three studies have shown cognitive dysfunction in HCV-infected patients with only mild liver disease [8,9].

The corresponding finding of the studies was a selective impairment of attention and concentration in HCV-infected patients. According to the data of Forton et al. [8], the cognitive decline in patients was accompanied by a significant increase in the choline/creatine ratio within a basal ganglia voxel studied by magnetic resonance spectroscopy.

In contrast to cirrhotic patients, HCV-infected patients show no deficits with regard to motor speed and accuracy. HCV-infected patients show clear attention deficits. These, however, are less pronounced than in cirrhotic patients with HE.

There thus seems to be a difference between HE and HCV infection-associated encephalopathy, namely the presence of motor dysfunction in HE but not HCV encephalopathy, whereas in both conditions we have to deal with significant attentional deficits (unpublished data).

From the Department of Neurology, Medizinische Hochschule Hannover, Hannover, Germany.

Primary Source
K Weissenborn and others. Neurological and neuropsychiatric syndromes associated with liver disease. AIDS 19(Suppl 3): S93-S98. October 2005.

1. Sherlock S, Summerskill WHJ, White LP, Phear EA. Portal-systemic encephalopathy. Neurological complications of liver disease. Lancet 1954; I:453-457.

2 .Schomerus H, Schreiegg J. Prevalence of latent portasystemic encephalopathy in an unselected population of patients with liver cirrhosis in general practice. Z Gastroenterol 1993; 31:231-234.

3. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30:890-895.

4. Barkhuizen A, Rosen HR, Wolf S, Flora K, Benner K, Bennett RM. Muskuloskeletal pain and fatigue are associated with chronic hepatitis C. A report of 239 hepatology clinic patients. Am J Gastroenterol 1999; 94:1355-1360.

5. Poynard T, Cacoub P, Ratziu V, Myers RP, Dezailles MH, Mercadier A, et al, for the Multivirc Group. Fatigue in patients with chronic hepatitis C. J Viral Hepat 2002; 9:295-303.

6. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998; 27:209-212.

7. Cacoub P, Ratziu V, Myers RP, Ghillani P, Piette JC, Moussalli J, et al, for the Multivirc Group. Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C. J Hepatol 2002; 36:812-818.

8. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002; 35:433-439.

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