The New England Journal Of MedicineMarch 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

ClassificationTYPE 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 blood-brain 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

astrocytesthe only cerebral cell capable of detoxifying Ammonia

Toxic Effects in CNS

• Brain: detoxification is ATP-dependent

• 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, non-absorbable

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

Lactulose1. 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 DNA-dependent 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/dl4. Respiratory insufficiency5. Anaemia ( Hb < 8 g/dl )6. Intercurrent infection

EXCLUSION CRITERIA contd….

7. An electrolyte abnormalitya) S. Sodium <125 mmol/Lb) S. Potassium <2.5 mmol/Lc) 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 – No tremors• Grade 1 – Few flapping motions• Grade 2 – Occasional flapping motions• Grade 3 – Frequent flapping motions• Grade 4 – 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 Fordtran’s 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/Neuropsychological Tests

• Bedside simple tests:– Retelling and interpretation a fable– forward digit span– backward digital span– reproduction of simple figures

Psychometric/Neuropsychological 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