Rifaximin's Effect on Covert Hepatic Encephalopathy With SIBO and Gastrointestinal Dysmotility
Rifaximin's Effect on Covert Hepatic Encephalopathy With SIBO and Gastrointestinal Dysmotility
Small Intestinal Bacterial Overgrowth (SIBO) is a common and increasingly recognized disorder
 in cirrhosis (30% to 73%). One of the most important predisposing factors of SIBO is small
 bowel dysmotility. Multiple studies have shown that the presence of SIBO is strongly linked
 to the pathogenesis of Minimal Hepatic Encephalopathy (MHE) also known as Covert Hepatic
 Encephalopathy (CHE). Consequently, altering and modulating the intestinal microbiota with
 ammonia-lowering agents and Rifaximin has been the target treatment strategy in CHE. The aim
 of this study is to determine the therapeutic effect of Rifaximin on patients with CHE and
 underlying SIBO while assessing the influence of Rifaximin on small bowel motility. In this
 prospective interventional study, 40 patients with liver cirrhosis will be screened for
 Covert Hepatic Encephalopathy (CHE) using neuro-psychometric tests. Patients diagnosed with
 CHE will undergo breath test (BT) for SIBO screening. Afterwards, wireless motility capsule
 (The SmartPill) will be performed in all patients with a positive BT. Thereafter, the
 cirrhotic patients diagnosed with CHE and SIBO will receive Rifaximin 550 mg PO twice daily
 for eight weeks. At the end of treatment, neuro-psychometric tests will be repeated to
 evaluate the therapeutic effect on CHE. In addition, BT and SmartPill will be repeated at the
 completion of the Rifaximin treatment period to assess the effect on small bowel motility.
 All collected clinical parameters at the end of the study will be compared to baseline
 values.
Small intestinal bacterial overgrowth (SIBO) is a common and an increasingly recognized
 disorder in liver cirrhosis, correlating with its severity. The prevalence of SIBO, assessed
 by the quantification of the bacterial density in the small intestinal aspirate, ranges from
 30% to 73%. Multiple physiological derangements leading to SIBO appear in cirrhosis from
 decreased secretion of gastric acid, impaired mucosal immune response to decreased bile acid,
 and more importantly, intestinal dysmotility. The latter remains the most common predisposing
 factor in the pathogenesis of bacterial overgrowth. A recent pilot study using a wireless
 motility capsule (the SmartPill) demonstrated that patients with cirrhosis have significant
 delays in small bowel transit that is more pronounced in those with more severe liver
 disease. Altered small bowel motility in cirrhosis has been attributed to autonomic
 dysfunction, altered levels of circulating neuropeptides and the effects of inflammatory
 mediators on gut muscle and the enteric nervous system.

 Hepatic Encephalopathy (HE) is a spectrum of neuro-cognitive impairment in cirrhosis that
 range from abnormal neuropsychiatric testing without clinical evidence of disease (Minimal
 Hepatic Encephalopathy[MHE]) to varying degrees of overt clinical findings: Overt Hepatic
 Encephalopathy (OHE). MHE is found in 30-84% of patients with liver cirrhosis. The
 neuro-cognitive deficit noted in MHE could predispose patient to impaired quality of life
 (QOL) which translates into lower QOL scores, higher risk of falls, driving problems and
 difficulties maintaining employment. Previous studies have shown that SIBO is prevalent and
 strongly linked to the pathogenesis of MHE. Consequently, altering and modulating the
 intestinal microbiota with ammonia-lowering and gut-selective agents has been the target
 treatment strategy. Multiple prior studies have evaluated Rifaximin efficacy in MHE and have
 shown improvements across a variety of study clinical end points including neuropsychiatric
 and QOL tests. However, the precise mechanism of action of Rifaximin in MHE is unclear. The
 proposed mechanisms by which Rifaximin may lead to improvement of MHE may be beyond the
 bactericidal/bacteriostatic effect, resulting in changes in bacterial metabolic
 function/virulence, to an anti-inflammatory and immune-modulatory effect.

 The investigators hypothesize that Rifaximin may have an additional effect on small bowel
 motility that may be independent of its effect on bacterial overgrowth. The effect may not be
 necessarily through changes in patient's microbiome but rather through a pro-motility
 mechanism. The investigators intend to test this hypothesis by comparing the motility at
 baseline in cirrhotic patients with MHE and clinically significant portal hypertension,
 before and after treatment of SIBO with Rifaximin.

 Aims:

 1. To determine the therapeutic effect of Rifaximin on patients with CHE and underlying
 SIBO and as it is related to small bowel motility.

 2. To determine the effect of Rifaximin on small bowel motility by using the SmartPill.

 Study Design:

 This is a prospective and interventional study. It will be conducted at the Gastroenterology
 and Hepatology outpatient clinics of MetroHealth Medical Center/Case Western Reserve
 University. Approximately 40 patients with liver cirrhosis will be assessed for eligibility
 by their hepatologist. Eligible patients will be referred to an expert psychologist for
 neuro-psychometric testing to confirm CHE. Then the patients with diagnosed with CHE will
 undergo Glucose Hydrogen Breath Test (BT) for SIBO screening. Subsequently, wireless motility
 capsule (the SmartPill) for motility testing will be performed in all patients with positive
 BT. Thereafter, cirrhotic patients diagnosed with both CHE and SIBO will be prescribed
 Rifaximin 550 mg PO twice daily for eight weeks. At the end of the treatment period,
 neuro-psychometric tests will be repeated to evaluate the therapeutic effect on CHE. In
 addition, BT and the SmartPill will be repeated at the completion of the treatment period
 with Rifaximin in order to assess the effect on small bowel motility.
Inclusion Criteria:

 1. Cirrhosis patients between 18-70years of age, without prior transjugular intrahepatic
 portosystemic shunt (TIPS) placement or prior overt hepatic encephalopathy.

 2. Cirrhosis diagnosed on the basis of liver biopsy, liver stiffness measurement
 (Fibroscan) or radiological study.

 3. CHE diagnosis using pre-defined criteria [two of the following should be abnormal as
 compared to healthy controls: number connection test A/B (NCT-A/B), Digit Symbol Test
 (DST), or Block Design Test (BDT)] at least 2 months prior to the start of the study
 (beyond 2 standard deviation of normal). Testing will be carried out by a trained
 psychologist.

 4. No prior episode of overt HE, not on therapy for overt HE, not on any psycho-active
 medications apart from stable doses of selective serotonin re-uptake inhibitors.

 Exclusion Criteria:

 1. Known allergy to rifaximin / rifabutin / rifampin.

 2. Current or recent (<6 months) abuse of alcohol or illicit drugs

 3. Use of antibiotics within last 6 weeks

 4. Use of lactulose / lactitol, probiotics, L-ornithine- L -aspartate, zinc,
 metronidazole, or neomycin, within last 6 weeks

 5. Use of any drug known to affect gastro-intestinal motility within the previous 2 to 4
 weeks (such as, Reglan, erythromycin, or domperidone)

 6. Use of drugs such as opiates and antidepressants (except stable doses of selective
 serotonin re-uptake inhibitors)

 7. Diarrhea or abdominal distention

 8. Patients deemed higher risk for capsule retention including a history of esophageal
 stricture or Zenker's diverticulum, partial or complete bowel obstruction, known
 ﬁstula, known large or numerous diverticula and dementia

 9. Diseases associated with poor gastrointestinal motility such as cardiac and pulmonary
 dysfunction, renal insufficiency, diabetes, rheumatological disorders (such as
 scleroderma and mixed connective tissue disorders)

 10. History of gastrointestinal tract or abdominal surgery

 11. Spontaneous peritonitis or other severe infections

 12. Colonoscopy or enema treatment within 4 weeks

 13. Hepatic encephalopathy with clinical signs

 14. Inability to complete neuropsychiatric testing due to hearing loss, poor vision, etc.

 15. Poorly compliant patients

 16. Rifaximin - Pregnancy Category C- There are no adequate and well controlled studies in
 pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at
 doses that caused maternal toxicity. Female study subjects of childbearing potential
 must have a negative pregnancy test and agree to use an acceptable method of
 contraception throughout the study.