manejo’del’paciente’con’esteatohepatitis’no’alcohólica papel’ de’la...
TRANSCRIPT
Manejo del paciente con esteatohepatitis no alcohólicaPapel de la pérdida de peso a través de la modificación en el estilo
de vida y cirugía bariátrica.
Eduardo Vilar-Gomez, M.D., Ph.D., MSc.Virgen Macarena – Virgen del Rocío University Hospitals
CIBERehdIBIS
Key points for the consensus
Programs of lifestyle intervention to induce weight loss.
ü Lifestyle programs -‐ diet, exercise, behavioral therapies.
üBariatric surgery
ü Sustainability of weight loss after lifestyle interventions.
Weight loss in patients with NAFLD.
ü Impact on liver histology -‐ how long is required? – the role of physical activity.
ü Futility rules for guiding the decision-‐making process.
üWL efficacy in high-‐risk subgroups?
Can we predict improvement in hard histological outcomes?üHow a clinical scoring system may predict histological resolution of NASH?
Beneficial effects of weight loss on obesity-‐related comorbidities.
Weight loss as the first line of therapy in patients with NAFL
-‐ Who should treated within NAFL spectrum?
-‐ What is the best strategy based on the risk of disease progression?
NAFLD – SPECTRUM AND BURDEN OF DISEASE
Overall survival free of liver transplantation
Angulo, et al. Gastroenterology 2015; Ekstedt, et al. Hepatology 2015; Younossi, et al . Hepatology 2016.
Simple steatosis NASH F0-‐F1 F2-‐F4
Who should be treated and what is the best strategy based on risk of disease progression?
Severity of NAFL
Risk of complications
All NAFL patients should be treated but:Steatosis simple: healthy lifestyle and control of comorbiditiesNASH or presence of fibrosis: Intensive lifestyle interventions as the first optionBariatric surgery should be considered for patients who fail LI or have morbid obesity
Blackburn G. Obes Res. 1995;3(suppl 2):211-216; Foster GD. Arch Intern Med. 2009;169:1619-1626; Greg EW. JAMA. 2012;308:2489-2496; Sjostrom L. J Intern Med. 2013;273:219-234; Christou NV. Surg Obes Relat Dis. 2008;4:691-695.
How much weight loss is required to ameliorate/reversecomorbidities?
Previous improvements +Reductions in CVD events
Reductions in all-cause mortalityReductions in cancer risks(only with bariatric surgery
≥ 15%
≥ 5%
T2D prevention and controlWeight-related QoL
Improvements in CVD riskHDL-C, cholesterol,
triglycerides, BP
Previous improvements +T2D remission
Improvements in sleep apnea Reductions in intima-media thickness
≥ 10%
Weight loss is an excellent surrogate markerGreater WL – Bigger benefits
What is the best program to weight loss? Diet
Weight loss (Kg)
Type of diet 6 months, 12 months
Low carbohydrate 8.73 (7.27-‐10.20) 7.25 (5.33-‐9.25)
Low fat 7.99 (6.01-‐9.92) 7.27 (5.26-‐9.34)
Meta-‐analysis of 48 RCT
7286 overweight/obese subjectsEffectiveness of two type of diets (low-‐carbohydrate vs. Low-‐fat)Outcome: weight loss rates at 6 and 12 months
Johnston BC, et al JAMA. 2014;312:923-‐933
Dietary composition may have a similar effect on weight loss rates
Sacks FM et al. N Engl J Med. 2009;360:859–873.
RCT – 811 overweight / obese pts
515 females and 296 malesRandomly assigned to one of four diet groups
No significant difference were observed on WL rates during the run-‐in and maintenance phases
0
–1
–2
–3
–4
–5
–6
–7
Weight Loss (kg)
0 6 12 18 24Months
Diet Composition (%)Carbohydrate / Protein / Fat65/15/20 (low-‐fat, average protein)55/25/20 (low-‐fat, high-‐protein)45/15/40 (High-‐fat, average-‐protein)35/25/40 (High-‐fat, high-‐protein)
WL phase Maintenance phase
Diets represented a deficit of 750 kcal/day
8% or less of saturated fatCH low-‐glycemic index (all diets)Behavioral therapies (individual and group sessions)
90 minutes of moderate exercise per week
R/ 30-‐35% -‐ WL>5% and 14-‐15% -‐ WL>10%Diet adherence associated to long-‐term success
What is the best program to weight loss? Physical activity
High activity required for weight loss maintenance
Jakicic JM et al. Arch Intern Med. 2008;168:1550–1560
Marginal benefit adding structured exercise to diet during run-‐in phase
Heilbronn LK, et al. JAMA. 2006;295:1539-‐1548
48 overweight subjects were randomized into 4 groups.
1. Control group (no caloric restriction).2. Calorie restriction (25%).3. Calorie restriction (12.5%) plus 12.5% increase in energy expenditure by structured exercise).4. Very low calorie diet (890 kcal/d] until 15% reduction in body weight, followed by a weight maintenance diet).
RCT / 201 overweight and obese women
All were told to reduce 1200-‐1500 kcal/dRandomly assigned to 4 groups of exercise on PA energy expenditure and intensity
1.Moderate intensity/energy expenditure
2.Moderate intensity/ high energy exp.3.Vigorous intensity/moderate energy exp.4.Vigorous intensity/high energy exp.
What is the best program to weight loss? Bariatric surgery
Sleeve gastrectomy Gastric bypass Adjustable gastric banding
Weight loss +++ +++ ++Complications ++ +++ +Mortality ++ +++ +Reoperation + + +++
Body weight reduction overtime. Analysis of 5 years
Chong SH, et al. JAMA Surgery 2014; 149: 275–287
Mortality rate (<30 days): 0.08%
Mortality rate (>30 days): 0.31%
Meta-‐analysis including 37 RCT and 127 observational studies161, 756 morbid obese patients
Effects of Bariatric surgery on NASH patients at 1 year. Analysis by Kleiner score Lille Bariatric Cohort: BMI >40 or BMI >35 with at least one comorbidity factor for at least 5 years and resistance to medical treatment.Surgical procedures: Biliointestinal bypass, gastric band and gastric bypass.
LassaillyG, et al. Gastroenterology 2015; 149:379.388.
85%
78%
60%
39%
Baseline 1 year
F2-‐F4N=48
32%
19%
24%
17%
4%
3%
Baseline 1 year
F2 F3 F4
F2-‐F4N=31
21%
13%
7%
1%
Effects of Bariatric surgery on fibrosis regression at 1 year. Analysis by Kleiner score Lille Bariatric Cohort: BMI >40 or BMI >35 with at least one comorbidity factor for at least 5 years and resistance to medical treatmentSurgical procedures: Biliointestinal bypass, gastric band and gastric bypass
Proportion of patients with F2-‐F3-‐F4
LassaillyG, et al. Gastroenterology 2015; 149:379.388.
How sustainable is weight loss after ILI?
8-‐Year weight loss in the Look AHEAD Trial
-‐8,5
-‐4,16 -‐4,7
-‐0,63-‐1,01
-‐2,1
-‐9
-‐8
-‐7
-‐6
-‐5
-‐4
-‐3
-‐2
-‐1
0
0 1 2 3 4 5 6 7 8Years
ILI
DSE
Repeated measures adjusted for clinic and baseline level. P value for average effect across all visits: P < 0.0001.DSE, diabetes support and education; ILI , intensive lifestyle intervention.Look AHEAD Research Group, Obesity 2014; 22:5-‐13.
Look AHEAD – RCT including 5,145 overweight/obese with T2D
Effects of intentional weight loss on CV morbidity and mortalityPts were randomly assigned to ILI or diabetes support and education.
68%
50%
38%
27%
16%11%
0%
10%
20%
30%
40%
50%
60%
70%
80%
1 year 8 Year
>= 5% >=10% >=15%
Mean changes in body w
eight (%) from baseline
Prop
ortio
n of patien
ts
54%
Regain
How sustainable is weight loss after ILI?
8-‐Year weight loss in the Look AHEAD Trial – Impact of initial WL at 1 year
58% of patients with a WL>5% at 1 year may maintain significant WL>5% at 8 years
Look AHEAD Research Group, Obesity 2014; 22:5-‐13.
WL>5% = 65% WL>5% = 48%
-‐18-‐17-‐16-‐15-‐14-‐13-‐12-‐11-‐10-‐9-‐8-‐7-‐6-‐5-‐4-‐3-‐2-‐10
0 1 2 3 4 5 6 7 8
N=324 (39.3%)
N=213 (25.8%)
-‐15-‐14-‐13-‐12-‐11-‐10-‐9-‐8-‐7-‐6-‐5-‐4-‐3-‐2-‐10
0 1 2 3 4 5 6 7 8N=141 (22.3%)
N=162 (25.6%)
Change in body weight (%)
-‐4-‐3-‐2-‐10123456789
0 1 2 3 4 5 6 7 8N=156 (23.8%)
N=274 (41.8%)
WL<5% = 66%
Years Years Years
WL ≥10% at 1 year WL 5-‐10% at 1 year WL <5% at 1 year
Lifestyle Intervention is clinically effective in all subsets of an ethnically and demographically diverse population
Wadden TA et al. Obesity (Silver Spring). 2009;;17(4):713–722.
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Reduction (%) in Initial Weight
in ILI Participants
AfricanAmerican Hispanic Other/Mixed
Non-Hispanic White
MaleFemale
What correlates with weight loss“LOOK AHEAD”
At 1 year, ILI participants lost more weight if:
Attended more treatment sessions
Exercised more
Consumed more meal replacement products
-‐1,09
-‐0,42 -‐0,3-‐0,35
-‐3,9
-‐1,5-‐1,2 -‐1,3
NAS Steatosis Ballooning Lob. Inflamm
WL< 7% WL >7%
-‐1,7
-‐0,54 -‐0,45-‐0,63
-‐3,9
-‐1,8
-‐0,9-‐1,22
NAS Steatosis Ballooning Lob. Inflamm
WL< 10% WL >10%
Weight loss and histological outcomes of NAFL patients How much impact the duration of ILI?
Vilar-Gomez E, et al Gastroenterology 2015;; 149:367-378
Vilar-Gomez E, et al. APT 2009;; 30:999-1009.
ILI – 24 weeks
-‐1,18
-‐0,41 -‐0,53 -‐0,24
-‐3,45
-‐1,36 -‐1,27
-‐0,82
NAS Steatosis Ballooning Lob. Inflamm
WL< 7% WL >7%
ILI – 48 weeks
-‐1,08
-‐0,39 -‐0,44-‐0,46
-‐3,4
-‐1,45
-‐1 -‐0,96
NAS Steatosis Ballooning Lob. Inflamm
WL< 9% WL >9%
Orlistat – 36 weeks
ILI – 52 weeks
Pomrat K, et al. Hepatology 2010; 51:121-‐129.
Harrison S, et al. Hepatology 2009;49:80-‐86.10
Weight loss and histological outcomes of NAFL patients
36%
13%
28%
40% 39%
88%
64%
84%88%
76%
100%
90% 89%
100% 100%
0%
20%
40%
60%
80%
100%
NAS NASH RES Ballooning Lob. Inflamm
Steatosis
WL<7 WL 7-‐10 WL >10
How much impact the duration of treatment? 24 versus 52 weeks
Vilar-Gomez E, et al Gastroenterology 2015;; 149:367-378Vilar-Gomez E, et al. Alimentary Pharmacology and Therapeutics 2009;; 30:999-1009.
14% 14%
29%
43%
29%
75% 75%
50%
75% 75%
100%
67%
78%
89%
100%
0%
20%
40%
60%
80%
100%
NAS NASH RES Ballooning Lob. Inflamm
Steatosis
WL<7 WL 7-‐10 WL >10
Proportio
n of patients
24 weeks 52 weeks
Physical activity and histological outcomes of NAFLD patients
Orci LA, et al Clinical Gastroenterology and Hepatology 2016 (in press)
Physical activity improves steatosis but no other histological outcomes
Physical activity and histological outcomes of NAFLD patients
Orci LA, et al Clinical Gastroenterology and Hepatology 2016 (in press)
ALT AST
Futility rules in patients treated with lifestyle interventions
Hall, et al. Am J Physiol 2010;; 298:E449-66
Vilar-Gomez, et al Gastroenterology 2015;; 149:367-378
Successful WL period
Successful WL period
Body weight change
Hall, et al. Am J Physiol 2010;; 298:E449-66
Typical diet energy balance
Can we choice a WL cutoff for guiding the decision-making process at 24 weeks?
ILI (low-fat diet and moderate intensity exercise during 24 wks)20 patients with biopsy-proven non-cirrhotic NAFLD17/20 had NASH / 12/20 had fibrosis (F1=8, F2=4, F3=1)Mean weight loss = 10.9 ± 6.2 % - 16/20 (80%) WL>5%
Vilar-Gomez E, et al. data extracted from study published in APT 2009;; 30:999-1009.
63%
81%88%
63%
75%
25% 25%
Resol NASH2-point in NAS Steatosis Ballooning Lob Inflamm
>5% <5%
1016
1316
1416
1016
1216
04
04
04
14
14
THE WEIGHT LOSS CLOCK FOR NAFLD -‐ GOING TO LIVER HEALTHY
Vilar-Gomez E, et al. Gastroenterology 2015;; 149:367-378
10
7 5
3
0
26%
62%
38%
NASHresolution
NASimprovement
Fibrosisimprovement
10%
32%
19%
NASHresolution
NASimprovement
Fibrosisimprovement
Healthy liver
Fibrosis worsening (21%)-‐ Higher BMI-‐ Diabetes
70%
11%
9%
10%
WL 7-‐10% higher rates of histological improvement but >10% is required for NASH resolution and fibrosis
16%
63%
21%18%
74%
8%
16%
84%
0%
45%
55%
0%0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Regressed Stabilized WorsenedWeight loss <5% Weight loss 5-7% Weight loss 7-10% Weight loss >10%
33/205 6/34 4/25 13/29 129/205 25/34 21/25 16/29 43/205 3/34 0/290/25
How much impact weight loss on fibrosis status at end of LI?
Fibrosis is stable or improved in 92% of patients with WL ≥ 5%45% of subjects with WL > 10% have fibrosis improvement
Vilar-Gomez E, et al. Gastroenterology 2015;; 149:367-378
<5%
>10%
Weight loss and improvement on histological outcomesImpact of severity of NASH
27%45%
30%56%
NASH resolution NAS improvement
F0-‐F1 F2-‐F3
43%60%
17%40%
NASH resolution NAS improvementNAS <5 NAS >=5
23%8%
100%67%
100% 100%
NAS 3-‐4 NAS >= 5<7% 7-‐10% >10%
67%100%
39%75%
<10% >10%F0-‐F1 F2-‐F3
Analysis based on baseline fibrosis
Resolution of NASH
Post-‐hoc analyses performed on patients with paired liver biopsies. Vilar-‐Gomez E, et al. Gastroenterology 2015; 149:367-‐378
Resolution of NASH
Analysis based on severity of NAS
Severity of baseline fibrosis did not affect NAS-‐NASH resolution rates
WL 7-‐10% induce 100% of NASH resolution if NAS<5 but WL>10% is required if NAS ≥5
Severity of NAS negatively affect NAS-‐NASH resolution rates
Weight loss and improvement on histological outcomesImpact of high-risk subgroups
0%
32%
63% 65%100% 93%
T2D Non T2D<7% 7-‐10% >10%
By diabetes
Post-‐hoc analyses. Vilar-‐Gomez E, et al. Gastroenterology 2015; 149:367-‐378
21%44%
63%
100%100% 100%
T2D Non T2D<7% 7-‐10% >10%
2-‐point improvement in NAS
Resolution of NASHBy diabetes
17%40%
57%
100%100% 100%
BMI >35 BMI < 35<7% 7-‐10% >10%
32% 38%
82%100%100% 100%
ALT>60 ALT<60<7% 7-‐10% >10%
By BMI >35 By ALT >60
0%15%
43%
72%100% 84%
BMI >35 BMI <35<7% 7-‐10% >10%
By BMI >35
20% 9%
63% 65%70%100%
ALT >60 ALT <60<7% 7-‐10% >10%
By ALT >60
WL 7-‐10% provides maximum benefit on NAS improvement in subjects without unfavorable risk factors
WL >10% are required to achieve higher benefits on NASH resolution irrespective of unfavorable risk factors
Weight loss and 1-point improvement in the fibrosis scoreImpact of baseline fibrosis
67%
100%
39%
75%
<10% >10%F1 F2-‐F3
Post-‐hoc analyses. Vilar-‐Gomez E, et al. Gastroenterology 2015; 149:367-‐378
71%
44% 44%
F1 F2 F3
Fibrosis improvement by baseline fibrosis in 102 subjects
At least 1-‐point improvement in the fibrosis score occur mostly in patients with mild fibrosis.WL > 10% is highly effective in reducing at least 1-‐point of fibrosis score irrespective of baseline fibrosis.
Fibrosis at baseline
P for trend <0.05
P = 0.68P = 0.04
ALT AST HOMA-IR HbA1C GGT Cholest
erolTriglycerides NFS FIB-4 eGFR-
CKDWL <7% -12,9 -6,9 -1,19 -0,32 -7,64 -0,29 0,08 -0,18 -0,15 -0,45WL 7-10% -19,7 -7,9 -3,92 -0,83 -14,6 -0,78 -0,68 -0,28 -0,24 -0,83WL >10% -34 -12,9 -3,17 -0,88 -17,7 -0,73 -0,63 -0,88 -0,25 3,24
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
Change from
baseline
Analysis of 261 pts with paired liver biopsies
Weight loss and improvement of NASH-related metabolic and biochemical parameters
Post-‐hoc analyses performed on patients with paired liver biopsies. Vilar-‐Gomez E, et al. Gastroenterology 2015; 149:367-‐378
Impact of weight loss and improvement in kidney function Impact of improvement of histological outcomes
Vilar-‐Gomez E, et al. submitted to Hepatology 2016
ILI (low-fat diet and exercise 200 min/wk during 52 wks)263 patients with biopsy-proven non-cirrhotic NASH
eGFR cut-‐offs (ml/min/1.73 m2), CKD-‐EPI, n (%)
eGFR > 120 6 (2%) 9 (3.4%)
eGFR 90-‐120 132 (51%) 120 (46%)
eGFR 60-‐89 118 (45%) 123 (47%)
eGFR 40-‐59 5 (2%) 9 (3.4%)
P<o.o1
Factors influencing on NASH resolution rates
Vilar-‐Gomez e, et al. Hepatology 2016;63:1875-‐1887
Factors associated to resolution of steatohepatitis rates.Practical applicability of a non-invasive model to predict NASH resolution
NASHRES formula for calculating NASH resolution probability: EXP (0.047 + 0.972 x weight loss + 2.194 x normal levels of ALT
(EOT) – 3.076 x type 2 diabetes – 2.376 x NAS ≥ 5 – 0.102 x age) / (1 + EXP (0.047 + 0.972 x weight loss + 2.194 x normal levels of ALT
(EOT) – 3.076 x type 2 diabetes – 2.376 x NAS ≥ 5 – 0.102 x age)) x 100.
Development and validation of a noninvasive model “NASH resolution model” -- NASHRES261 patients treated with lifestyle intervention and paired liver biopsies (140 in derivation set / 121 in temporary validation set)
AUC in derivation (0.96) and validation (0.95) sets
≤ 46.15 (low probability of NASHRES) NPV = 92%
≥ 69.72 (high probability of NASHRES) PPV = 92%
Using both cutoffs (≤ 46.15 and ≥ 69.72)
Liver biopsies would have been avoided in 88% with an accurate
prediction in 91%. Only 12% would it be required to show lack of
NASH resolution.
Normal ALT defined as <19 U/L (women) <30 U/L (men)
Non-invasive prediction of histological NASH resolution without fibrosis worsening after lifestyle intervention
Validation on external cohort (at 24 weeks)
60 pts treated with ILI or ILI + antioxidants during 24 wks. 42 had paired liver biopsies.AUC = 0.89. Using a cutoff < 46.15 (NPV=86%) and using cutoff > 69.72 (PPV=97%)
Gray zone or indeterminate: 7%
Post-hoc analysis, Vilar-Gomez E, et al. Alimentary Pharmacology and Therapeutics 2009;; 30:999-1009.
Calculator
Practical examples
0.00
0.25
0.50
0.75
1.00
Sensitivity
0.00 0.25 0.50 0.75 1.001 - Specificity
Area under ROC curve = 0.89
Vilar-‐Gomez e, et al. Hepatology 2016;63:1875-‐1887
Algorithm for the practical management of patients with NAFLD
≥ 10%
Healthy liver
< 10%
Compute NASH resolution score
≥ 69.72 ≤ 46.15
Consider drug therapyConsider long-‐term weight-‐ and -‐noninvasive fibrosis management
46.15 – 69.72
Liver biopsy
Consider weight loss at 12 months
BMI <40 or <35 kg/m2 with significant morbidities
Intensive Lifestyle interventions at least for 1 year
Unfavorable patient-‐ and disease-‐related factorsType 2 diabetes, women, a NAS ≥ 5 and older people
Yes
No
NAFLD
Histology-‐proven NASH or significant fibrosis determined by non-‐invasive methodsNo
Healthy lifestyleControl of
comorbiditiesDecompensated cirrhosis
Consider bariatric surgery No
NoYes
YesDietPhysical activityBehavioral therapy
Consider weight loss at 6 months
High motivation to adopt lifestyle modification
< 5%
> 5%
Consider LTx
Adapted from Vilar-‐Gomez e, et al. Hepatology 2016;63:1875-‐1887
KEY POINTS TO TAKE HOME
Hay una relación dosis-dependiente entre la pérdida de peso y la mejoría bioquímica, metabólica e histológica del NAFL. (A1)
Dadas las bajas tasas de pérdidas de peso tras cambios en el estilo de vida, se deben considerar: motivación, comorbilidades y preferencias del paciente. (A1)
Las máximas tasas de pérdida de peso se obtienen combinando dieta, ejercicio físico y terapias conductuales. La adherencia a la dieta parece ser el factor más importante. (A1)
La cirugía bariátrica es un proceder seguro y eficaz para tratar pacientes con NAFL y obesidad mórbida. Datos de seguridad en cirróticos con HTP son controversiales. (A1)
Pérdidas de peso entre el 7-10% mejorar muchos parámetros del NAFL, pero los máximos beneficios se observan con PP >10%. (A1)
La identificación de pacientes respondedores a través del empleo de métodosno invasivos debe ser prioritario en la toma de decisiones durante y al finalizarel tratamiento. (A1)
Los cambios intensivos en el estilo de vida se deben ofrecer a todos los pacientes con NAFL. (A1)