Impacts of the Obesity Epidemic on Liver Transplantation
Associate Professor Simone StrasserAW Morrow Gastroenterology and Liver Centre
Australian National Liver Transplant UnitRoyal Prince Alfred Hospital and University of Sydney
Sydney, AUSTRALIA
Disclosures
Dr Strasser has received honoraria for advisory boards or speaking from:
• Bayer Healthcare• Sirtex• Gilead• BMS• MSD• AbbVie• Norgine• Astellas• Novartis• Eisai• Ipsen• Pfizer
• Trends in the burden of obesity, NAFLD and NASH‐HCC
• NASH and NASH‐HCC as an indication for transplantation
• Impact of population obesity on liver donor pool
• Impact of obesity in patients requiring transplantation
Outline
Science. 3 JULY 2015
WHO BMI classifications of overweight and obesity reflect risk for type 2 diabetes and cardiovascular diseases
WHO BMI classifications of overweight and obesity
Asian populations have different associations between BMI, percentage of body fat, and health risks than do European populations.
Appropriate body‐mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363: 157–63
Overweight BMI ≥23 (vs ≥25)Obese BMI ≥25 (vs ≥ 30)
Wang et al. Lancet 2011; 378: 815–25
Rates of overweight and obesity are increasing!
Australia
In 2010, overweight and obesity were estimated to cause 3∙4 million deaths, 4% of years of life lost, and 4% of disability‐adjusted life‐years (DALYs) worldwide
The impacts of obesity on global health outcomes are worsening
Major costs associated with diabetes, CVD and osteoarthritis
Korea
USAEngland
According to 2007 statistics from the World Health Organization (WHO), New Zealand has the second-highest prevalence of overweight adults in the English-speaking world.
Indicator: Overweight or obese: BMI of 25.0 or greater (or IOTF equivalent for 15‐17 years)
https://minhealthnz.shinyapps.io/nz‐health‐survey‐2017‐18‐annual‐data‐explorer/_w_0811ceee/_w_a219969c/_w_8ee879eb/#!/explore‐indicators
Obesity rate increased from 27% in 2006/7 to 32% in 2017/8 47% of Maori adults, 17% Maori children ; 65% of Pacific adults, 30% Maori children
Jensen, Thomas. Journal of Hepatology 68, 1063‐75 (2018)Younossi et al. Nature Reviews Gastroenterology & Hepatology 15, 11–20 (2018)
Strong association between obesity, NAFLD and sugar consumption
Global prevalence of NAFLD is estimated at 24%
Highest rates are reportedfrom South America (31%) and the Middle East (32%), followed by Asia (27%), the USA (24%) and Europe (23%)
Being overweight in childhood and adolescence is associated with increased risk of NAFLD later in life
Complications of obesity
InflammatoryAsthmaThyroid diseasePsoriasisPancreatitis
PsychologicalDepressionAnxietyPanic disordersEating disorders
DegenerativeAtherosclerosisPulmonary HT
NeoplasticOesophagealBreastColonEndometrialLiverPancreatic
MetabolicDiabetesHyperlipidaemiaHypertensionGallstonesNon‐Alcoholic Fatty Liver Disease
AnatomicOsteoarthritisGORDOSA
The Bacchino, Valerio Cioli, Boboli Gardens, Florence, ItalyClin Liver Dis 18 (2014) 1–18
Pts with NAFLD
related to obesity at risk of all these health issues
Global burden and natural history of NAFLD
Asrani et al. J Hepatol 2019:70;151–171
NOTE: Liver disease the 3rd leading cause of death in patients with NAFLD (13%) of deaths
Independent predictors of liver failure and liver cancer in NAFLD is related to co‐factors
HR 95% CI P Value
Age 1.02 1.00‐1.04 0.04
Alcohol Consumption 1.002 1.001‐1.002 <0.001
Diabetes 2.75 1.56‐4.84 <0.001
Insulin Resistance (HOMA‐IR)
1.01 1.01‐1.02 <0.001
Total‐LDL Cholesterol ratio
2.64 1.67‐4.16 <0.001
Waist circumference‐BMIratio
3.70 1.74‐7.89 0.001
Multivariate Backward Stepwise Elimination Cox Regression Analysis
Aberg et al. Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology 2018;67:2141‐2149
Finnish population‐based Health 2000 Study (2000‐2001)
World J Gastroenterol 2017 April 21; 23(15): 2763-2770
p < 0.05
1998‐2012
• Trends in the burden of obesity, NAFLD and NASH‐HCC
• NASH and NASH‐HCC as an indication for transplantation
• Impact of population obesity on liver donor pool
• Impact of obesity in patients requiring transplantation
Outline
HCV
NAFLD/NASH
HCCIncreasingly due to NASH
Liver Transplantation in Australia and New Zealand
Goldberg D et al. Gastroenterology 2017;152:1090–1099
HCV HCV
NASH
Alcohol
NASHAlcohol
In USA, LT wait‐listing for HCV is declining since DAAs but NASH and ARLD is increasing as indication for LT
Chronic Liver Failure
HCC
NASH now third most frequent etiology of CLD in patientstransplanted with concomitant HCC by 2017 in ANZ (and rising rapidly)
Calzadilla‐Bertot L et al. Liver Transplantation. 2019:25;25‒34
• 26,121 /158,347 (16.5%) adult LT candidates had HCC
• Increased from 6.4% to 23%
Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of HCC in Liver Transplant Candidates in USA
11.8x increase
Younossi et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):748‐755
SRTR 2002‐2016
Characteristic 2007(n=6494)
2017(n=8082)
Age ≥ 65 years 11% 22.4%
BMI30‐35≥35
20.6%12.45
23.5%14.9%
DiagnosisHCVALDHCCOther/Unknown
24.9%19.4%13.9%26.8%
13.4%25.1%17.6%31.6%
Diabetes 24.4% 28.7%
Combined LK Transplant 7.3% 9.6%
OPTN/SRTR 2017 Annual Data Report: Liver. Am J Transplant. 2019 Feb;19 Suppl 2:184‐283
Trends in Liver Transplantation in USA 2007 to 2017
Mostly NASH
• Compared with other aetiologies of HCC, NASH patients are:
• Older (62.9 ± 6.8 years)• Higher BMI (31.9 ± 5.7) • Obesity (60.5%)• Type 2 diabetes (60.3%)• Coronary artery disease (5.6%)• Stroke (1.7%)• Hypertension (47.3%)
Characteristics of waitlisted patients with NASH‐HCC
All p<0.001
Younossi et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):748‐755
Outcomes of Liver Transplant in NASH
• Survival after liver transplant is similar between NASH recipients and non‐NASH recipients
• NASH recipients have increased deaths due to:
• Cardiovascular complications OR 1.65 (1.01‐2.70)• Sepsis OR 1.71 (1.17‐2.50)
• NASH recipients have fewer deaths from:
• Graft failure OR 0.21 (0.05‐0.89)
Wang et al. Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis:A Systematic Review and Meta‐analysis. Clin Gastro Hepatol 2014;12:394–402
J Gastroenterol Hepatol. 2016 May;31(5):1016‐24
Obese + Diabetes
n=617 2003 and 2009
adjusted Hazard Ratio [aHR] 2.40, 95%CI 1.32‐4.38
Obese‐diabetic patients had longer intensive care and hospital stays, and higher overall mortality
Nonalcoholic Steatohepatitis is the Most Rapidly Growing Indication for Simultaneous Liver Kidney Transplantation in the United States
NASH and CC with BMI ≥ 30PBC/PSC/ALD
Hep C/Hep B/HCC
NASH and CC with BMI ≥ 30
PBC/PSC/ALDHep C/Hep B/HCC
Singal A et al. Transplantation 2016;100: 607–612
5.6% (n=2162) of 38,533 patients underwent SLK 2002‐2100 (UNOS)
6.3% 19.2%% of a
ll SLK tran
splants
% of a
ll liver tran
splants
Patients requiring SLK for NASH were significantly (p<0001)…
• Female• Older (mean 59 years)• Diabetic (65%)• Higher BMI (mean 33)
Kidney survival is worse after SLK transplant for NASH/obesity than for other indications of SLK
P < 0.0001
79%
70%NASH and CC with BMI ≥ 30
PBC/PSC/ALD
Singal A et al. Transplantation 2016;100: 607–612
Due to impact of metabolic risk factors, immunosuppression ?
• Trends in the burden of obesity, NAFLD and NASH‐HCC
• NASH and NASH‐HCC as an indication for transplantation
• Impact of population obesity on liver donor pool
• Impact of obesity in patients requiring transplantation
Outline
Impact of the obesity epidemic on deceased liver donors
• Donor age is increasing and donor death more often cerebrovascular disease• Referral of obese donors is increasing• Obese donors are more likely to be declined (34%) than non‐obese donors (22%)• When biopsied, obese donors are more likely to have macrosteatosis (21%) than non‐obese donors (12%)
• Liver allografts with >30% macrosteatosis are associated with higher rates of primary nonfunction, early allograft dysfunction and worse survival
• Transplantation from high‐BMI donors is associated with lower graft survival• The obese patient on the waiting list may have fewer donor options as size matching important
Bloom et al. J Am Coll Surg. 2015;220:38‐47Steggerda et al. Transplantation 2018 (in press)
• Trends in the burden of obesity, NAFLD and NASH‐HCC
• NASH and NASH‐HCC as an indication for transplantation
• Impact of population obesity on liver donor pool
• Impact of obesity in patients requiring transplantation
Outline
Pre‐LT Peri‐LT Post‐LT
Spengler et al. Transplantation. 101(10):2288‐2296, October 2017.
Pre‐LT Peri‐LT Post‐LT
Spengler et al. Transplantation. 101(10):2288‐2296, October 2017.
Metabolic comorbidities
Cardiovascular comorbidities
Socioeconomic factors
Nutritional status
Bone health
Airway management
and ventilation
Anaestheticdrug
metabolism
Surgical considerations
Technical aspects
Wound management
Graft size
Infections
IS drug PK
Weight gain
De-novo comorbidities
CVD
Malignancy
MetSand
NASH
Liver transplant assessment in NASH/Obesity • Routine transplant assessment• Extensive cardiovascular assessment
• Stress echocardiography, Coronary angiography, Carotid doppler
• Nutritional assessment and management• Malnutrition, Obesity, sarcopenic obesity
• Diabetes assessment and management• Renal assessment and decision re SLKT• Screening for malignancy• Screening for OSA• Monitoring and management of HCC on waiting list
Dietary Modification
Common metabolic complications after OLTComplication Incidence % Risk factors
Obesity 30‐50% NAFLD, corticosteroids, lifestyle factors
Hypertension 60‐70% CKD, CNIs, corticosteroids, pre‐existing HT
Diabetes Mellitus 30‐40% Corticosteroids, CNIs, mTORi, obesity, HCV, pre‐existing insulin resistance
Hyperlipidaemia 45‐69% CNIs, mTORi, corticosteroids, obesity, cholestatic LD, pre‐existing hyperlipidaemia
Coronary artery disease 9‐25% HT, hyperlipidaemia, diabetes, previous CAD, NAFLD, smoking, family history
Chronic kidney disease 8‐25% Pretransplant kidney injury, HT, CNIs (high early exposure), nephrotoxins, diabetes
Recurrent NAFLD Up to 78% NASH, age, obesity, diet, genetics, diabetes, corticosteroids, CNIs, sarcopenia, ?microbiome
Modified from Singh S, Watt KD. Mayo Clin Proc. 2012 Aug;87(8):779‐90.
Bariatric surgery
• Bariatric surgery contraindicated in patients with decompensated cirrhosis
• Sleeve gastrectomy favoured over bypass procedures in transplant patients.
• Sleeve gastrectomy may be considered at the time of liver transplant
• Sleeve gastrectomy should be considered after transplantation in patients with obesity and metabolic syndrome
Roux‐en‐Y Gastric Bypass Surgery
Sleeve Gastrectomy
• With the global obesity epidemic, obesity‐related liver disease and HCC rapidly becoming the leading indication for liver transplantation around the world
• Obesity and its complications pose significant challenges in liver transplantation
Conclusions
The Global Obesity Epidemic
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