manejo’del’paciente’con’esteatohepatitis’no’alcohólica papel’ de’la...
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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
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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?
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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
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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
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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
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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.
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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
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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%
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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.
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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
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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
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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
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-‐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
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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
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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
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Physical activity and histological outcomes of NAFLD patients
Orci LA, et al Clinical Gastroenterology and Hepatology 2016 (in press)
ALT AST
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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
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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
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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%
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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
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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
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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
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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
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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
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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)
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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
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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
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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)