GWAS and enrichment analyses of non-alcoholic fatty liver ...
Non alcoholic fatty liver disease: what can we do about it?
-
Upload
philaberry -
Category
Health & Medicine
-
view
902 -
download
0
description
Transcript of Non alcoholic fatty liver disease: what can we do about it?
Cryptogenic cirrhosis = NASH
[O’Leary et al, 2008 Gastro]
NAFLD and NASH
• Excess liver fat (NAFLD)– >30% adults– 13% children
• Fat and liver injury (NASH)– 3-4% adults– 15-20% obese adults
& < 2 alcoholic drinks/day
Obesity and hypertension
Overall survival of subjects in the study with NASH or bland steatosis. n=256; median follow up 24 years
[Soderberg et al, Hepatology 2010]
Effect on life expectancy
[Targher et al. Dia Care 2007]
Copyright © 2011 American Diabetes Association, Inc.
Type 2 Diabetes
NAFLD
No NAFLD
NAFLD is linked to vascular disease
PathogenesisTwo-hit hypothesisInsulin resistance crucial
An approach to NAFLD/NASH
Awareness
Diagnosis
Treatment
Monitoring
?
• Metabolic syndrome:– Central obesity or BMI >30 AND 2
of...– TG > 1.7 mmol/L– HDL <1.03 mmol/L– BP >130 sys or >85 dias– Fasting glucose > 5.6 mmol/L or
known Type II DM
Awareness – who to target
The new normal
MALES: 30 U/LFEMALES: 19U/L
Diagnosis – LFTs +...
USS – ‘bright’ liver
Biopsy – remains the gold standard
Biopsy – remains the gold standard
…but not entirely reliable
Fibroscan
FibroscanScan: - AUROC 0.94- Sens 0.94- Spec 0.95
Fibrosis scoresScore: - AUROC 0.85- Sens 0.9- Spec 0.97
• Weight loss– Altered diet/exercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins• Alcohol?
Treatment – the weak link
Weight loss: non-surgical
Safe≥5% weight loss improves
steatosis and cardio-metabolic variables
≥7% weight loss improves histological disease activity in NASH
Achieved by <50% individuals even in RCTs adopting intensive multidisciplinary lifestyle interventions
• Weight loss– Altered diet/exercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins
Treatment – the weak link
Weight loss: surgicalMeta-analysis of bariatric surgery
assessing 766 paired liver biopsies from 15 studies reported:
- improvement in steatosis in 91.6% - improvement in steatohepatitis in
81.3% - improvement in fibrosis in 65.5% - complete NASH resolution in 69.5% - improvements occurred primarily in
patients showing the greatest improvement in components of metabolic syndrome and insulin resistance.
[Mummadi et al, Gastroent Hepatol 2008]
• Weight loss– Altered diet/excercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins
Treatment – the weak link
Thiazolidinediones
Improve steatosis and necroinflammation
Slow fibrosis progressionAmeliorate glucose and
lipid metabolism ? long-term safety and
efficacyWeight gain
Musso et al, Diabetalogia 2012
Steatosis Inflammation
Thiazolidinediones
Musso et al, Diabetalogia 2012
Ballooning Fibrosis
Thiazolidinediones
• Weight loss– Altered diet/excercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins
Treatment – the weak link
Vitamin E
Mixed results on liver histology
Improve histological disease activity when administered for 2 years or when implemented with vigorous weight-loss regimens
• “Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes.
Sanyal et al, NEJM 2010
Vitamin E
Steatosis Inflammation
Ballooning Fibrosis
• Weight loss– Altered diet/excercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins
Treatment – the weak link
Statins
• Safe• Reduce ALT and steatosis in
hyperlipidaemic patients
• [Ezetemibe]– Reduced ballooning and
fibrosis in one RCT• [Fibrates]
– No effect
RIP
• Weight loss– Altered diet/excercise– Bariatric surgery
• Insulin sensitisers– Metformin– Thiazolidinediones
• Antioxidants– Vitamin E
• Statins
Treatment – the weak link