2. Treatment of Hepatic Encephalopathy Sepehr Khashaei, MD Department of Internal Medicine 11/5/10

3. Definition of Hepatic Encephalopathy Hepatic encephalopathy or portosystemic encephalopathy (PSE) represents a reversible impairment of neuropsychiatric function associated with impaired hepatic function.

4. Pathogenesis of Hepatic Encephalopathy Lack of clear understanding. Experience suggests: – Increased ammonia concentration (60-80% have increase in ammonia level). – ? Inhibitory neurotransmission through gamma-aminobutyric acid (GABA) receptors in the CNS Current therapies therefore based on above hypotheses

5. Treating the precipitating cause Will reverse 80% of cases. Main factors to treat: – GI bleed – Hypokalemic alkalosis – Infection – Constipation – Hypoxia – Use of sedatives and tranquilizers

6. Correction of hypokalemia Essential Hypokalemia increases renal ammonia production. Hypokalemia causes metabolic alkalosis which causes easier passage of ammonia into the brain.

7. Lactulose (and Lactitol) Synthetic disaccharides Mainstay of therapy Limited evidence More effective than placebo for health-related quality of life and cognitive function. No significant benefit on mortality. Lactitol not available in US (more palatable, fewer SEs, as effective as lactulose)

8. Lactulose (continuted) Also benefit in minimal HE. Dose 45-90 g/day titrated to 2-3 soft stools per day with PH <6. 70-80% improve. Principal toxicity: – Cramping – Diarrhea – Flatulence

9. Lactulose (Continued) Also used to help prevent recurrence of HE. Although no significant difference in deaths or rates of readmission for causes other than HE. Use as enema also effective (1-3 L of 20% solution). Oral preferred to enema due to convenience although no clear studies showing any difference.

10. Dietary protein restriction No good clinical evidence supporting this. Exception: Severe HE in patients with TIPS or surgical postsystemic shunt. Consider using vegetable protein or protein restriction in these patients. Oral BCAA may benefit patients who are significantly protein intolerant only.

11. Oral Neomycin Controlled trials show different results. Ototoxicity Nephrotoxicity. Toxicity less likely to occur with oral neomycin.

12. Other oral antibiotics Metronidazole Vancomycin Rifaximin Effective in limited clinical trials and are better tolerated than neomycin.

13. Rifaximin Similar efficacy to lactulose Better tolerated Shown effective in prevention of recurrence of HE.

14. Acarbose Inhibitor of alpha glycosidase Approved for treatment of HE Studies show effective in grade 1 and 2 HE GI side effects limit its tolerability.

15. General problems with oral antibiotics Can cause alteration in gut flora. Some can be much more costly than lactulose. Therefore, use in patients who cannot tolerate or are resistant to lactulose.

16. Probiotics Role still being investigated.

17. HE at UNM for July 2009 to June 2010 Primary Dx of HE Any Dx of HE # of cases29104 Mean LOS6.76 days11.00 days % ICU cases17.2453.85 Mean ICU LOS3.60 days5.50 days % mortality3.4525.96 Mean total cost$ 14,248$32,486 % 30 day readmit 14.299.09

18. MedicationDollar Cost to UNMDollar Cost to Patient Lactulose 30gm po5.9614.45 Lactulose 1 L of 20% solution enema 56.99116.50 Rifaximin 400mg tab (2 of 200mg tab) 18.1138.75 Acarbose 50mg tab0.984.50 Neomycin 500mg tab 1.986.45 Metronidazole 500mg tab 0.834.20 Vancomycin 250mg (IV given as oral at UNM) 6.3017.60

19. Summary of my recommendations from literature search

20. Always identify and try to correct the precipitating cause (70-80% improvement): – Hypovolemia (diarrhea, vomiting, hemorrhage, diuretics, large volume paracentesis) – GI bleeding – Hypokalemia and/or metabolic alkalosis – Other electrolyte disturbances – Hypoxia – Sedatives or tranquilizers or narcotics or alcohol – Hypoglycemia – Infection (including SBP) – Vascular occlusion (hepatic or portal vein thrombosis)

21. Use lactulose as the initial drug therapy. 45-90 g/day titrated to achieve 2-3 soft stools per day with a PH below 6. Lactulose enema if cannot take lactulose orally (1-3 L of 20% solution).

22. If lactulose not effective by itself, then add a non-absorbed antibiotics. Rifaximin is the preferred agent to neomycin. – 400mg po tid or – 550mg po bid If need to use neomycin: – 500mg po tid or – 1gm po bid – Consider waiting a few days for lactulose to work before considering neomycin

23. Lactulose for prevention of recurrence Protein restriction not needed unless HE resistant to lactulose. Substitute proteins from fish, milk, or meat with vegetable proteins or Add oral branched-chained amino acids to a low protein diet if severely protein intolerant.

24. Consider acarbose, oral vancomycin, and/or oral metronidazole as an alternative treatment if everything else fails or patient intolerant to other treatments.

25. References 1.Fessel, JN, Conn, HO. An analysis of the causes and prevention of hepatic coma. Gastroenterology 1972; 62:191. 2.Gabduzda, GJ, Hall PW, 3 rd. Relation of potassium depletion to renal ammonium metabolism and hepatic coma. Medicine (Baltimore) 1966; 45:481. 3.Als-Nielsen, B, Gluud, LL, Gluud, C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev 2004; :CD003044. 4.Uribe, M, Campollo, O, Vargas, F, et al. Acidifying enemas (lactitil and lactulose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double- blind, randomized clinical trial. Hepatogoly 1987; 7:639.

26. 5.Ferenci, P, Herneth, A, Steindl, P. Newer approaches to therapy of hepatic encephalopathy. Semin Liver Dis 1996; 16:329. 6.Conn, HO, Leevy, CM, Vlahcevic, ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; 72:573. 7.Sharma, BC, Sharma, P, Agrawal, A, et al. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137:885. 8.Coroba, J, Lopez-Hellin, J, Planas, M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol 2004; 41:38. 9.Straus, E, Tramote, R, Silva, EP, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992; 39:542.

27. 10.Tarao, K, Ikeda, T, Hayashi, K, et al. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut 1990; 31:702. 11.Bucci, L Palmieri, GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephlopathy. Curr Med Res Opin 1993; 13:109. 12.Williams, R, James OF, Warnes, TW, Morgan, MY. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study. Eur J Gastroenterol Hepatol 2000; 12:203. 13.Jiang, Q, Jiang, XH, Zheng, MH, et al. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta- analysis. Eur J Gastroetnerol Hepatol 2008; 20:1064. 14.Bass, NM, Mullen, KD, Sanyal, A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071. 15.Horst, D, Grace, ND, Conn, HO, et al. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 1984; 4:279.