dr jeremy woodward - bapen

Dr Jeremy Woodward

Nutritional Issues in Liver Transplantation

Dr Jeremy Woodward Addenbrooke’s Hospital

Cambridge

Nutrition and liver disease

Nutritional issues in

Liver transplantation


• Does nutritional status affect outcome of transplantation?

• Can nutritional status be improved on the waiting list?

• Does improved nutritional status improve outcomes?

• Is there a role for ‘smart’ nutrition in liver transplantation?


Case History

SH 4/4/80

• FAP (mother, aunt, brother) • 2002 Panproctocolectomy • 2003 Desmoid disease – sub-total enterectomy –

started PN • 2004 Recurrent desmoid – total enterectomy • 2006 weight loss and fatigue


SH status 2006 • Residual anatomy and function: - Choledocho-gastric anastomosis – 24F venting PEG - Liver biopsy 2004 – steatosis, mild fibrosis - No GI tract beyond pylorus - No spleen or pancreas (diabetic) - Uterus and ovaries intact - Anal sphincter ablation for pelvic collection - Functionally hypoadrenal - Excellent renal preservation - Small residual desmoid in left rectus sheath • PN uncomplicated – no venous thromboses, no infections,insulin

added to PN • Gastric stasis/fermentation – non absorbed antibiotics • Living with mother, teacher training course


SH admission 2006 • Losing weight (55Kg to 45 Kg over one year) • Low energy and mood, unable to complete studies, wheelchair

• Normal biochemical liver and renal function • Normal baseline biochemistry – no deficiencies • Negative inflammatory markers • Normal full blood count • Adequate blood sugar control

• Imaging – no residual pelvic collection • Pituitary function, sex hormones, essential fatty acids, carnitine • CMV, Toxo, Borrelia, Brucella, Chlamydia, Syphilis, HIV • Cervical lymph node biopsy

• Changed lipid/CHO ratio, changed fat source (omega 3, MCT),

removed fat, increased calories beyond requirements, reduced calories, insulin pump


1/04 1/05 1/06 1/07

Mild fibrosis Cirrhosis

Reasons for late presentation

• Inadvertent ‘shunt’ • No enteric derived nutrients in portal inflow • Preserved portal inflow via left kidney • Nutritional maintenance, exogenous insulin

• Window onto hepatic metabolism

Metabolic effects of ESLD (Bemeur et al, J Nut Metab 2010)

• Increased protein catabolism • Increased BCAA utilisation (BCAA:AAA – 3.5:1 – 1:1) • Decreased ureagenesis

• Decreased hepatic and skeletal muscle glycogen synthesis • Increased gluconeogenesis • Glucose intolerance and insulin resistance (DM 38% Nishida, 2006)

• Increased lipolysis • Enhanced turnover and oxidation of fatty acids • Increased ketogenesis

Causes of malnutrition in ESLD (Bemeur et al, J Nut

Metab 2010)

• Inadequate dietary intake • Inadequate hepatic synthesis and storage • Impaired absorption • Increased protein losses (ascites, portal enteropathy) • Hypermetabolic state

– Cardiac output – Cytokine clearance

• Insulin resistance • Ascites • Infection

36% pts on waiting list >10% LOBW 17% <5%ile anthropometry Hade et al, 2003

‘Hypermetabolism’ (Greco et al, 1998)

Control (8) Cirrhosis (10) p

Fasting npRQ 0.82+/- 0.04 0.76 +/- 0.05 <0.05 REE (Kj/24hrs) 5868+/-489 7881+/-1125 <0.01 24hr EE (Kj/24hrs) 6825+/-507 8567+/-764 <0.001 Lipid oxidation (KJ/24hrs) 2278+/-320 4231+/- 866 <0.001 Protein oxidation (KJ/24hrs) 825+/-51 976+/-167 <0.05 Fat mass (Kg) 14.2+/-3.2 11.5+/-6.3 NS BMI (Kg/m2) 24.4+/-1.4 23.1+/-2.2 NS FFM (Kg) 53.6+/-7.1 55.7+/- 9.4 NS Child-Pugh 7.7 +/-0.82

Nutrition pre-transplantation

‘Malnutrition is not a contraindication to liver transplantation’

Plauth et al, ESPEN guidelines 1997

How should malnutrition affect the transplant decision?

• Listing • Timing • Organ allocation • Donor-recipient matching

9.6xLn [creatinine] + 3.8x Ln [bilirubin] +11.2 x INR + 6.4

MELD-Na; iMELD; UKELD; MELD-XI; MELD-gender; reweighted MELD

Medical urgency – not post transplant survival risk

RFH-SGA N=222

• Hypermetabolic patients lower transplant free survival than normometabolic (9.7 vs 31.8 months, p<0.05) - independent of MELD and Child Pugh - increased REE even in normal range associated with lower survival - β−blockers improved metabolism and survival (Mathur et al, 2007)

∆REE 0%

∆REE 0 - 20% ∆REE >20%

IC vs HB

1997

Nutritional risk P<0.01

Child-Pugh p=0.4

‘Malnutrition was the only independent risk factor for the length of stay in the ICU and total number of days in hospital’

• Both deaths and both graft loss in malnourished patients • SGA best index

n=38

2009

• 53 patients followed prospectively

• Handgrip strength correlated with ICU stay • Low BCAA levels associated with post op infections

• No correlation of any nutritional indices with mortality

• Low mortality rate (7.5% vs 24% at one year) • Better nutritional start point • Different immunosuppression • Use of isotope dilution rather than Bioimpedance

• 61 patients followed prospectively – outcome after transplantation

• Child-Pugh and MELD – no correlation with HGS, TSFT, MAMC

• No correlation of Child-Pugh or MELD with outcome

• Weak but significant association of death and MAC and TSFT.

2005


• Does nutritional status affect outcome of transplantation? YES

• Can nutritional status be improved on the waiting list?



Nutrition and liver disease Can nutrition support improve nutritional status pre-transplant?

• Dietary intervention • Oral nutrition supplements • Enteral tube feeding • Parenteral nutrition

Dietary intervention

• Bories and Campillo 1994 – 30 days in hospital high calorie high protein diet – 40kcals/kg/day – Severe malnourished (<5%ile)

• Significant improvement in MMC, TSFT, fat mass

Interventional studies - ONS

• Cunha et al, 2004 – n=28 A/B/C – 6/14/8 – Dietary counselling + ONS 500kcals, 32g protein – 3 month follow up

Interventional studies - ONS

8.3 6.6

32

37 P=0.005

P=0.0007

P=0.003

Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomised 12 month trial Planck et al, 2008

• n= 52 vs 51 cirrhotics – 28/13/11 vs 24/18/9 • ONS - Ensure plus – 710 kcals, 26g protein • Randomised to be drunk 2100-0700 or 0900-1900

Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomised 12 month trial Planck et al, 2008



• Can nutritional status be improved on the waiting list? YES - BUT



Oral nutrition supplement trials - outcomes

• Bunout et al, 1989 n=17+19 ALD – NS decrease in mortality

• Hirsch et al 1993 – N=26 vs 25 1000kcals 34g protein – 3 vs 6 deaths (NS) – Reduction in hospital admissions – Improvement in nutritional status

• Mendenhall et al, 1993 n=137+136 Alc hep – Moderately malnourished: Mortality = 9% vs 20.9% at 1 month (p<0.05);

20% vs 37% at 6 months (p<0.05) – No significant difference in severely malnourished

Interventional studies – EN

• Cabre et al, 1990 • n=35 (19 vs 16) – ‘severely malnourished’ • 2115 Kcals per day via ng. Hospitalised pts, av 23 days

P<0.001 P<0.001

TSF MAMC

Albumin Child-Pugh score

12% vs 47% mortality p=0.02


A PROSPECTIVE RANDOMIZED STUDY OF PREOPERATIVE NUTRITIONAL SUPPLEMENTATION IN PATIENTS AWAITING ELECTIVE ORTHOTOPIC LIVER TRANSPLANTATION1 Le Cornu, Kathryn A.; McKiernan, F. Jane; Kapadia, Suneil A.; Neuberger, James M. Transplantation 2000 69(7) 1364

• n=42 +40 awaiting liver transplantation 3/20/19 vs 4/11/25 <25%ile MAMC • 750Kcal 20g protein, 33.5g fat supplement

• MAC, MAMC increased significantly (supplemented and control) • HGS increased in supplemented group

• HGS <85% normal predicted post operative complications (Figueireido, 2000)

• No significant benefit of supplementation on outcome



• Can nutritional status be improved on the waiting list? YES- BUT


CAN’T SAY • Is there a role for ‘smart’ nutrition in liver

transplantation?

Post transplant nutrition

Restorative PPC

OLTx

‘Sarcopenic obesity’ – 17% (Schutz et al, 2012)

Protein synthesis in cirrhosis

Tessari et al, 2002

Smart bricks

http://www.solarnavigator.net/history/victory.htm

40% of essential amino acids

Leucine, Isoleucine, Valine

Low BCAA:AAA in cirrhosis

Leucine

mTOR

Protein synthesis

Branched chain amino acids

Why does blood urea increase with an upper GI haemorrhage?

Isoleucine

Modification of the effects of blood on amino acid metabolism by intravenous Isoleucine Deutz N, Reijven P, Bost M, Berlo C, Soeters P Gastroenterology 1991 101 1613-1620

Isoleucine infusion during ‘simulated’ upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients Olde Damink S, Jalan R, Deutz N, Dejong CH, Redhead D, Hynd P, Hayes P, Soeters P Hepatology 2007 45 560-658

Fenton et al – Milk and cheese diet in porto-systemic encephalopathy Lancet 1966

BCAA in cirrhosis

Marchesini et al, 2003

N=174

Oral BCAA supplementation

Maltodextrin (isocaloric)

Lactalbumin (isocaloric, isonitrogenous)

Primary outcome – death or progression to exclusion criteria

15.5%

27.1%

32.1%

Muto et al, 2005

• n= 314 vs 311 multicentre, 2yr follow up • 118/138/5 vs 105/125/7 • Randomised to BCAA granules – 1 sachet each meal or dietary advice. • No significant differences in intake between groups over the

trial

• Kaido et al, 2010 – BCAA supplementation negative predictive risk

factor for post transplant sepsis – N=50 p=0.028

Summary • Nutrition support - dietetic, ONS or EN – can improve

nutritional status and length of survival in moderately/severely malnourished pts pre transplant

• Nutritional status affects post transplant outcome

• No evidence to suggest that nutritional supplementation improves outcome post transplant

• Nutritional status needs to be considered in organ allocation and transplant timing – how?

More information needed…..

• Definitive study required to determine whether early transplant or trying to improve nutritional status is best approach (hypermetabolic group)

• New studies of optimal nutrition in ESLD with outcome data: – high protein – fast avoidance – BCAA

dr jeremy woodward - bapen

Documents