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2 Contents 1. Prevalence of Malnutrition in End Stage Liver Disease 2. Assessment of Malnutrition in Liver cirrhosis 3. Prognosis of Malnutrition in ESLD or LC 4. Metabolic Derangement in ESLD or LC 5. Practical Strategies for Nutritional Managements in LC

3 1. Prevalence and Prognosis of Malnutrition in ESLD or Liver cirrhosis (LC) Malnutrition is a well-known complication in LC patients. Malnutrition has important prognostic implications because it is an independent predictor of mortality. : associated with decompensation, complications (ascites, encephalopathy, SBP, hepatorenal syndrome) and a poor quality of life. Malnutrition is present in more than half of cirrhotic patients. Nutritional status in LC is so important that it was part of the original Child-Turcotte scale. In 1973, Pugh replaced it with the prothrombin time. Nutrition 29 (2013) 1279, Best Pract Res Clin Gastroenterol 2013;27:619

4 Prevalence of Malnutrition in Liver cirrhosis According to severity of liver disease Compensated LC : 20% Decompensated LC : 80% (Child B: 40%, Child C: 90%) Undergoing LT : nearly 100% According to etiology Alcoholic cirrhosis Viral cirrhosis Nutrition 29 (2013) Sanchez et al. Liver Transpl 2006 Caregaro et al. Am J Clin Nutr 1996 Nutrition abnormalities were mainly conditioned by the severity of the liver disease and not by the presence of an alcohol-related or virus-b-related origin of the cirrhosis, whereas in females, both etiology and severity of liver disease seem to contribute to nutritional impairment. Italian Multicentre Cooperative Project. J Hepatol 1994;21:317

5 Prevalence and Prognosis of Malnutrition in LC Italian Multicentre Cooperative Project on Nutrition in Liver Cirrhosis : 1,492 cirrhotic patients with varying severity of liver impairment : Alcohol-related (37%), HBV-related (28%), cryptogenic cirrhosis (31%) Child-Pugh class C Nutritional status Not affect survival Child-Pugh class A and B Significant muscular depletion Worse life expectancy (Sarcopenia) Italian Multicentre Cooperative Project. J Hepatol 1994;21:317. Merli M et al. Hepatology 1996;23: ,

Due to the increasing prevalence of NAFLD, Sarcopenic Obesity, in which the patient loses muscle mass but not adipose tissue, is

6 Prevalence and Prognosis of Malnutrition in LC Pretransplant sarcopenia predicts worse outcomes after transplantation. Sarcopenia usually develops along with loss of visceral and subcutaneous adipose tissue mass. Due to the increasing prevalence of NAFLD, Sarcopenic Obesity, in which the patient loses muscle mass but not adipose tissue, is becoming more common. When comparing malnutrition between genders, Men tend to lose more muscle mass, whereas Women lose more adipose tissue mass. J Hepatol 1994;21:317. Nutrition 29 (2013) 1279.

7 Prevalence and Prognosis of Malnutrition in LC Independent predictor of survival in 212 Italian LC pts Study MAMC > 75 th %ile MAMC < 75 th %ile MAMC < 10 th %ile MAMC < 5 th %ile Alberino et al. Nutrition 2001 Malnutrition in cirrhosis consists mostly of loss of skeletal muscle mass or sarcopenia, which is associated with higher mortality and worse quality of life. Nutrition 29 (2013)

8 Prevalence and Prognosis of Malnutrition in LC Nutritional Index as pre-transplantation mortality in 222 UK study RFH-SGA - BMI - MAMC - Dietary intake Gunsar et al. Aliment Pharmacol Ther 2006

9 2. Causes of Malnutrition in Liver Diseases Decreased intake of nutrients - Abdominal distention (ascites, splenomegaly) - Nausea and vomiting - Anorexia (chronic esophagitis and portal gastropathy) - Encephalopathy-related decreased oral intake - Impaired gastric emptying - Iatrogenic causes (unnecessary restriction of protein for encephalopathy, repeated fasting due to diagnostic tests) - Impairment of taste (zinc deficiency) - Inhibition of gluconeogenesis due to alcohol abuse - Alcohol-related malabsorption of some nutrients (folate, vitamin B12, thiamine, magnesium) - Poor socioeconomic status - Recurrent uncontrolled infections in cirrhotic patients Metabolic derangements - Insulin resistance and its consequences - Increase in resting metabolic rate Malabsorption - Impairment of bile flow in chronic cholestasis - Bacterial overgrowth - Concomitant chronic pancreatitis (particularly in alcoholic steatohepatitis) - Concomitant chronic autoimmune liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis) Drug- or toxin-induced malnutrition - Use of cholestyramine and colestipol leading to lipid malabsorption - Metformin use for insulin resistance leading to vitamin B12 deficiency - Chronic steroid use leading to calcium and vitamin D malabsorption Best Pract Res Clin Gastroenterol 2013;27:619

10 Causes of Malnutrition in ESLD & LC The causes of malnutrition in liver disease are complex and multifactorial! Bemeur C et al. J Nutr Metab 2010

11 3. Assessment of Malnutrition in ESLD and LC Recommended methods include the following: Anthropometry Bioelectrical impedance Biochemical parameters Subjective Global Assessment Hand-grip strength L3 skeletal muscle index As patients with liver cirrhosis face an high risk of experiencing malnutrition, Screening by means of the SGA or Anthropometric method should be initiated as early as possible to improve the clinical outcomes. Best Practice & Research Clinical Gastroenterology 27 (2013) Nutrition 29 (2013)

12 Anthropometric measurements Anthropometric evaluation included the measurement of body weight, height, triceps skinfold thickness (TSF), midupper arm circumference (MAC), and midarm muscle circumference (MAMC). The TSF was measured by a Holtain caliper (Holtain Ltd, UK) at the middle point between acromion and olecranon of nondominant arm: skinfolds measured to the nearest mm of contact surface area. The MAMC was calculated by the following formula : MAMC (cm) = MAC - (0.314 X TSF [mm]) ; where MAMC (cm) was measured with tape at the same site as TSF. Diagnosis of Malnutrition is established by values of MAMC and/or TSF below the 5th percentile in patients aged years, or the 10th percentile in patients aged over 74 years. Nutrition Volume 17, Number 6, 2001 Best Pract Res Clin Gastroenterol 2013;27:619

13 Anthropometric measurements Another useful and practical parameter is the Body mass index (BMI) : Although sometimes limited by water overload (ascites and edema), it is a simple and easy-to-perform method. The reference values for malnutrition in cirrhosis are the following : No ascites, BMI 22 kg/m 2 Mild ascites, BMI 23 kg/m 2 Tension ascites, BMI 25 kg/m 2 Nutrition 29 (2013) Best Pract Res Clin Gastroenterol 2013;27:619 (It was proved that cirrhotic patients with BMI < 20 kg/m 2 have greater mortality) Upper mid-arm muscle area (MAMA) and upper mid-arm fat area (MAFA) were calculated as the following formula, and were used as estimates of muscle mass and fat deposits in each patient. (Journal of Hepatology 1994; 21: )

14 Methods to assess protein-energy malnutrition and sarcopenia in liver cirrhosis patients World J Gastroenterol 2014 June 21; 20(23): 7286 There is No gold standard to assess the nutritional status of patients with chronic liver disease!

15 Vectorial Bioelectrical Impedance (BI) Inbody Xc, reactance; R, resistance; H, height;, Child A patient;, Child B patient;, Child C patient Nutrition 29 (2013) BI is a reliable, noninvasive and inexpensive method that indirectly assesses the body composition!

16 Subjective Global Assessment Questionnaire History 1. Weight Change Loss in last six months Change in two weeks 2. Dietary changes: Search for the Presence of starvation, full liquid diet, hypocaloric, and suboptimal liquid diet 3. Presence or absence of nausea, vomiting, and diarrhea persisting for last two weeks 4. Functional status 5. Evaluation of individual nutritional requirements Note the primary diagnosis and evaluate the presence of metabolic stress (no, low, moderate and high stress) Physical examination 0 = normal, 1+ = mild, 2+ = moderate, 3+ = severe 1. Loss of subcutaneous fat in triceps and chest 2. Muscle wasting in deltoids and quadriceps 3. Ankle edema 4. Sacral edema 5. Ascites SGA rating: A = well nourished B = moderately malnourished C = severely malnourished Use simple methods such as Subjective Global Assessment (SGA) and Anthropometry to identify patients at risk of undernutrition! [2006 ESPEN Guideline on Enteral Nutrition] Clinical Nutrition 25 (2006) Nutrition 29 (2013)

17 4. Metabolic Derangement in LC and ESLD Reduced glycogen storage in cirrhotic liver! Decreased numbers of hepatic parenchymal cells Impaired glycogen synthesis d/t insulin resistance Arakawa et al. Hepatol Res. 2004

18 Metabolic Derangement in LC Metabolic alterations leading to malnutrition in ESLD Protein Increased catabolism Increased utilization of BCAAs Decreased ureagenesis Carbohydrate Decreased hepatic and skeletal muscle glycogen synthesis Increased gluconeogenesis Glucose intolerance and insulin resistance Fat Increased lipolysis Enhanced turnover and oxidation of fatty acids Increased Ketogenesis Bemeur C et al. J Nutr Metab 2010

19 Metabolic Derangement in LC Starvation type metabolism Earlier and more accentuated pattern in cirrhosis Owen s study Splanchnic vessel metabolism in cirrhosis during fast : Increased hepatic gluconeogenesis and ketogenesis Fuel oxidation in cirrhosis during fast : Fat %, Carbohydrate % Owen et al J. Clin. Invest & 1983 Owen et al. have demonstrated that due to the limited glycogen reserve that cirrhotic patients have, a single overnight fast is the equivalent of a 3-d starvation period in a healthy individual. : Thus, prolonged fasts should be avoided in cirrhotic patients because they induce the consumption of lipids and proteins for gluconeogenesis. (Hence, a late evening snack of approximately 200 kcal is recommended for these patients to suppress muscle protein disruption) Nutrition 29 (2013)

20 Metabolic Derangement in LC Interorgan Ammonia Trafficking in Hepatic Encephalopathy Cordoba J. Semin Liver Dis 2008:28:70-80 NH3, ammonia; GLU, glutamate; GLN, glutamine; GNASE, glutaminase; BBB, blood-brain barrier

21 Metabolic Derangement in LC Decreased Fischer s ratio (Val+Leu+Ile / Phe+Tyr) Decreased BCAAs Increased oxidation of BCAA increased energy consumption Increased BCAA uptake by muscles hyperinsulinemia Increased metabolism of BCAA in muscles hyperammonemia Increased AAAs Decreased capacity for the disposal of AA in liver Arakawa et al. Hepatol Res. 2004

22 Interorgan ammonia trafficking and metabolism Ammonia from gut and kidneys, mainly due to glutaminase activity must be detoxified in muscles because liver dysfunction. Skeletal muscle is capable of decreasing blood ammonia by metabolizing ammonia to glutamine! Bemeur C et al. J Nutr Metab 2010

23 Malnutrition and HE in LC Malnutrition SFT and/or MAMC < 5 th %tile and/or BMI < 20 kg/m 2, and/or weight loss > 5 10% in the previous 3 6 months Kalaitzakis E et al. Liver Int 2007; 27:

24 Nutritional Intervention Study 1st controlled study randomizing cirrhotic patients with HE to receive different amounts of dietary protein Low protein diet with progressive increment Vs. Normal protein diet from the start 1. The outcome of HEP : not significantly different 2. Protein synthesis : similar 3. Protein breakdown : higher in low-protein diet group Cordoba et al. J Hepatol 2004;41:38 43.

25 New Concept in HE Management In the past, restriction of dietary protein was considered for patients with encephalopathy; however, the negative impact of that maneuver on overall nutrition is thought to outweigh the benefit when treating encephalopathy, and it is thus discouraged. There may be some benefit to replacing animal-based protein with vegetable-based protein in some patients with encephalopathy that is difficult to manage. Bacon BR.In Harrison s Textbook 17 th 2008, 18 th 2011

26 5. Practical Strategies for Nutritional Managements in LC (Current Guideline) Normal and Higher Energy & Protein Supplementation Nocturnal Energy Supplementation (Late Evening Snack) BCAA Supplementation Different quality of protein Water, electrolytes, vitamins, trace elements

27 1997 ESPEN Guideline in LC Plauth M et al. Clin Nutr 1997

28 2009 ESPEN Guideline in LC Clinical Nutrition (2006) 25, Clinical Nutrition 28 (2009)

29 Recommended daily values for cirrhotic patients Encephalopathy No encephalopathy Glucose intolerance without encephalopathy Calories (kcal/kg/d) Malnourished Proteins Carbohydrates Lipids (g/kg) (%) (%) Echephalopathy grades I II Encephalopathy grades III IV Nutrition 2013;29:

30 Hepatic encephalopathy, 2014 EASL

31 Hepatic encephalopathy, 2014 EASL

32 Hepatic encephalopathy, 2014 EASL Modulation of nitrogen metabolism is crucial Protein uptake : 1.2~1.5g/kg/d Vegetable protein >> animal protein Initial <40g/d, chronic protein restriction is detrimental Protein requirement greater than heathy patients Risk of accelerated fasting metabolism Malnutrition, Sarcopenia- Risk factor of HE Moderate hyperalimentation Energy intake : 35-40kcal/kg/d 300~400g/d of Glucose to prevent protein catabolism Small meals evenly distributed, late night snack Glycogen storage, insuline resistance Increase use of Oral BCAA Fat intake : 30-35% of energy (<40%)

33 Hepatic encephalopathy, 2014 EASL The use of a multivitamin is generally recommended! Zinc supplementation is considered when treating HE Wernicke s is suspected large doses of thiamine should be given parenterally and before any glucose administration!

34 Late Evening Snack (Nocturnal Energy Supplementation) LES (Late Evening Snack) & Divided Meals (4 ~7 meals per day) : Compensation for overnight fast period Avoidance of accelerated gluconeogensis : Improvement of nitrogen balance Improvement of body composition 1. Swart et al. Br Med J st article about LES 2. Miwa Y et al. Hepatol. Res ONS (Ensure) LES 3. Okamoto et al. Hepatol Res Nakaya et al. Nutrition 2007 BCAA LES 5. Plank et al. Hepatology 2008 Long term nutritional benefit of LES

35 2009 ESPEN Guideline for PN in LC Indication and timing of PN Moderately or severely malnourished cirrhotics who cannot be nourished sufficiently by either oral or enteral route. Patients with unprotected airways and encephalopathy (HE) when cough and swallow reflexes are compromised. Temporary abstinence (including nocturnal fasting!) for more than 12 h : I.V. glucose at 2 3g/kg/d Fasting period longer than 72 h : Total PN Nutrient Intake - General Provide energy to cover 1.3 x REE Give glucose to cover 50 % - 60 % of non-protein energy requirements Reduce glucose infusion rate to 2 3 g/ kg/d in case of hyperglycemia and use consider the use of i.v. insulin. Use lipid emulsions with a content of n-6 unsaturated fatty acids lower than in traditional pure soybean oil emulsions

36 2009 ESPEN Guideline for PN in LC Energy Intake Amino Acid 1.2 g/kg/d in compensated cirrhosis without malnutrition. 1.5 g/kg/d in decompensated cirrhosis with severe malnutrition. In encephalopathy III or IV, consider the use of solutions rich in BCAA and low in AAA, methionine and tryptophane. Water, electrolytes, vitamins, trace elements All water soluble vitamins and fat soluble vitamins : daily Vitamin B1 (Thiamine) high risk of Wernicke s encephalopathy in alcoholics, prior to starting i.v. glucose!! treatment (500 mg i.v. t.i.d. for 2-3 days) Zinc : twice the normal daily requirement of zinc (2x5mg/d) Prevention of refeeding syndrome additional phosphate, potassium and magnesium, together with water soluble vitamins

37 BCAA Supplementation IV BCAA with Acute Encephalopathy Meta-analysis (Als-Nielsen et al. Cochrane Database Syst Rev 2003) Significant, positive effect on the course of HE, but not on survival Summary of 2009 ESPEN guideline Standard solution should be given in mild encephalopathy (II) Liver-adapted complete amino acid solution should be given in more severe encephalopathy (III IV)

38 BCAA Supplementation Long-term Oral BCAA and Clinical Outcome 2 randomized controlled studies Marchesini et al. Gastroenterology 2003 (Italy) Improvement of death rate, progression of liver ds., hospital admission rate, QOL Muto et al. Clin Gastroenterol Hepatol 2005 (Japan) Improvement of event-free survival, serum albumin concentration, QOL Summary of 2006 ESPEN guideline Oral BCAA supplementation can improve clinical outcome in advanced cirrhosis.

39 Protein Quality : Vegetable Protein Advantage Higher intestinal clearance of nitrogen-waste products Increased transit time Reduced colonic ph entrapping ammonia in the intestinal lumen Lower percentages of methionine and tryptophan Supported by some studies Uribe et al. 1982; Bianchi et al. 1993; Amodio et al Disadvantage Bloating, flatulence and early satiety poor tolerance Need of cheese and other milk-derived dietary products supplementation Not supported by others Shaw et al. 1983; Chiarino et al Merli & Riggio. Metab Brain Dis (2009) 24:

40 A practical approach for managing liver cirrhosis patients with sarcopenia or sarcopenic obesity World J Gastroenterol 2014 June 21; 20(23): 7286

41 Practice points!! Patients with different forms of hepatic disorders are vulnerable to developing malnutrition. Alcoholic liver disease is a strong predictor for malnutrition due to the numerous malnutrition risk factors associated with chronic alcohol abuse. Patients with liver cirrhosis also face an extraordinary risk of experiencing malnutrition. Malnourished patients with liver diseases generally have a higher risk of developing adverse clinical outcomes and increased healthcare costs. Nutrition screening with the Subjective Global Assessment (SGA) scale and anthropometric measurements is an important first step in the early identification of malnutrition. Hepatologists should be strongly urged to focus on addressing the challenges of malnutrition in terms of detection, diagnosis, and treatment!

NUTRITIONAL OPTIMIZATION IN PRE LIVER TRANSPLANT PATIENTS

NUTRITIONAL OPTIMIZATION IN PRE LIVER TRANSPLANT PATIENTS ACHIEVING NUTRITIONAL ADEQUACY Dr N MURUGAN Consultant Hepatologist Apollo Hospitals Chennai NUTRITION IN LIVER FAILURE extent of problem and consequences