Hepatic Encephalopathy Exploring the neuropsychiatric consequences of cirrhosis

Hepatic Encephalopathy: Exploring the neuropsychiatric consequences of cirrhosis Module 2 Overt HE This material was prepared under the guidance of Dr. Christopher Rose, Dr. Hemant Shah, Dr. Puneeta Tandon and Dr. Philip Wong Use for education purposes only This educational program has been endorsed by the Canadian Association for the Study of the Liver (CASL)

Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver Hendrik Vilstrup, Piero Amodio, Jasmohan Bajaj, Juan Cordoba, Peter Ferenci, Kevin D. Mullen, Karin Weissenborn, and Philip Wong Hepatology. 2014 Aug; 60(2): 715 -35, co-published in the Journal of Hepatology September 2014 volume 61 , Issue 3 , 642 - 659 Use this slide deck for education purposes only Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 715– 735. doi: 10. 1002/hep. 27210

Overt HE Indicates a Poor Prognosis Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999; 30: 890 -895.

Diagnosis and Testing for OHE West Haven criteria for classification. Hepatic encephalopathy should be divided into various stages of severity, reflecting the degree of selfsufficiency and the need for care. OHE still remains a diagnosis of exclusion. High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD. 1, 2 1. Lockwood AH. Blood ammonia levels and hepatic encephalopathy. Metab Brain Dis. 2004; 19: 345 -349. 2. Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 715– 735. doi: 10. 1002/hep. 27210

Clinical Classification of HE (West-Haven criteria) Level of Consciousness Neuropsychiatric Symptoms Neurological Symptoms Normal Impairments only measurable with psychometric tests None "Minimal HE" Slight mental slowing Euphoria/dysphoria irritability and anxiety, shortened attention span Fine motor skills affected Increased fatigue, apathy or lethargy Slight personality disorder, slight disorientation to time and place. Flapping tremor, ataxia, slurred speech Somnolence Aggression, marked disorientation to time and place. Rigour, clonus, asterixis Coma -

The Clinical HE Staging Scale CHESS: Correlation between the global score of the Clinical Hepatic Encephalopathy Staging Scale and the adapted-West-Haven criteria (r=0. 64) A Score of 3+ is equivalent to a HE ≥ grade 2 ORTIZ, M. , CÓRDOBA, J. , DOVAL, E. , JACAS, C. , PUJADAS, F. , ESTEBAN, R. and GUARDIA, J. (2007), Development of a clinical hepatic encephalopathy staging scale. Alimentary Pharmacology & Therapeutics, 26: 859– 867. doi: 10. 1111/j. 1365 -2036. 2007. 03394. x

Treatment of Overt Episodic HE An episode of OHE (whether spontaneous or precipitated) should be actively treated. Secondary prophylaxis after an episode for overt HE is recommended. Recurrent intractable OHE, together with liver failure, is an indication for Liver Transplant (LT). Level 1 A evidence does not exist for most of therapies currently used for HE. AASLD recommendations 10, 11, 13 Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 715– 735. doi: 10. 1002/hep. 27210

Treatment of Overt HE

Nonabsorbable Disaccharides Lactulose

Lactulose Mode of Action • • Titrated daily to at least two soft bowel movements per day. Overuse can lead to aspiration, dehydration, electrolyte imbalance, severe perianal skin irritation or even precipitate HE. Weber, et al. Lactulose and combination therapy of hepatic encephalopathy: the role of the intestinal microflora. Dig Dis. 1996; 14 (Suppl 1): 53 -63.

Open Label RCT Lactulose Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology. 2009; 137: 885 -891.

Antibiotics Rifaximin Metronidazole Neomycin

Rifaximin Mode of Action Rifaximin has been used for therapy of HE in a number of trials. These trials showed effect of Rifaximin that was equivalent or superior to the compared agents with good tolerability. 1 Trial with patients having two earlier OHE bouts to maintain remission showed the superiority of rifaximin (+lactulose) versus placebo. 2 1. Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis. 2013; 28: 307 -312. 2. Bass NM, et al. Rifaximin treatment in hepatic ehalopathy. N Engl J Med. 2010; 362: 1071 -1081.

Rifaximin in Prevention of Recurrence of OHE Rifaximin as an addon to lactulose is recommended for prevention of recurrent episodes of HE after the second episode. From N Engl J Med. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. 2010; 362: 1071 -1081. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

What does it all mean? From N Engl J Med. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. 2010; 362: 1071 -1081. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Rates of HE-related hospitalizations Adapted from Mullen et al. Clinical Gastroenterology and Hepatology Volume 12, Issue 8, Pages 1390 -1397. e 2 DOI: 10. 1016/j. cgh. 2013. 12. 021

Metronidazole As short-term therapy, metronidazole also has advocates for its use. However, long-term potential for CNS toxicity, peripheral neuropathy and carcinogenesis. 1 Metronidazole is an alternative choice for treatment of OHE (multiple time series, dramatic uncontrolled experiments – off-label). 2 1. Product Monograph Flagyl (Metronidazole), Submission Control No. 167573. Version 6. 0 dated Nov 7 2013. 2. Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 715– 735. doi: 10. 1002/hep. 27210

Neomycin Useful primarily in infections involving aerobic, Gram-negative bacteria, some mycobacteria. Mostly ineffective against anaerobic bacteria and fungi. Its use as therapy for HE has declined due toxicity (ototoxicity, nephrotoxicity), and it is no longer available in Canada. Hawkins RA. Adv Exp Med Biol. 1994; 368: 125 -34. .

Summary HE treatments Treatment Pro’s Con’s Lactulose First-line, readily available. Prebiotic and laxative properties. Overuse can precipitate HE. Non adherence due to GI adverse effects. Rifaximin Useful for lactulose intolerant patients, or those that develop recurrent HE on lactulose. No evidence as monotherapy. Metronidazole Inexpensive short-term use. Not for long-term use, CNS toxicity, peripheral neuropathy and carcinogenesis. Neomycin (not Glutaminase inhibitor, inexpensive, short-term use. Not for long-term use, can cause ototoxicity, nephrotoxicity. available in Canada) Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 715– 735. doi: 10. 1002/hep. 27210

Dietary Modification BCAA’s (Branched-Chain Amino Acids) Nutrition in cirrhosis

BCAA Mode of Action • • A systematic Cochrane Review of controlled trials (RCTs) indicated that oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE. 1 There is no effect of BCAA on the episodic bout of HE. 2 1. Gluud LL, Dam G, Les I, Córdoba J, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No. : CD 001939. DOI: 10. 1002/14651858. CD 001939. pub 3. 2. Naylor CD, et al. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A metaanalysis. Gastroenterology. 1989; 97: 1033 -1042. 3. H Moriwaki, et al, “Branched-Chain Amino Acids as a Protein- and Energy-Source in Liver Cirrhosis. Biochemical and Biophysical Research Communications. 313, 2004: 405407.

BCAA in HE Adapted by permission from Macmillan Publishers Ltd: Am J Gastroenterol. Les L, Doval E, Martinez RG, Planas M, Cardenas G, Gomez P, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. 2011; 106, 1081 -1088 doi: 10. 1038/ajg. 2011. 9 , copyright 2011

Nutrition Chronic protein restriction is detrimental because patients’ protein requirements are relatively greater than that of healthy patients and they are at risk of accelerated fasting metabolism. Malnutrition and loss of muscle mass is a risk factor for development of HE.

Hepatic encephalopathy stage Low protein diet is not necessary and might be detrimental 4 low protein diet normal protein diet 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Day Córdoba J, López-Hellín J, Planas M, Sabín P, Sanpedro F, Castro F, Esteban R, Guardia J. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004 Jul; 41(1): 38 -43.

Suggested Intake Malnutrition can be found in 65 -95% of cirrhotic patients 1. M. Plauth et al. ESPEN Guidelines for nutrition in liver disease and transplantation. Clinical Nutrition. 1997; 16: 43 -55. 2. Greenberger NJ, Carley J, Schenker S, et al. Effect of vegetable and animal protein diets in chronic hepatic encephalopathy. Am J Dig Dis. 1977; 22: 845– 855.

Conclusion Module 2

Summary HE is under-recognized and under-treated in Canada. HE episode treatment should concentrate on investigating and treating precipitating factors. Protein intake should not be restricted in patients with HE. Lactulose and rifaximin can prevent relapse of HE for out-patients.

HE treatment guidelines recomendations RECOMMENDATION 10 • An episode of overt hepatic encephalopathy (OHE) (whether spontaneous or precipitated) should be actively treated (GRADE II-2, A, 1). RECOMMENDATION 11 • Secondary prophylaxis after an episode for overt hepatic encephalopathy (OHE) is recommended (GRADE I, A, 1). RECOMMENDATION 19 • Lactulose is the first choice for treatment of episodic overt hepatic encephalopathy (OHE) (GRADE II-1, B, 1). RECOMMENDATION 20 • Rifaximin is an effective add-on therapy to lactulose for prevention of overt hepatic encephalopathy (OHE) recurrence (GRADE I, A, 1). Vilstrup, H. , Amodio, P. , Bajaj, J. , Cordoba, J. , Ferenci, P. , Mullen, K. D. , Weissenborn, K. and Wong, P. (2014), Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60: 71 – 735. doi: 10. 1002/hep. 27210

Thank you very much for reviewing the HE Modules! These modules were recorded by Dr. Philip Wong, MD. Use for education purposes only