1. Hepatic Failure: Nutrition Issues in Liver Disease John K. DiBaise, MD Associate Professor of Medicine Mayo Clinic Arizona 2007 AGA GI Fellows’ Nutrition Course

2. Outline Chronic liver disease Liver transplantation Acute liver failure

3. Liver Functions Metabolism of carbohydrate, protein and fat Activation and storage of vitamins Detoxification and excretion of substances Severe liver injury  Metabolic derangements  PEM

4. Protein Energy Malnutrition in Liver Disease Rare in most acute liver disease and chronic liver disease w/o cirrhosis Up to 20% with compensated disease 65-90% with advanced disease Nearly 100% awaiting liver transplant Correlation between severity of liver disease and severity of malnutrition – –Cholestatic: calorie and fat-soluble vitamin deficiencies – –Non-cholestatic: protein deficiency McCullough AJ et al. AJG 1997;92:734 Zaina FE et al. Transpl Proc 2004;36:923

5. Consequences of Malnutrition in Chronic Liver Disease Increased rate of portal hypertensive complications Decreased survival rate Unclear whether PEM independent predictor of survival or reflects severity of liver disease Merli M et al. Hepatology 1996;23:1041

6. Prognostic Implications of PEM in Liver Transplant Candidates Increased rate of transplant complications Increased intraop PRBC requirements Increased time on ventilator postop Higher incidence of graft failure Decreased survival postop Increased costs Figueiredo FA et al. Transplantation 2000;70:1347 Stephenson G et al. Transplantation 2001;72:666

7. Which of the following is the most important contributor to malnutrition in cirrhotics? A. A. Poor oral intake B. B. Malabsorption C. C. Altered metabolism D. D. None of the above

8. Contributing Factors to Malnutrition in CLD Poor oral intake – –Anorexia – –Nausea, early satiety – –Altered taste – –Dietary and fluid restrictions – –Low-grade encephalopathy – –Lifestyle

9. Contributing Factors to Malnutrition in CLD Malabsorption – –Bile salt deficiency – –Small bowel bacterial overgrowth – –Portal hypertensive enteropathy – –Medications Diuretics, cholestyramine, lactulose, neomycin – –Pancreatic insufficiency

10. Contributing Factors to Malnutrition in CLD Metabolic abnormalities - hypermetabolism – –State of catabolism similar to starvation/sepsis – –Up to one-third with stable cirrhosis – –Another third hypo-metabolic – –Lower respiratory quotient – –Not readily identified by markers of liver disease – –? extrahepatic manifestation – –Adversely effects survival after liver transplant – –No association with gender, etiology, severity, protein deficit or presence of ascites/tumor Peng S et al. Am J Clin Nutr 2007;85:1257 Selberg O et al. Hepatology 1997;25:652

11. Predisposing Factors of Hypermetabolism Infection Ascites Altered pattern of fuel metabolism – –Glucose intolerance/hyperinsulinemia/insulin resistance – –Decreased glycogen storage – –Increased protein catabolism – –Decreased meal-induced protein synthesis – –Accelerated gluconeogenesis from AA – –Increased lipid catabolism McCullough AJ et al. Sem Liver Dis 1991;11:265 Scolapio JS et al. JPEN 2000;24:150

12. Which of the following is a useful marker of nutritional status in decompensated cirrhosis? A. A. BMI B. B. Prealbumin C. C. Harris-Benedict equation D. D. None of the above

13. Nutritional Assessment History – –GI symptoms – –Weight loss – –Calorie/diet intake (prospective) – –Food preferences Exam – –Fluid retention – –Muscle wasting

14. Nutritional Assessment Caveats Weight/Body mass index (BMI) – –? BMI adjusted for ascites Biochemical tests – –Albumin, prealbumin Campillo B et al. Gastro Clin Biol 2006;30:1137 Serum protein half-lives Protein Half- life Albumin18 d Transferrin8 d Prealbumin2–3 d Retinol- binding protein 2 d Ferritin30 h

15. Nutritional Assessment Alternatives Anthropometric measurements – –Triceps skin-fold thickness – –Mid-arm muscle circumference Assessment of muscle function – –Hand-grip strength – –Respiratory-muscle strength

16. Nutritional Assessment Alternatives Subjective global assessment (SGA) – –Weight loss last 6 months, changes in diet intake, GI symptoms, functional capacity, fluid retention – –High specificity but poor sensitivity in cirrhotics – –Useful in predicting outcome after transplant

17. Nutritional Assessment Alternatives Global nutrition assessment scheme – –BMI, MAMC, dietary intake data – –Reproducible, validated, predictive method in cirrhotics Morgan MY et al. Hepatology 2006;44:823

18. Nutritional Assessment Body Composition Body cell mass – –Isotope dilution – –Whole-body potassium – –In vivo neutron activation – –Bioelectrical impedance – –Dual-energy x-ray absorptiometry (DXA)

19. Nutritional Assessment Energy Expenditure Indirect calorimetry – –Evaluate status of energy metabolism – –Allows calculation of RQ – –Hypermetabolic if measured REE > 10-20% predicted REE Predictive equations – –Harris-Benedict, Mifflin-St. Jeor, etc. – –Limited by dependence upon weight Muller MJ et al. Am J Clin Nutr 1999;69:1194

20. Treatment Goals Improve PEM Correct nutritional deficiencies Oral, enteral, parenteral or combination

21. General Nutrition Guidelines (ESPEN Consensus) Compensated cirrhosis – –25-35 kcal/kg/day; 1-1.2 g/kg/day protein Complicated cirrhosis – –35-40 kcal/kg/day; 1.5 g/kg/day protein Mild-moderate encephalopathy – –25-35 kcal/kg/day; 0.5-1.5 g/kg/day protein – –Restrict protein as briefly as possible Severe encephalopathy – –25-35 kcal/kg/day; 0.5 g/kg/day protein – –Restrict protein as briefly as possible Plauth M et al. Clin Nutr 1997;16:43

22. T/F: Fluid restriction should be initiated in all cirrhotics with evidence of fluid retention.

23. General Nutrition Guidelines Consume 6-7 small meals/day including a bedtime snack rich in CHO Initiate enteral intake when oral intake inadequate – –Nasoenteral vs. gastrostomy Identify and correct nutrient deficiencies – –Alcohol/HCV – thiamine, folate – –Cholestatic – fat-soluble vitamins Sodium restrict – only when fluid retention Fluid restrict – only when sodium < 120 mEq/L

24. No Need for Routine Protein Restriction in Encephalopathy RCT of 20 malnourished cirrhotics hospitalized with PSE (mean, stage 2) Gradual increase in protein vs. 1.2 g/kg/d via feeding tube All received lactulose; precipitating factors treated Cordoba J et al. J Hepatol 2004;41:38

25. No Need for Routine Protein Restriction in Encephalopathy Outcomes – –No difference in PSE, survival, ammonia level – –Better nitrogen balance in 1.2 g/kg/d group Cordoba J et al. J Hepatol 2004;41:38

26. T/F: BCAA have been recommended for use in protein-intolerant cirrhotics.

27. What About Branched Chain Amino Acids (BCAA)? Isoleucine, leucine and valine Play role in protein breakdown Depleted in cirrhosis (and sepsis/trauma) – –Increase uptake by muscle to generate substrates for gluconeogenesis – –BCAA/AAA imbalance – –? mediated by hyperinsulinemia

28. BCAA and Hypothetical Role in Encephalopathy BCAA depletion enhances passage of AAA (tryptophan) across BBB  false neurotransmitters Role of supplementation to treat PSE remains controversial ? role in refractory PSE

29. BCAA in Protein- Intolerant Cirrhotics Tolerate < 40 g protein/day Randomized to 70 g/day either as casein or BCAA supplement Treatment failure = worsening PSE – –7/12 failures in casein group vs. 1/14 in BCAA group Basis for ESPEN recommendation to use BCAA in this situation Horst D et al. Hepatology 1984;4:279

30. BCAA Supplementation in Advanced Cirrhosis RCT of 174 advanced cirrhotics (B and C) – –1 year: BCAA, maltodextrins or lactoalbumin – –Patients not malnourished or encephalopathic – –BCAA tended to improve survival, disease progression and hospital admits (PP not ITT analysis) Results limited d/t large number of drop-outs b/c poor palatability of BCAA Marchesini G et al. Gastro 2003;124:1792

31. Enteral Nutrition in Cirrhosis Should be encouraged early if PO intake inadequate – –Nasoenteral preferred – –At least 3 weeks Benefit seen mainly in severely malnourished – –Improved in-hospital survival, Child score, albumin, bilirubin, encephalopathy – –Improved nitrogen balance and reduced infections post transplant Cabre E et al. Gastro 1990;98:715 Kearns PJ et al. Gastro 1992;102:200

32. Practical Issues in Nutrition Therapy Oral supplementation – –Often unsuccessful due to GI symptoms Short-term tube feeding – –Generally helpful but of uncertain long- term benefit Long-term tube feeding – –Difficult due to reliance on nasoenteral tubes

33. Parenteral Nutrition in Cirrhosis Reserve for those who can’t tolerate EN – –Increased cost and complications Standard AA adequate for most Optimal macronutrient composition remains unclear ? role in perioperative liver transplant setting for severely malnourished

34. Effect of TIPS on Nutritional Status Open-label study of 14 consecutive cirrhotics with refractory ascites Improved body composition and several nutritional parameters at 3 and 12 months – –Dry body weight – –Total body nitrogen – –Muscle strength – –REE – –Food intake Allard JP et al. AJG 2001;96:2442

35. Liver Transplantation Most candidates are malnourished PEM associated with poor outcome Body cell mass assessment is better predictor of outcome than Child-Pugh score Predictive equations of BEE compare poorly to indirect calorimetry Deschennes M et al. Liver Transpl Surg 1997;3:532 Madden AM et al. Hepatology 1999;30:655

36. Pre-Transplant Nutrition Support Goal – prevent further depletion and slow deterioration Establish calorie and protein goals Avoid protein, sodium and fluid restrictions when possible Provide multivitamin and other micronutrient supplementation as needed

37. Pre-Transplant Nutrition Support - Enteral RCT of 82 ESLD pts with MAMC < 25 percentile Enteral feeds + oral diet vs. oral diet alone until transplantation No effect on post-transplant complications or survival Trend toward improved pre- transplant survival in enteral feed group (p=0.075) Le Cornu KA et al. Transplantation 2000;69:1364

38. Post-Transplant Nutrition Support – Enteral (< 12 hrs) 50 transplant recipients received either nasoenteral feeding (placed during surgery) or IVF until oral intake resumed – –Greater calorie/protein intake and faster recovery of grip strength but no difference in REE – –Reduced viral infections (17.7% vs. 0%) and trend toward reduced overall infections (47.1% vs. 21.4%) Hasse JM et al. JPEN 1995;19:437

39. Post-Transplant Nutrition Support - Parenteral RCT of 28 patients after transplant TPN (35 kcal/kg/d) w/BCAA (1.5 g/d) vs. TPN w/standard AA vs. no TPN for 1 week – –Decreased ICU length of stay – –Improved nitrogen balance – –No difference b/w BCAA and standard AA – –Offset the expense of TPN Reilly J et al. JPEN 1990;14:386

40. Post-Transplant Nutrition Support Recommendations generally based on uncontrolled studies Recommend nasoenteral feeding in severely malnourished postoperatively with transition to PO as tolerated – –TPN only when unable to use the gut Weimann A et al. Transpl Int 1998;11:S289

41. Acute Liver Failure No data from controlled trials regarding benefit of nutrition support Metabolic physiology similar to “acute stress syndrome” (hypercatabolic) – –Severe protein catabolism with increased AA overall but decreased BCAA – –? benefit more from supplying BCAA than conventional AA Lack of liver impairs the ability to tolerate nutrition support Schutz T et al. Clin Nutr 2004;23:975

42. Acute Liver Failure General recommendations – –Limit fluid intake; prevent hypoglycemia – –High calorie/protein requirements – start slowly Limit protein (0.6 g/kg/day) in coma/severe PSE (? role of BCAA) Make adjustments based on patient’s condition – –Try enteral feeding first if gut working Schutz T et al. Clin Nutr 2004;23:975

43. Take Home Points Malnutrition is an important complication of cirrhosis with prognostic implications Multifactorial causation Nutritional assessment should be performed in all with chronic liver disease

44. Take Home Points Nutrition therapy can reduce the risk of complications and improve survival Standard products are safe in most situations Adequate protein can safely be administered to patients with encephalopathy – –?? BCAA in severely malnourished or refractory encephalopathy