Rifaximin

This review highlights the causes, types and clinical staging of hepatic encephalopathy (HE). Current concepts on the probable pathogenetic mechanisms and currently practiced therapeutic options are discussed.

HE may be covert and overt. Also known as minimal HE. Covert HE, where there are behavioral abnormalities and impairment in activities of daily living with intact sensorium. The pathophysiology of HE remains poorly understood. There is disturbance of the urea cycle due to liver disease leading to increased production of ammonia. The ammonium ion enters the astrocytes along with glutamate (converted to glutamine by ammonia) and myo-inositol, thereby increasing the osmolality of the astrocytic cytoplasm. This osmotic gradient results in accumulation of water inside the astrocytes resulting in cerebral edema and increase in brain volume. Additionally, current research has noted the role of cerebral oxidative/nitrosative stress and the synergistic effects of increased cerebral ammonia and alteration in neurotransmitters, neurometabolites, and cortical excitability due to systemic inflammation. In advanced liver disease with systemic infection or inflammation, neuroinflammatory processes play significant role in the development of HE. Inflammatory cytokines like TNF-α, IL-6, IL-17 in presence of hyperammonemia have been found to induce neurotoxicity of ammonia by passing through the blood brain barrier and causing enlarged/swollen pale astrocytes, resulting in HE. Disrupted enterohepatic circulation in end stage liver disease also causes elevation of bile acids which induces neuroinflammation. Manganese and zinc play as co-factors of enzymatic reaction. These metal deposition causes multiple psychomotor symptoms observed in HE. The gut environment has a major impact on brain function in patients with HE. Toxins such as ammonia and inflammatory cytokines produced by this impaired intestinal flora access the circulation through porto-systemic anastomoses and exacerbate or precipitate HE. Finally, as a result of recurrent cerebral edema from astrocytic dysfunction and neuroinflammation, permanent neurodegeneration occurs with cognitive decline and motor disturbances, especially parkinsonian features and gait disturbances. This is the stage of chronic hepatic encephalopathy. Currently L-ornithine L-aspartate (LOLA) is being used to lower the ammonia level by stimulating the urea cycle. HE comprises a broad spectrum of neurological and/or psychiatric abnormalities caused by hepatic insufficiency and/or portal-systemic shunting in the absence of any other causes of brain dysfunction. HE may be caused or precipitated by several factors like infections, intoxications and drugs. The encephalopathic features may be covert or overt. The pathogenetic mechanisms for HE may be different. In the presence of liver disease, HE primarily results from disturbed urea cycle with hyperammonemia causing astrocytic swelling and cerebral edema. Porto-systemic anastomoses with intact liver function can cause HE by allowing ammonia and other toxins produced by the gut microbial flora and allowing these to bypass detoxification by the liver and exposing the brain to their harmful effects. Principles of therapy are twofold. First protecting the liver and the brain from gut generated ammonia and other toxins by ensuring smooth bowel function and avoiding stagnation with the use of osmotic laxatives like lactulose or lactitol and also reducing the gut microbial load with use of anti-bacterials/bacteriophages like neomycin and rifaximin along with metronidazole. Second, reducing the already generated cerebral edema by use of mannitol and appropriate ventilatory support. Currently L-ornithine L-aspartate (LOLA) is being used to reduce the ammonia load to the liver. LOLA is a stable compound formed from two amino acids. L-ornithine plays a crucial role in stimulating the urea cycle, leading to a reduction in ammonia levels. Both L-ornithine and L-aspartate serve as substrates for the enzyme glutamate transaminase, and their administration results in elevated glutamate concentrations. Ammonia is subsequently utilized in the conversion of glutamate to glutamine through the action of glutamine synthetase. Finally in resistant cases the use of liver transplant needs to be considered. Alternatively extracorporeal liver assist devices may be used like Molecular Adsorbent Recirculating System (MARS) or Single-Pass Albumin Dialysis (SPAD).

Covert hepatic encephalopathy (CHE) leads to devastating outcomes in patients with cirrhosis. This study aims to elucidate the current management and future perspectives of CHE in Japan.

A questionnaire-based cross-sectional study was conducted among physicians involved in managing cirrhosis in Japan. The primary aim was to elucidate the real-world management of CHE, including testing and treatment. Factors influencing the implementation of CHE testing were analyzed using a logistic regression model. Limitations and future perspectives for improving the management of CHE were also evaluated.

Of 511 physicians surveyed, 93.9% recognized CHE as a significant problem, and 86.9% agreed that it should be tested. Overall, 62.8% of physicians tested for CHE, whereas 37.2% did not. Multivariable analysis identified institutional factors and certifying board as significant determinants of CHE test implementation. The Stroop (68.2%) and neuropsychiatric tests (57.5%) were the most commonly used methods of identifying CHE. Among those who tested for CHE, 87.7% treated CHE; the most common treatments were lactulose (81.5%), rifaximin (76.3%), and branched-chain amino acids (70.4%). Among non-testers, the primary barrier was the time requirement for testing. Proposals to encourage CHE testing included the development of simple tests and integration of multidisciplinary teams.

Most physicians involved in cirrhosis care in Japan recognize CHE as a significant problem that warrants testing. However, testing for CHE remains limited by institutional factors and physician specialties. Time requirements for CHE testing are the primary barrier, and simple tests and multidisciplinary teams are recommended to enhance CHE management.