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PROF DR NASIR KHOKHAR MD FACP FACG
PROFESSOR OF MEDICINE AND AND DIRECTOR, DIVISION OF
GASTROENTEROLOGYSHIFA INTERNATIONAL HOSPITAL
ISLAMABAD
Portosystemic Encephalopathy:Towards improved management
Spectrum of HE
Shapes of HE
Forms of HE
West Haven classification
Stages of Hepatic Encephalopathy
Ammonia effects
Ammonia Management
Clean the bowel bacteria: LactuloseKill the bowel bacteria: antibioticsImprove ammonia clearance: L-
ornithine L-aspartateMuscular metabolismSave brain
Empiric therapy of HE
Correction of underlying factor(s)Reducing production and absorption
of ammonia in gut
Precipitating causes of HE
SepsisGastrointestinal hemorrhageConstipationDietary protein overloadSedativesHypokalemia/diuretics/diarrheaPoor compliance with lactuloseAnesthesia
Ahmed H, et al. Factors precipitating Hepatic Encephalopathy in Cirrhosis LiverJ Postgrad Med Inst Jan 2001;15(1):91-7.
Hepatic Encephalopathy Precipitants
Inadequate clinical response
Improvement in 24-48 hours of treatment
If HE persists after 72 hours then consider:
Other causes of encephalopathyPrecipitating factor missed,
inadequately treatedEffective treatment not institutedEffects of therapy ?lactulose
Non-absorbable diasaccharides
Lactulose is a non-absorbable disaccharide that is fermented in the colon.
The exact mechanism of action remains unclear; acidification of colonic contents and mass evacuation of bacteria have been proposed.
Associated with improvement in mental statusMullen KD, Amodio P, Morgan MY. Therapeutic studies in hepatic encephalopathy. Metab Brain Dis 2007; 22: 407–23.
Als-Nielsen B, et al. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev 2004; 2: CD003044.
Efficacy of Lactulose and Protein Restriction
Lactulose has no significant effect on mortality in patients with hepatic encephalophathy compared with placebo
Protein restriction offers no apparent benefit
May create protein levels insufficient for maintaining positive nitrogen balance needed in cirrhosis
Shawcross D, Jalan R. Lancet. 2005;365:431-433.
Actions Of Lactulose
Antibiotics
NeomycinVancomycinMetronidazoleRifaximinQuinolones
Non-absorbable antibiotics
Rifaximin is a non-absorbable antibiotic Cochrane review recommends the use of non-
absorbable antibiotics.Given up to 1200 mg/day. Reduced hospitalization rates after rifaximin
therapy compared with that of lactulose. The drug expense remains a concern
Alcorn J. Review: rifaximin is equally or more effective than other antibiotics and lactulose for hepatic encephalopathy. ACP J Club 2008; 149: 11.
Rifaximin Study Design
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
Patients with recurrent HE, currently inremission
(N = 299)
Rifaximin 550 mg BID*(n = 140)
Placebo*(n = 159)
Mo 6
*Concomitant lactulose permitted.
Main Findings
Significantly fewer breakthrough HE episodes and significantly lower rate of hospitalizations involving HE observed among patients treated with rifaximin vs placebo Number needed to treat for 6 mos to prevent 1 overt HE
episode: 4 Number needed to treat for 6 mos to prevent 1 hospitalization
involving HE: 9
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
Outcome at Mo 6 Rifaximin, n (%)(n = 140)
Placebo, n (%) (n = 159)
HR for Time to First Event
(95% CI)P Value
Breakthrough HE 31 (22.1) 73 (45.9) 0.42 (0.28-0.64) < .001
Hospitalization 19 (13.6) 36 (22.6) 0.50 (0.29-0.87) .01
Summary of Key Conclusions
Rifaximin significantly more effective than placebo at preventing additional episodes of HE over 6-mo period in patients with recurrent HE in remission Risk of breakthrough HE reduced by 58% Risk reduction consistent across nearly all patient subgroups Majority of patients (> 90%) in both arms received
concomitant lactulose
Rifaximin also resulted in significant 50% reduced risk of hospitalization due to HE
Rifaximin well tolerated with no increased incidence of adverse events, serious adverse events, or infections compared with placebo
Bass NM, et al. N Engl J Med. 2010;362:1071-1081.
L ornithine L aspartate
LOLA can improve overt HE I or II patientsHospital stay was reduced. Data do not support the use of LOLA for
patients with subclinical hepatic encephalopathy.
Trials detecting efficacy and safety were of high quality.Abid S, et al. Efficacy of infusion of L-ornithine L-aspartate in cirrhotic patients with portosystemic encephalopathy: a placebo controlled study. J. Hepatol. 2005; 42 (Suppl. 2): 84.
Sodium benzoate
Sodium benzoate and sodium phenylacetate bind with ammonia substrates and thus take them out of the circulation.
One small study reported that sodium benzoate was as effective as lactulose in reducing ammonia levels and improving cognitive function.
Severe accidental overdose has been reported Sushma S, et al. Sodium benzoate in the treatment of acute hepatic
encephalopathy: a double-blind randomized trial. Hepatology 1992;16:138–44.
Zinc
Zinc deficiency is common in cirrhosis. Zinc administration has the potential to
improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle.
Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials.
Hepatic encephalopathy improved in 2 studiesBresci G, et al. Management of hepatic encephalopathy with oral
zinc supplementation: a long-term treatment. Eur J Med. 1993;2(7):414-6.
Detoxification systems
The molecular adsorbant recirculating system (MARS) removes protein-bound and water-soluble toxins.
A short-term (5-day), multicenter, randomized study compared the use of MARS with standard medical therapy.
Significantly more rapid improvement in mental status was observed in the MARS group (p=0.044).
The role of albumin dialysis unclear.Hassanein TI, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy. Hepatology 2007;46: 1853–62.
Probiotics
Probiotics are live, microbiologic dietary supplements (e.g., yogurt).
Work by depriving pathogenic bacteria of substrates and providing fermentation products for beneficial bacteria.
Two small studies reported neuropsychological improvement in patients with MHE.
Malaguarnera M, et al. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebocontrolled study. Dig Dis Sci 2007;52:3259–65.Bajaj JS, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008;103:1707–15.
BRAIN
KIDNEY
GUT LIVER
MUSCLE
NH3
Glutamine
Lactulose AcarboseABX
LOLA
UREA
Mechanism of Action of Drugs
Other Management
Alternative targets for ammonia reduction Kidneys produce, excrete significant ammonia
Volume expansion promotes excretion, reduces plasma ammonia
Muscle converts ammonia to glutamine in hyperammonemia L-ornithin L-aspartate (LOLA) increases muscle detoxification
Reduction in inflammation and potential infection Targets: nitric oxide, proinflammatory cytokines, free radicals
Liver detoxicification via liver support systemsReduction in cerebral hyperemia, intracranial
hypertension Moderate hypothermia treatment reduces cerebral blood flow
Shawcross D, Jalan R. Lancet. 2005;365:431-433.
Liver transplant
The ultimate management goal for OHE is the replacement of the diseased liver.
Therefore, liver transplant work-up is crucial for the management of OHE after correction of the acute insult and prevention of recurrences.
THANK YOU FOR YOUR ATTENTION
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