NAFLD – 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