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, metabolized in healthy liver to urea & glutamine Brain can also detoxify ammonia. In HE increased diffusion into brain

Ammonia
GUT derived neurotoxins (e.g. 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

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)

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, glutamate, 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

Intestinal Cleansing
Suitable laxatives: MgSO4, nonabsorbable disaccharides Disaccharides: Lactulose and Lactitol dosage:30g to 60g 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

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

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

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

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

PHARMACOKINETIC DATA
Bioavailability - <0.4% Metabolism - hepatic Half life - 6 hours Excretion - fecal (97%)

ANTIMICROBIAL ACTIVITY

Broad-spectrum activity against aerobic and anaerobic gram positive and gram negative micro organisms

Other drugs

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

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

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 .

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

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

EXCLUSION CRITERIA contd .

7. a) b) c) An electrolyte abnormality S. Sodium <125 mmol/L S. Potassium <2.5 mmol/L S. Calcium > 10 mmol/L

8. Active SBP

RANDOMIZATION
ELIGIBLE SUBJECTS (299 SUBJECTS)

RIFAXIMIN 550 mg BD

PLACEBO

FOR 6 MONTHS

1:1

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

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

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.

Breakthrough episodes
Rifaximin group- 22.1% ( 31/140) Placebo group- 45.9% (73/159)
Hazard ratio 0.42%(p<0.001) Relative risk reduction -58%

HOSPITALISATION
Rifaximin group- 13.6%( 19/140) Placebo group- 22.2% (36/159)
Hazard ratio 0.50(p<0.001) Relative risk reduction -50%

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.

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

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

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

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

Thank you

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, MELD Score > 25 was not assessed

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

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

Pathogenesis of HE