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).

A subset of patients with ileal Crohn’s disease (CD) are colonized with adherent–invasive Escherichia coli (AIEC).

This prospective trial tested the efficacy of antibiotics for endoscopic response in CD patients colonized with AIEC.

Patients with endoscopically active, ileal CD, colonized with AIEC, were randomized to receive oral ciprofloxacin and rifaximin or double placebo for 12 weeks. AIEC was detected in ileal biopsies, by phenotypic analysis. The primary endpoint was endoscopic overall response, as defined by a CD endoscopic index of severity adapted to patients with ileal CD. Central readers blinded to the treatment scored video recordings of colonoscopies at preinclusion and week 12. We expected a strong signal of efficacy for antibiotics in this subgroup of patients.

Between May 2016 and June 2021, 155 patients were screened, and 24 patients were randomized, 12 in each arm. All patients’ AIEC were sensitive to ciprofloxacin and rifaximin in vitro. There was no statistical difference between the 2 arms for endoscopic overall response (50% in the Cipro–Rifa group vs 33% in the placebo group, estimated difference 17%; 95% CI, −23% to 51%). Within the antibiotics arm, 7/10 patients became AIEC− and 3/10 patients remained AIEC+ (and acquired resistance to ciprofloxacin), as compared to 7/12 AIEC− and 5/12 AIEC+ in the placebo arm, respectively. There was no association between AIEC clearance and endoscopic endpoints.

A combination of ciprofloxacin and rifaximin was not superior to placebo to achieve endoscopic endpoints in patients with ileal CD colonized with AIEC.