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

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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