Management of hepatic encephalopathy

1. Prof Dr Nasir Khokhar MD FACP FACG Professor of Medicine and and Director, Division of Gastroenterology Shifa international hospital islamabad Portosystemic Encephalopathy: Towards improved management

2. Spectrum of HE

3. Shapes of HE

4. Forms of HE

5. West Haven classification

6. Stages of Hepatic Encephalopathy

7. Ammonia effects

8. Ammonia Management Clean the bowel bacteria: Lactulose Kill the bowel bacteria: antibiotics Improve ammonia clearance: L- ornithine L- aspartate Muscular metabolism Save brain

9. Empiric therapy of HE Correction of underlying factor(s) Reducing production and absorption of ammonia in gut

10. Precipitating causes of HE Sepsis Gastrointestinal hemorrhage Constipation Dietary protein overload Sedatives Hypokalemia /diuretics/diarrhea Poor compliance with lactulose Anesthesia Ahmed H, et al. Factors precipitating Hepatic Encephalopathy in Cirrhosis Liver J Postgrad Med Inst Jan 2001;15(1):91-7.

11. Hepatic Encephalopathy Precipitants

12. Inadequate clinical response Improvement in 24-48 hours of treatment If HE persists after 72 hours then consider: Other causes of encephalopathy Precipitating factor missed, inadequately treated Effective treatment not instituted Effects of therapy ? lactulose

13. 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 status Mullen 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.

14. 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 .

15. Actions Of Lactulose

16. Antibiotics Neomycin Vancomycin Metronidazole Rifaximin Quinolones

17. 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.

18. 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.

19. 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

20. 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.

21. L ornithine L aspartate LOLA can improve overt HE I or II patients Hospital 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.

22. 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.

23. 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 studies Bresci G, et al. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment.  Eur J Med .  1993;2(7):414-6. 

24. 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.

25. 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.

26. BRAIN KIDNEY GUT LIVER MUSCLE NH3 Glutamine Lactulose Acarbose ABX LOLA UREA Mechanism of Action of Drugs

27. 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 systems Reduction in cerebral hyperemia, intracranial hypertension Moderate hypothermia treatment reduces cerebral blood flow Shawcross D, Jalan R. Lancet. 2005;365:431-433 .

28. 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.

29. THANK YOU FOR YOUR ATTENTION