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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