Hepatic Encephalopathy

The diagnosis and management of hepatic encephalopathy (HE), a common neuropsychiatric disorder that occurs in patients with acute liver failure and advanced chronic liver disease, represents a significant challenge for clinicians. HE manifests as a wide spectrum of neuropsychiatric abnormalities and motor disturbances that are associated with varying degrees of disability and poor quality of life. Depending on the stage of the disease, the neurologic impairments associated with HE can range from subtle alteration in cognitive ability detectable only by specialized psychometric testing to overt motor dysfunction and impaired consciousness that can progress to coma and death if left untreated. The precise mechanism for the pathogenesis of HE remains unclear. Evidence from animal models and clinical studies supports a central role for ammonia. Advances in neuroimaging clearly indicate that the pathogenesis of HE is a complex multifactorial process involving ammonia, cerebral edema, and mediators of immune response. The precise contribution of each of these factors to the pathogenesis of HE remains under investigation.

The diagnosis of HE is often confounded by the complexity of the disease. Minimal HE, the mildest form of HE, is common in patients with cirrhosis and is associated with mild cognitive and psychomotor deficits that impair daily functioning and overall quality of life. Despite the recognition for the need to identify and treat minimal HE, the required time commitment and overall difficulty in making this diagnosis represents a substantial barrier for most clinicians. For this reason, the majority of patients with mild forms of HE remain undiagnosed and untreated. Additionally, the diagnosis of overt HE is often complicated by the heterogeneity of clinical manifestations and overlapping symptoms with other neurologic disorders. Thus, diagnosis of overt HE is one of exclusion and requires detailed history and physical examination, laboratory testing, and neuroimaging to exclude all precipitating causes and other potential etiologies of neurologic impairment.

Although HE is progressive, it is also potentially reversible. However, no gold standard currently exists for treatment. Effective treatment options for HE are limited. Conventional therapeutic approaches are directed at reducing bacterial production of ammonia and enhancing its elimination. Traditionally, nonabsorbable disaccharides have been considered the first-line therapy for HE. However, the rationale for using these agents is predicated mainly on empirical rather than evidence-based medicine. A systematic review of clinical studies of nonabsorbable disaccharides did not support their use in the treatment of HE. Alternative therapies such as benzodiazepine receptor antagonists, branched-chain amino acids, and l-ornithine-l-aspartate also have limited clinical data supporting their use. Rifaximin, an orally administered, minimally absorbed antibiotic, has been studied recently in the treatment of HE in well-designed clinical studies. It appears to be well tolerated, and its therapeutic benefits appear to be greater than those of placebo and nonabsorbable disaccharides and at least comparable with those of systemic antibiotics. Other pharmacotherapies, including acarbose, levocarnitine, and probiotic therapy, are under clinical investigation.

Recently, a panel of expert hepatologists and gastroenterologists was convened to review the published literature pertaining to the pathogenesis, diagnostic methods, and pharmacologic treatment of HE. The goal of this panel was to develop a practical and comprehensive algorithm for the diagnosis and treatment of HE that would help clinicians in identifying the different forms of HE and selecting the appropriate treatment.

This supplement reviews their findings. Dr. Kevin Mullen provides an overview of the theories of pathogenesis, clinical manifestations, and challenges in the diagnosis of HE. An overview of the rationale, clinical experience, and limitations of conventional treatment approaches of HE is presented by Dr. Peter Ferenci. Dr. Nathan Bass then reviews the clinical experience with emerging therapies for HE. Dr. Carroll Leevy reviews recent studies of the economic impact of various treatment options for HE. The supplement concludes with the expert panel's recommendations for the management of HE, presenting an algorithm for diagnosis and treatment of minimal and overt HE. It is the hope of the panel that this algorithm will assist the treating physician in the practical management of HE.