Authors

1. Zucker, Donna RN, PhD, FAAN
2. Redulla, Rhoda DNP, RN

Abstract

Review question/objective: The purpose of this systematic review is to present the best available evidence for the use of disaccharides versus no treatment in the medical management of minimal hepatic encephalopathy. The objectives of this review are to identify effective medical management strategies for the prevention of minimal hepatic encephalopathy (MHE) and also minimize the adverse clinical manifestations of MHE.

Background: Hepatic encephalopathy (HE) is a major complication of liver cirrhosis and can be defined as the occurrence of confusion, an altered level of consciousness, and coma. It is considered a reversible syndrome of impaired brain function occurring in patients with advanced liver failure.1,2 It occurs in approximately 30 to 45 percent of patients with cirrhosis and 10 to 50 percent of patients with a transjugular intrahepatic portosystemic shunt (TIPS). TIPS is a surgical procedure wherein a shunt is placed between the portal vein and hepatic vein.3 Its frequency has continued to increase, with a 21 percent increase in 2010.4

In the advanced stages HE is called hepatic coma, and may ultimately lead to death. Hepatic encephalopathy can be reversible and thus its severity can be gauged and graded using the West Haven criteria that are based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.5 Three types are described : Type A (acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral edema; Type B (bypass) is caused by portal-systemic shunting without associated intrinsic liver disease; Type C (cirrhosis) occurs in patients with cirrhosis-this type is subdivided in episodic, persistent and minimal encephalopathy.6 The term MHE is defined as encephalopathy that does not lead to clinically-overt cognitive dysfunction but can be demonstrated with neuropsychological studies, and has been characterized in the medical literature for well over 35 years. This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life and increase the risk of involvement in road traffic accidents.7

Although the mechanisms causing brain dysfunction in liver failure are still unknown, metabolic factors are recognized to contribute to the development of HE. These include:

* Decreased oxygen delivery as a consequence of a variety of factors including gastrointestinal bleeding, sepsis, the effects of cytokines or compounds released from necrotic liver tissue;8

* Functional and structural changes in cerebral function independent of the liver failure (e.g. alcoholics, intravenous drug users, and patients with Wilson's disease);8

* Other events which can precipitate HE such as the administration of sedatives, hypokalemia, and hyponatremia;2 and

* The creation of a portosystemic shunt to treat portal hypertension, as with a transjugular intrahepatic portosystemic shunt.

Approach to treatment depends on the severity of patient's HE. General supportive care includes providing appropriate nutritional support, avoiding dehydration and electrolyte abnormalities, and providing a safe environment. Increases in blood ammonia as well as changes in normal electrolyte levels are influenced by good nutrition and adequate hydration. Additionally family and friends may see neuro-cognitive changes such as acute confusion, sleepiness and agitation. All of these factors are indicators of worsening encephalopathy and perhaps coma. For acute therapy, treatment involves identification and correction of precipitating causes (i.e. gastrointestinal bleeding, infection, hypokalemia) and interventions to lower the blood ammonia concentration.2 Drug therapy remains to be the mainstay of treatment for the latter. The standard of care for HE is non-absorbable disaccharides (e.g. lactulose, lactitol). These synthetic agents are broken down into short-chain amino acids which lowers the colonic pH. The decrease in pH favors the formation of the nonabsorbable NH4+ from NH3, trapping NH4+ in the colon and thus reducing plasma ammonia concentrations. There remains to be unclear evidence on the efficacy of non-absorbable disaccharides. Their use in MHE is also not well-established. Most trials of disaccharides included patients with overt hepatic encephalopathy.

Nonsystematic antibiotics (e.g. neomycin, rifaximin) also reduce the production and accumulation of neuroactive substances by altering the bacterial count in the GI flora.14 However, the efficacy of neomycin in HE alone or in combination with lactulose is questionable and raises tolerability concerns. Lactulose and rifaximin are commonly used while neomycin, an oral antibiotic, is used for second-line therapy. Lactulose and lactitol are also used for chronic therapy and if needed, rifaximin is added into the regimen. Lastly, patients with MHE may benefit from treatment with lactulose or lactitol, but the decision to treat should be individualized, based on the results of psychometric testing and the degree to which the encephalopathy has an impact on quality of life.11

The purpose of this systematic review is to present the best available research evidence for the use of disaccharides versus no treatment in the medical management of MHE. Despite the historically effective medical and surgical treatments, as well as current pharmacological advances, modalities of identification and prevention of MHE are not well described or translated into practice. The focus of this review is on the medical management of MHE and prevention of acceleration to increased symptoms associated with overt HE, severe confusion and possibly coma. Recent attention has been focused on neuro-cognitive testing recommendations with the goal of preventing MHE from developing into overt HE.5,9,10 Several systematic reviews and meta-analyses on hepatic encephalopathy exist in the literature. However, these are limited to very specific pharmacologic agents such as probiotics, rifaximin and non-absorbable disaccharides. The results from a meta-analysis conducted to evaluate the efficacy of rifaximin in the management of HE found that rifaximin was at least as effective as other conventional oral agents for the treatment of HE with a better safety profile.12 A Cochrane systematic review was completed in 2004 on the effects of non-absorbable dissacharides on HE. Results showed insufficient evidence to support or refute the use of non-absorbable disaccharides for HE.13 Some reviews on diagnostic and treatment strategies are also seen in the literature but did not utilize systematic review methodology. One trial which included 61 patients with MHE showed treatment with lactulose was associated with improvement in health-related quality of life and cognitive function. However, other trials failed to show this benefit. No work was found that addressed the comprehensive management of MHE.