Nutrition, Frailty, and Sarcopenia in CirrhosisANDREAS ZORI , MD

ASSISTANT PROFESSOR

UNIVERSITY OF FLORIDA

ObjectivesUnderstand frequency and symptoms of common nutritional deficiencies in patients with cirrhosis

Recognize the significance of sarcopenia and frailty in prognosis for patients with cirrhosis

Become familiar with assessment of frailty and sarcopenia

Outline evidence based interventions to address frailty in patients with cirrhosis

Be able to answer patient questions and concerns about nutrition based on evidence

Definitions: Sarcopenia and Frailty

Frailty - A syndrome of diminished strength, endurance, and reduced physiological function that increases vulnerability for developing physical dependency and death.

Sarcopenia – loss of skeletal muscle mass, strength and function◦ Major component/indicator of Frailty

sSarcopenia

Frailty

Pathophysiology of Sarcopenia/Malnutrition

Trovato, 2016

Assessment of SarcopeniaAnatomic Assessment◦ Psoas Muscle Area – CT, DEXA

◦ Skeletal muscle index - Standardized by height and sex

◦ Upper arm circumference

◦ Bioelectric impedance

Functional Assessment◦ Grip strength

◦ Time to 5 chair stands

◦ Balance

◦ 6 minute walk

Bhanji, 2017

Assessment of Frailty Lai, 2017Sa

rco

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ia

Liver Frailty Index https://liverfrailtyindex.ucsf.edu/

Implications of LFI Pre-TransplantMortality of frail patients higher than predicted by MELD

Management: ◦ Refer for transplant at lower MELD

◦ Counselled regarding high risk donors/live donation

◦ Consider palliative care earlier in non-transplant patients with elevated MELD

Lai, 2017

Sarcopenia Pre-TransplantSarcopenia measured at L3 Psoas with CT associated with poor survival◦ Proprietary software (SliceOmatic) used to make

measurements

Resulted in development of novel risk score

If sarcopenia, add 10.35 to MELD

MELD-Sarcopenia outperformed MELD in predicting waitlist mortailty

Montano-Loza, 2015

Energy Metabolism in Cirrhosis

Fasting

FA used as energy supply

Poor hepatic glycogen stores

Skeletal muscles require glucose

Skeletal muscle use branched chain amino

acids from protein catabolism

Accelerated starvation and

tissue breakdown

Anand, 2017

Nutritional Interventions

Smaller more frequent meals (4-6)◦ Limit inpatient fasting

35-40kcal/kg/day

Increased Protein intake (1.2-1.5g/kg/day)◦ Do not decrease due to Encephalopathy

◦ Plant and dairy protein > animal protein

Limit dietary restrictions

Late Night Snack◦ Improvement in HE and ascites

◦ AST/ALT, albumin, PT improved

Amodio, 2013; Chen 2013

Hyperammonemia and Sarcopenia

Hyperammonemia is associated with sarcopenia

Management:◦ Aggressive treatment of HE is indicated in all

◦ Improvement in HE is seen with improvement in sarcopenia

◦ No evidence ammonia reduction improves sarcopenia◦ Serum ammonia reduction should NOT be target for HE or

sarcopenia

Hyperammonemia

Muscle disposal of ammonia

Depletion of TCA cycle intermediates

Impaired muscle energy metabolism

Increased use of BCAA

Increased muscle breakdown

Sarcopenia

Dasarathy, 2016

Branched Chain Amino Acids (BCAA)BCAA = valine, leucine, and isoleucine

Used for substrate for ammonia detoxification and energy metabolism

Supplementation of ~12g/day reduces: ◦ Encephalopathy

◦ General health Perception

◦ Event free survival◦ Decompensation

◦ Variceal bleeding

◦ Development of HCC

◦ Death

Muto, 2005Gluud, 2017

Exercise for SarcopeniaVery limited data regarding exercise and outcomes in cirrhosis

Improvement in muscle mass with exercise in cirrhosis

Pre-transplant exercise capacity improved post-transplant outcomes

Recommendations: ◦ Combination of endurance and resistance

training

◦ Advise against heavy lifting and excessive straining

Jones, 2012

TIPS for SarcopeniaReduced portal pressures:◦ Improves gut motility

◦ Improves Intestinal absorption

◦ Increases appetite from reduced ascites

◦ decreases myostatin and increases IGF-1

◦ Reduces protein loss from paracentesis

Improved Sarcopenia in 41/57 patients◦ 12-month mortality with improvement of

sarcopenia 9.8% vs. 43.5% when sarcopeniapersisted (P = 0.007).

◦ Sarcopenia did not change in matched controls

Consider early TIPS in patients with sarcopeniaand ascites

Tsien, 2013

Testosterone90% of men with cirrhosis have low Testosterone due to increased aromatase activity

Testosterone inhibits myostatin and improves muscle mass

In small RCT of men with low T, supplementation improves lean mass and grip strength

No difference in outcomes or complications◦ Not powered to detect differences

Consider testing Testosterone in men with significant sarcopenia

Sinclair, 2016

Vitamin ASymptoms of deficiency◦ Skin scaling, Hyperkeratosis

◦ Nightblindness

◦ Conjunctival xerosis

70-95% of transplant candidates are deficient◦ Up to 100% in Child-Pugh C

◦ More common in hepatocellular than cholestaticliver disease

Impaired dark adaptation found in 40%

Treatment:◦ 10,000-20,000 units daily

◦ Repeat Vit A level in 3 months

Venu 2013; Abbott-Johnson 2011

Vitamin DLiver integral to Vit D metabolism◦ Bile acids required for intestinal absorption

◦ 25-hydroxylation takes place in liver

◦ 80% of 25-OH Vit D is bound to protein made by liver

Prevalence 64-92%◦ Does not correlate with Child-Pugh

Osteopenia and Osteoporosis Common◦ Pre-transplant 45% and 18%

Fractures◦ Increased 30 day and 1 year mortaily after hip fracture

◦ Less likely to have necessary surgeries

◦ Post transplant 5-35% have vertebral fractures

Konstantakis, 2016; Venu 2013; Montomoli, 2018; Compston, 2003

ZincSymptoms:◦ Dysguesia

◦ Impaired wound healing

◦ Impaired immune function

Zinc Deficiency common in Cirrhosis, 60-90%◦ Increased with higher MELD and Child-pugh

Supplementation for hepatic encephalopathy likely improves HE◦ Supplementation can cause nausea

◦ Deficiency impairs amino acid metabolism

No high quality data on transplant free and overall survival outcomes after supplementation

Himoto, 2018; Sengupta, 2015

Our ApproachAssess Frailty in all transplant candidates

Counsel all patients regarding protein intake and exercise◦ Recommend high protein snack before bed

◦ All transplant evaluations meet with nutritionist

Consider early TIPS in patients with ascites, especially if significant sarcopenia

Consider BCAA supplementation in patients with HE and sarcopenia

Screen all transplant candidates/decompensated cirrhotics for A, D, E, and Zinc Deficiencies◦ Supplement for deficiency

◦ Recheck levels to verify correction

Screen selected males with sarcopenia for low testosterone

ReferencesFrancesca Maria Trovato, Flavia Concetta Aiello, Licia Larocca, and Simon D. Taylor-Robinson. The Role of Physical Activity and Nutrition in the Sarcopenia of Cirrhosis. J. Funct. Morphol. Kinesiol. 2016, 1(1), 118-125

Rahima A. Bhanji, Elizabeth J. Carey, Liu Yang, and Kymberly D. Watt. The Long Winding Road to Transplant: How Sarcopenia and Debility Impact Morbidity and Mortality on the Waitlist. Clinical Gastroenterology and Hepatology 2017;15:1492–1497.

Jennifer C. Lai, Kenneth E. Covinsky, Jennifer L. Dodge, W. John Boscardin, Dorry L. Segev, John P. Roberts, and Sandy Feng. Development of a Novel Frailty Index to Predict Mortality in Patients With End-Stage Liver Disease. HEPATOLOGY, VOL. 66, NO. 2, 2017

Jeroen Laurens Ad van Vugt , Louise Johanna Maria Alferink , Stefan Buettner, Marcia Patricia Gaspersz, Daphne Bot, Sarwa Darwish Murad, ShirinFeshtali, Peter Martinus Adranius van Ooijen, Wojciech Grzegorz Polak, Robert Jack Porte, Bart van Hoek, Aad Pieter van den Berg, Herold J Metselaar, Jan Nicolaas Maria Ijzermans. A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: a competing risk analysis in a national cohort. Journal of Hepatology 2018 vol. 68 j 707–714

Aldo J. Montano-Loza, Andres Duarte-Rojo, Judith Meza-Junco, Vickie E. Baracos, Michael B. Sawyer, Jack X.Q. Pang, Crystal Beaumont, Nina Esfandiari, and Robert P. Myers. Inclusion of Sarcopenia Within MELD (MELD-Sarcopenia) and the Prediction of Mortality in Patients With Cirrhosis. Clinical and Translational Gastroenterology (2015) 6, e102

Srinivasan Dasarathy, Manuela Merli. Sarcopenia from mechanism to diagnosis and treatment in liver disease. Journal of Hepatology 2016 vol. 65 j 1232–1244

Piero Amodio, Chantal Bemeur, Roger Butterworth, Juan Cordoba, Akinobu Kato, Sara Montagnese, Misael Uribe, Hendrik Vilstrup, and Marsha Y. Morgan. The Nutritional Management of Hepatic Encephalopathy in Patients With Cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology. 2013 Jul;58(1):325-36

Chen-Ju Chen, Liang-Chao Wang, Hsing-Tao Kuo, Yu-Chiung Fang and Huan-Fang Lee. Significant effects of late evening snack on liver functions in patients with liver cirrhosis: A meta-analysis of randomized controlled trials.

Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD001939.

References Cont.YASUTOSHI MUTO, SHUNICHI SATO, AKIHARU WATANABE, HISATAKA MORIWAKI, KAZUYUKI SUZUKI, AKINOBU KATO, MASAHIKO KATO, TEIJI NAKAMURA, KIYOHIRO HIGUCHI, SHUHEI NISHIGUCHI, and HIROMITSU KUMADA, FOR THE LONG-TERM SURVIVAL STUDY (LOTUS) GROUP Effects of Oral Branched-Chain Amino Acid Granules on Event-Free Survival in Patients With Liver Cirrhosis. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:705–713

Jacqueline C. Jones, Jeff S. Coombes, and Graeme A. Macdonald. Exercise Capacity and Muscle Strength in Patients With Cirrhosis. LIVER TRANSPLANTATION 18:146-151, 2012

Cynthia Tsien, Shetal N. Shah, Arthur J. McCullough and Srinivasan Dasarathy, Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent European Journal of Gastroenterology & Hepatology 2013, 25:85–93

Christos Konstantakis, Paraskevi Tselekouni, Maria Kalafateli, Christos Triantos. Vitamin D defi ciency in patients with liver cirrhosis. Annals of Gastroenterology (2016) 29, 297-306.

Winsome Abbott-Johnson, Paul Kerlin, Alan Clague, Helen Johnson and Ross Cuneo. Relationships between blood levels of fat soluble vitamins and disease etiology and severity in adults awaiting liver transplantation. Journal of Gastroenterology and Hepatology 26 (2011) 1402–1410

Tammy M. Johnson, Erin B. Overgard, Ashley E. Cohen, and John K. DiBaise. Nutrition Assessment and Management in Advanced Liver Disease. Nutrition in Clinical Practice Volume 28 Number 1 February 2013 15-29

Mukund Venu, Eric Martin, Kia Saeian, and Samer Gawrieh. High Prevalence of Vitamin A Deficiency and Vitamin D Deficiency in Patients Evaluated for Liver Transplantation. LIVER TRANSPLANTATION 19:627–633, 2013

Jonathan Montomoli, Rune Erichsen, Henrik Gammelager, Alma B Pedersen. Liver disease and mortality among patients with hip fracture: a population-based cohort study. Clinical Epidemiology 2018:10 991–1000

Juliet E. Compston. Osteoporosis After Liver Transplantation. Liver Transpl. 2003 Apr;9(4):321-30.

Takashi Himoto and Tsutomu Masaki. Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease. Nutrients 2018, 10, 88

Shreya Sengupta, Kristen Wroblewski, Andrew Aronsohn, Nancy Reau, K. Gautham Reddy, Donald Jensen, Helen Te. Screening for Zinc Deficiency in Patients with Cirrhosis: When Should We Start? Dig Dis Sci (2015) 60:3130–3135