The New England Journal Of Medicine March 25 , 2010 RIFAXIMIN TREATMENT IN HEPATIC ENCEPHALOPATHY

‡ MODERATORS ‡ Dr C. BARUAH Asso.Prof. ‡ Dr. A.K.PEGU Asst. Prof. Dept. of Medicine ‡ PRESENTER ‡ Dr. JOSY.J.V PGT Medicine

Hepatic Encephalopathy
‡ Hepatic (portosystemic) encephalopathy is a complex neuropsychiatric syndrome ± disturbances in consciousness and behavior, ± personality changes ± fluctuating neurologic signs, asterixis or "flapping tremor," ± distinctive electroencephalographic changes.

Incidence & Prevalence

‡ Majority of cirrhotics will develop some form of HE in their lifetime ‡ Overt HE in 30-45% of cirrhotics ‡ MHE in 30-80% of cirrhotics

Classification TYPE A associated with acute liver failure TYPE B associated with porto-systemic shunting without intrinsic liver disease TYPE C in Chronic liver disease/cirrhosis & portal hypertension .

‡ Episodic HE ± 1)Precipitated ± 2)Spontaneous ± 3)Recurrent ‡ Persistent HE ± 1)Mild ± 2)Severe ± 3)Treatment dependent ‡ Minimal HE .

Pathogenesis of HE ‡ Gut derived Endotoxins ‡ Increased permeability of bloodbrain barrier ‡ Change in Neurotransmitter and receptors .

Ammonia ‡ Healthy individuals: equilibrium between the production and detoxifications ‡ Main sites of synthesis: ± Intestine ± Muscle ± Kidneys .

Ammonia as a toxin ‡ Enters portal circulation across the gut by specific transporters. ‡ In HE increased diffusion into brain . metabolized in healthy liver to urea & glutamine ‡ Brain can also detoxify ammonia.

Ammonia) bypass the liver (shunts) or are not metabolized by liver (cirrhosis) reaches brain changes the neurotransmission encephalopathy ‡ Gliopathy due to swelling of Alzheimer s Type II astrocytes the only cerebral cell capable of detoxifying Ammonia .g.Ammonia ‡ GUT derived neurotoxins (e.

Toxic Effects in CNS ‡ Brain: detoxification is ATPdependent ‡ Hyperammonemia more energy consumption ‡ Swelling of Astroyctes ‡ No linear correlation between ammonia level and CNS dysfunction .

GABA/BENZODIAZEPINE HYPOTHESIS ‡ GABA mediated neurotransmission is neuro-inhibitory in nature ‡ Benzodiazepines are produced in excess in the gut by bacteria in HE up regulates GABA receptors ‡ Brain conc of GABA is also high in HE .

Precipitating Factors ‡ Increased nitrogen load ± Gastrointestinal bleeding: ± Excess dietary protein ± Azotemia ± Constipation .

Precipitating Factors ‡ Electrolyte and metabolic imbalance ± Hypokalemia. Alkalosis: increased renal production of ammonia and free form of NH3 ± Hypoxia ± Hyponatremia ± Hypovolemia: reduced liver metabolism of ammonia ± Acidosis: inhibition of urea synthesis .

Precipitating Factors ‡ Drugs ± Narcotics: CNS depression ± Tranquilizers ± Sedatives: CNS depression. prolonged half-life ± Diuretics: cause electrolyte imbalance and hypovolemia .

Precipitating Factors ‡ Miscellaneous ± Infection ± Surgery ± Hypothyroidism ± Superimposed acute liver disease ± Progressive liver disease ± Portal-systemic shunts ± Infection with Helicobacter pylori? .

Diagnostic methods ‡ Various tools for diagnosis-Neuropsychological tests -Neuropsychometric tests -Regional cerebral blood flow changes -Magnetic resonance spectroscopy -Critical flicker frequency (CFF) .

glutamate.Imaging Techniques ‡ CT: only to exclude other intracranial lesions ‡ PET: impaired basal ganglia functions ‡ MRI:T1WI: hyperintensive signals in basal ganglia: poor clinical correlation ‡ MRS: higher levels of glutamine. and aspartate .

Treatment
‡ Treatment of precipitating factors ‡ Diet ‡ Reduction of NH3 producing gut flora ‡ Antimicrobials ‡ Enhancing ammonia metabolism ‡ Transplantation

Treatment of Precipitating Factors
‡ GI bleedings: control bleeding and hemodynamically stabilise the pt. ‡ Infections: antimicrobials, esp. SBP ‡ Acidosis: impair urea synthesis ‡ Diuretics: inhibit urea synthesis ‡ Sedatives: stop ‡ hypoglycemia: correct

Diet Control of HE
‡ X: Severe protein restriction->catabolism of protein --> ammonia formation increased and susceptibility to infection ‡ Cirrhosis patients: 0.8 to 1.0g/Kg ‡ acute episode of HE: limited to 20g.day initially, then increased as clinical situations improves

Diet Control of HE ‡ Adequate caloric intake ‡ Increased vegetable protein ± improved nitrogen balance ± better tolerated ± fibers accelerating GI transit ± May tolerate 30g to 40g daily .

based on clinical sign and 2 to 4 soft stools daily ± degraded into short-chain organic acids in colon(acetic and lactic acid) ± cannot be hydrolyzed or absorbed in small intestine .Intestinal Cleansing ‡ Suitable laxatives: MgSO4. nonabsorbable disaccharides ‡ Disaccharides: Lactulose and Lactitol ± dosage:30g to 60g daily.

This favors conversion of NH3 to NH4 + 3. Lactulose (1-4 beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are nonabsorbable disaccharides 2. inhibits ammoniagenic coliform bacteria .Lactulose 1. Lactulose to lactic acid results in acidification of the gut lumen.

Adverse Effects of Disaccharides ‡ flatulence ‡ Diarrhea ‡ pronounced diarrhea may lead to hypovolemia and electrolyte imbalance --> aggravated HE .

Antibacterial ‡ Non-absorbable aminoglycosides: Neomycin and Paromomycin ‡ 3% would be absorbed --> ototoxicity and nephrotoxicity ‡ Should not be used for longer than 1 month ‡ Rifaximin may be useful as alternative ‡ Dosage : 400 mg tds for 7 to 21 days .

RIFAXIMIN .

‡ Additional pyridoimidazole ring makes it virtually non-absorbable. .INTRODUCTION ‡ Semi synthetic derivative of rifamycin. ‡ Apparently modify bacterial pathogenicity. ‡ Binds to beta subunit of bacterial DNAdependent RNA polymerase causing inhibition of RNA synthesis initiation.

RIFAXIMIN was generally well tolerated.  flatulence  headache  abdominal pain  rectal tenesmus  defecation urgency  nausea .SIDE EFFECTS ‡ In clinical trials.

PHARMACOKINETIC DATA Bioavailability .fecal (97%) ‡ .<0.hepatic ‡ Half life .4% ‡ Metabolism .6 hours ‡ Excretion .

ANTIMICROBIAL ACTIVITY ‡ Broad-spectrum activity against aerobic and anaerobic gram positive and gram negative micro organisms .

Other drugs ‡ Benzodiazepine antagonists ( Flumazenil. Anexate. Probiotics or Synbiotics L-Ornithine L-Aspertate (LOLA) Sodium benzoate Zinc ‡ ‡ ‡ ‡ ‡ ‡ . Lanexat. Romazicon) Prebiotics.

cerebellar degeneration. extrapyramidal disorders ‡ acute liver failure with HE: candidate for transplantation . spastic paraparesis.Liver transplantation ‡ severe and treatment refractory HE: dementia.

Conclusion Treat precipitating factors first lactulose orally or as an enema Antimicrobials :rifaximin Flumazenil: treat BZD induced HE Protein restriction in acute stage ( daily < 20g) ‡ amino acid solution ‡ Transplantation: treat refractory HE ‡ ‡ ‡ ‡ ‡ .

TRIAL DESIGN Phase 3 multicenter randomized double blind placebo-controlled study conducted over 6 months period between Dec 2005 to Aug 2008 in 70 investigative sites . .

Remission at enrollment 4.INCLUSION CRITERIA 1. with hepatic cirrhosis during previous 6 months 3. Age > 18 yrs 2. Atleast 2 episodes of overt hepatic encephalopathy asso. MELD score less than or equal to 25 .

2. Respiratory insufficiency 5. Anaemia ( Hb < 8 g/dl ) 6. 3.EXCLUSION CRITERIA : 1. Cr >2 mg/dl 4. Expectation of liver transplantation within 1 month after the screening visit. CRF with S. Presence of conditions that are known precipitants of hepatic encephalopathy. Intercurrent infection .

Sodium <125 mmol/L S.EXCLUSION CRITERIA contd . Potassium <2. Active SBP . a) b) c) An electrolyte abnormality S. 7.5 mmol/L S. Calcium > 10 mmol/L 8.

RANDOMIZATION ELIGIBLE SUBJECTS (299 SUBJECTS) RIFAXIMIN 550 mg BD PLACEBO FOR 6 MONTHS 1:1 .

70. 126 & 154. ‡ Assessments include  CONN SCORE  ASTERIXIS GRADE .FOLLOW UP Clinic visits occurred on days 7 and 14 and every 2 weeks thereafter through day 168 with optional visits on days 42. 98.

‡ Grade 4 . disorientation with respect to time.Lethargy. impairment of ability to add or subtract.CONN SCORE ‡ Grade 0 .Somnolence or semistupor. ‡ Grade 2 .Coma. gross disorientation . .Trivial lack of awareness. euphoria or anxiety.No personality abnormality ‡ Grade 1 . ‡ Grade 3 . inappropriate behaviour.

ASTERIXIS Grade ‡ ‡ ‡ ‡ ‡ Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 No tremors Few flapping motions Occasional flapping motions Frequent flapping motions Almost continuous flapping motions .

PRIMARY ENDPOINT Time to first breakthrough episode of hepatic encephalopathy defined by ‡ in Conn score from a baseline of 0 or 1 to a score of 2 or more OR ‡ in baseline Conn score of 0 to 1 + 1 unit increase in the asterixis grade. .

SECONDARY ENDPOINT ‡ Time to the first hospitalization involving hepatic encephalopathy .

RESULTS .

Baseline Characteristics ‡ Base line characteristics such as Age Sex Race Use of lactulose (91%) were similar in the 2 gps. .

001) ‡ Relative risk reduction -58% .Breakthrough episodes ‡ Rifaximin group.9% (73/159) ‡ Hazard ratio 0.45.1% ( 31/140) ‡ Placebo group.42%(p<0.22.

13.2% (36/159) ‡ Hazard ratio 0.22.6%( 19/140) ‡ Placebo group.001) ‡ Relative risk reduction -50% .HOSPITALISATION ‡ Rifaximin group.50(p<0.

Adverse events ‡ Similar in both the gps ‡ Rifaximin -80% ‡ Placebo -79.9% .

DISCUSSION ‡ Use of rifaximin reduced the risk of breakthrough episode of hepatic encephalopathy during a 6 month period among patients in remission who had a recent history of recurrent overt hepatic encephalopathy( >2 episodes within the previous 6 months) ‡ The reduced risk was seen across subgroups. .

. ‡ The incidences of adverse events were similar in both groups. ‡ Rifaximin therapy reduce the risk of hospitalization involving hepatic encephalopathy .DISCUSSION cont.

Gabriella Filippazzo M.reduction of blood ammonia more with rifaximin.) ‡ After 21 days of treatment.Related studies ‡ Rifaximin versus neomycin in the treatment of portosystemic encephalopathy.23:403-7. Ital J Gastroenterol 1991.Valenza LM. ‡ Side effects more with neomycin . (Di Piazza S. et al.

Zheng MH.. Jiang XH. Eur J Gastroenterology Hepatol2008. .Related studies ‡ Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis ‡ Jiang Q.20:1064-70. Chen YP. JiangLM. Wang L.

Eur J Gastroentero Hepatol 2001. 34: 768-773 ‡ ‡ . J Hepato. 96(7): 1968-1975 Neuropsychological characterization of hepatic encephalopathy J Hepatol. 60(6): 1353-1370 Treatment of Hepatic Encephalopathy.Reference ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Sleisenger and Fordtran¶s Gastrointestinal and liver disease 8th edition Hepatic Encephalopathy in Liver Cirrhosis. 2001. 37(5): 1069-1080 Oral L-ornithine-L-asparate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. 32: 748-753 Brain electrical activity mapping of EEG for the diagnosos of subclinical hepatic encephalopathy in chronic liver disease. 13: 325-334 Hyperammonemia in Urea Cycle Disorders: Role of the Nephrologist. J Hepato. Eur J of Gasteroentero Hepatol 2001. 2000. Drugs 2000 Dec. 2001. A J Kidney Dis. 1998. 28: 856-864 Screening of subclinical hepatic encephalopathy. A J Gastroentero. NEJM 1997 337(7): 473-479 Hepatic Encephalopathy. 13: 513-552 Hepatic Encephalopathy. 2001.

Thank you .

MELD Score > 25 was not assessed .Draw backs of the study ‡ Benefit of rifaximin without concomitant use of lactulose was not assessed ‡ Due to the short duration of the study only the effect of rifaximin on the morbidity of HE was assessed but not the mortality ‡ The benefit of rifaximin in severely ill patient ie.

Draw backs of the study ‡ The study did not provide information of for how long rifaximin should be continued. ‡ The study has not assessed whether the use of rifaximin in HE delays the requirement of liver transplantation .

INDICATIONS ‡ ‡ ‡ ‡ ‡ ‡ ‡ Traveller s diarrhea Hepatic encephalopathy Irritable bowel syndrome Inflammatory bowel disease Hyperammonaemia Small intestinal bacterial over growth Diverticular disease of colon .

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Classification of HE .

Abnormalities of Neurotransmission .

Diagnostic Tools ‡ Psychometric/neuropsychological tests ‡ Electrophysiologic studies ‡ Image techniques ‡ Clinical laboratory tests .

Psychometric/Neuropsychologi cal Tests ‡ Bedside simple tests: ± Retelling and interpretation a fable ± forward digit span ± backward digital span ± reproduction of simple figures .

Psychometric/Neuropsychologi cal Tests ‡ ‡ ‡ ‡ WAIS performance IQ Line tracing tests: LTT Number connecting test: NCT Digital-symbol test: DST .

Treatment .

Grading of hepatic encephalopathy 1) West Haven criteria 2) Parson-Smith grading system 3) Reigler and Lake s modification of West Haven 4) Glasgow-coma scale 5) Mini-mental score .

EDEMA .

Asterixis .

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Pathogenesis of HE .