The document discusses NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis). It notes that excess liver fat and liver injury are common, especially in adults who are obese or have diabetes. The pathogenesis involves insulin resistance and a two-hit hypothesis. Treatment options discussed include weight loss through diet/exercise or bariatric surgery, insulin sensitizers like metformin and thiazolidinediones, antioxidants like vitamin E, and statins. However, weight loss interventions are often not effective long-term and treatment options generally have weak or mixed results.

1. NAFLD – what can we do
about it?

2. Cryptogenic cirrhosis = NASH
[O’Leary et al, 2008 Gastro]

3. 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

4. Obesity and hypertension

5. 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

6. [Targher et al. Dia Care 2007]
Copyright © 2011 American Diabetes Association, Inc.
Type 2 Diabetes
NAFLD
No NAFLD
NAFLD is linked to vascular disease

7. Pathogenesis
Two-hit hypothesis
Insulin resistance crucial

8. An approach to NAFLD/NASH
Awareness
Diagnosis
Treatment
Monitoring



?

9. • 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

10. The new normal
MALES: 30 U/L
FEMALES: 19U/L
Diagnosis – LFTs +...
USS – ‘bright’
liver

11. Biopsy – remains the gold standard

12. Biopsy – remains the gold standard
…but not entirely reliable

13. Fibroscan

14. Fibroscan
Scan:
- AUROC 0.94
- Sens 0.94
- Spec 0.95

15. Fibrosis scores
Score:
- AUROC 0.85
- Sens 0.9
- Spec 0.97

16. • Weight loss
– Altered diet/exercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
• Alcohol?
Treatment – the weak link

17. 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

18. • Weight loss
– Altered diet/exercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
Treatment – the weak link

19. Weight loss: surgical
Meta-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]

20. • Weight loss
– Altered diet/excercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
Treatment – the weak link

21. Thiazolidinediones
Improve steatosis and
necroinflammation
Slow fibrosis progression
Ameliorate glucose and
lipid metabolism
? long-term safety and
efficacy
Weight gain

22. Musso et al, Diabetalogia 2012
Steatosis Inflammation
Thiazolidinediones

23. Musso et al, Diabetalogia 2012
Ballooning Fibrosis
Thiazolidinediones

24. • Weight loss
– Altered diet/excercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
Treatment – the weak link

25. 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

26. Vitamin E
Steatosis Inflammation
Ballooning Fibrosis

27. • Weight loss
– Altered diet/excercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
Treatment – the weak link

28. Statins
• Safe
• Reduce ALT and steatosis in
hyperlipidaemic patients
• [Ezetemibe]
– Reduced ballooning and
fibrosis in one RCT
• [Fibrates]
– No effect

29. RIP

30. • Weight loss
– Altered diet/excercise
– Bariatric surgery
• Insulin sensitisers
– Metformin
– Thiazolidinediones
• Antioxidants
– Vitamin E
• Statins
Treatment – the weak link