Translational research in hepatic encephalopathy: New diagnostic possibilities and new therapeutic approaches

Abstract

Chronic liver disease (e.g. cirrhosis) affects brain function. There is a high incidence of mild cognitive impairment and psychomotor slowing in patients with cirrhosis. This condition, known as minimal hepatic encephalopathy (MHE) affects more than 2 million people in the European Union and has serious health, social and economic consequences. There are no effective treatments for MHE.

Rat models of MHE reproduce cognitive and motor alterations seen in patients, showing reduced performance in different types of cognitive tests, including learning a conditional discrimination task in a Y maze.

Reduced ability to learn the Y maze task is due to reduced function of the glutamate–nitric oxide (NO)–cGMP pathway in cerebellum, assessed in vivo by microdialysis. This results in reduced formation of cGMP in response to activation of NMDA receptors and impairment of learning ability.

Both hyperammonemia and neuroinflammation contribute to impair this pathway. The effect is mediated by enhanced tonic activation of NMDA and GABA_A receptors and of MAP-kinase p38.

Based on these mechanistic studies new therapeutic strategies acting on specific targets in the brain have been designed and tested, which have successfully restored the function of the glutamate-NO-cGMP pathway in vivo and learning ability in rats with MHE. This can be achieved by therapeutic treatments using:

• a)

  phosphodiesterase 5 inhibitors (sildenafil, zaprinast), that increase cGMP levels by reducing its degradation

• b)

  extracellular cGMP

• c)

  antagonists of type A GABA receptors (bicuculline)

• d)

  neurosteroids that modulate GABAergic tone (pregnenolone sulfate)

• e)

  inhibitors of cyclooxygenase (ibuprofen) which reduce neuroinflammation

• f)

  inhibitors of MAP- kinase p38 (SB239063), that reduce microglial activation and neuroinflammation

Translation of some of these treatments to clinical practice would improve cognitive function, quality of life and life span of patients with cirrhosis and MHE and reduce health systems costs.

Focal points

• •

  Benchside

  The mechanisms underlying cognitive and motor alterations in minimal hepatic encephalopathy (MHE) are beginning to be clarified in animal models. A number of therapeutic targets have been identified to improve cognitive and motor function in MHE. Also, serum level of 3-nitrotyrosine is the first peripheral biomarker identified for diagnosis of MHE in cirrhotic patients, with high diagnostic accuracy, high sensitivity and specificity.

• •

  Bedside

  In the European Union more than 2 million patients with liver cirrhosis show MHE with mild cognitive impairment. MHE is an important, until now underestimated, health, social and economic problem. Early diagnosis and treatment of MHE will significantly improve quality of life and life span of the patients and reduce costs of hospitalization and treatment

• •

  Industry

  There are no specific treatments for the neurological alterations in MHE. A number of therapeutic targets have been identified in animal models to improve cognitive and motor function in MHE. This is a new market waiting for development of appropriate therapeutic treatments which would improve quality of life and survival of patients. Development of a kit for diagnosis of MHE in clinical practice is pending.

• •

  Governments – regulatory agencies

  Early diagnosis and treatment of MHE will significantly improve quality of life and life span of the patients and reduce costs of hospitalization and treatment. Screening of the presence of MHE in patients with liver diseases will reduce costs.