2. NAFLD- Histology Non-alcoholic fatty liver (NAFLD)
∙Presence of hepatic steatosis with NO evidence of hepatocellular injury
Non- alcoholic steatohepatitis (NASH)
∙ Presence of hepatic steatosis and inflammation with hepatocyte injury with or without fibrosis- may progress to cirrhosis and becoming leading cause of cirrhosis

3. Natural Progression of NAFLD

5. Etiology

6. Non alcohol vs alcohol

7. Definition of NAFLD vs ALD
Steatosis by imaging or histology and :
Men- >21 drinks per week is ALD, less is likely NAFLD
Women- >14 drinks per week is ALD, less is likely NAFLD
NAFLD also linked to metabolic syndrome

10. Prevalence

11. Prevalence among races etc

12. High Risk Groups Visceral obesity a major risk
Over 90% in patients having bariatric surgery
Type 2 DM- 69% prevalence on US
Progression more likely in older pts
Ethnicity as shown

14. Increasing in Prevalence
Autopsy review shows increased NAFLD prevalence
Obese patients: 23%-1980s
49% -1990s
60%- present
Nonobese patients: 12% 1980s>>27% 1990s>>36% present
Japan prevalence 12% now 28 %
USA 30-45%
Lee Ys, et al. DDW 2012: Abstract 1054.

15. Steatosis 170 NAFLD patients on biopsy Followed for mean of 20.7 years
48 patients died
Leading cause of death: cardiovascular (38%)
Second leading cause: Cancer (17%)
2 patients developed cirrhosis (1.2%)
Dam- Larsen S, et al. Scand J Gastroenterol. 2009:

16. Fibrosis is the Issue !
Retrospective analysis of 610 NAFLD pts (median follow up 12.6 years)
No histologic features of NASH except fibrosis associated independently with long term overall mortality

17. Major Indicators for NASH
Age
Hispanic
HTN
Obese
Diabetes
ALT and AST elevation
Insulin resistance

18. Radiologic Diagnosis
Ultrasound is 85 % sensitive and 94 % specific for fatty liver disease – accuracy worse if significant obesity
The sensitivities of noncontrast CT, contrast-enhanced CT, and MRI for detecting hepatic steatosis were 33, 50, and 88 percent, respectively. The specificities were 100, 83, and 63 percent
MR spectroscopy is excellent but not widely available
?Transient elastography

19. Transient Elastography, Etc.
Measures velocity of low frequency elastic shear wave propagating through the liver
Good for eliminating advanced stage disease
Not as good in : morbid obesity, ascites, operator experience matter

20. Biopsy or Not Difficult decision- Case by Case
∙ Has peripheral stigmata of chronic liver disease (suggestive of cirrhosis)
Has splenomegaly (suggestive of cirrhosis)
Has cytopenias (suggestive of cirrhosis)
Has a serum ferritin >1.5 times the upper limit of normal (suggestive of NASH and advanced fibrosis)
Is >45 years of age with associated obesity or diabetes (increased risk of advanced fibrosis)

21. Biopsy or Not Stages Fibrosis Coexisting liver disease excluded
No improvement in liver tests with lifestyle changes- ?alternate etiology
Before drug treatment initiation
Prognostics

23. NAFLD Fibrosis Score
NAFLDSCORE.COM

24. NAFLD Fibrosis Score
Higher scores associated with increased mortality from cardiovascular disease
Predicts advanced fibrosis taking into account 6 different variables
Endorsed by AASLD
Negative predictive value of 93%
Positive predictive value of 90%
Applying this model can avoid liver bx in 75% and is accurate in about 90%
Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007.

25. Biopsy algorithm
Stal, P. World J Gastroenterol Oct 21;21(39): doi: /wjg.v21.i

26. Secondary Causes of Fatty Liver
Secondary causes of fatty liver include:
Hepatitis C
Alcohol use
Celiac disease
Thyroid disease
Medication use including tamoxifen, amiodarone, tetracycline, methotrexate, corticosteroids and anti-retroviral drugs
Lipid disorders including hypobetalipoproteinemia and cholesterol ester storage disease

27. Treatments Lifestyle modification No FDA approved therapies
Multiple compounds and existing drugs being studied
Vitamin E, TZD’s, Experimental

28. Treatments Lifestyle modification
Program assessed benefits of dietician led lifestyle modification for 12 mos
Received reccs on low fat, hypo-caloric diet
Daily food diary and encouraged to walk 200 mins/week
2 hour behavioral session every 8 weeks

29. Lifestyle Modification
293 biopsy proven NASH patients enrolled
88 (30%) lost >5% body weight
72 (25%) resolution of NASH
138 (47%) reduction in NASH
56 (19%) had regression of fibrosis
Villar-Gomez E, et al. Gastro 2015; 149:367-78

30. Weight loss
2010 study by Promrat et al determined that 9.3% body weight loss improvement in steatosis, necrosis, and inflammation; not fibrosis
3-5% weight loss improves steatosis but more is needed to improve inflammation

31. Plant based diets Not been extensively studied but they :
Typically cause weight loss4 and can lower the concentrations of blood fats (eg, triglycerides) that contribute to nonalcoholic fatty liver disease
Such diets are also associated with reduced insulin resistance, another symptom of NAFLD and greater antioxidant protection, compared with omnivorous diets
In addition, iron accumulation aggravates insulin resistance and oxidative stress. Plant–based diets have somewhat less iron bioavailability, and vegetarians have lower body–iron stores
5. Mach T. Fatty liver––current look at the old disease. Med Sci Monit. 2000;6:209– Kuo CS, Lai NS, Ho LT, Lin CL. Insulin sensitivity in Chinese ovo–lactovegetarians compared with omnivores. Eur J Clin Nutr. 2004;58:312– Szeto YT, Kwok TC, Benzie IF. Effects of a long–term vegetarian diet on biomarkers of antioxidant status and cardiovascular disease risk. Nutrition. 2004;20:863– Gawrieh S, Opara EC, Koch TR. Oxidative stress in nonalcoholic fatty liver disease: pathogenesis and antioxidant therapies. J Investig Med. 2004;52:506– Hua NW, Stoohs RA, Facchini FS. Low iron status and enhanced insulin sensitivity in lacto–ovo vegetarians. Br J Nutr. 2001;86:515–519.

32. Diets
Cross sectional retrospective study of vegetarian Buddhist monks vs normal population and prevalence of NAFLD
Did not show a protective effect
Choi SH, et al. Turk J Gastro 2015

33. Coffee?? Validated questionnaire in 2012 study
Showed that mild coffee consumption (2-3 cups/day)can be a benign adjunct to help prevent advanced fibrosis
Molloy JW, Calcagno CJ, Williams CD, et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012

34. Statins – Harm vs benefit
Statins CAN BE and SHOULD BE used if indicated in most NASH/NAFLD patients despite mild elevation in transaminases
Greace study- Concluded statins significantly improve liver biochemistries and CV outcomes in pts with elevated enzymes likely due to NASH (Athyros et al. Lancet 2010)
Several studies show NAFLD and NASH pts are not at increased risk of liver injury over general population

35. Bariatric surgery and NASH
109 NASH patients underwent gastric bypass or gastric band
At 1 year 82/109 had paired liver bx
NASH disappearance in 85% of cases and all histological features improved
NASH probability of response higher in patients with mild NASH vs severe
Lassailly G, et al. Gastro 2015; 149:379-88

37. Vitamin E
Arendt patients 1000 IU/day- improved steatosis on CT scan vs placebo
Sanyal patients, 800 IU/day, improved steatosis, inflammation,and ballooning vs placebo and vs TZD- PIVENS STUDY
Lavine pts, 800 IU/day, improved steatohepatitis and ballooning vs placebo
Sanyal patients, 400 IU/day, improved steatosis vs baseline

38. Vitamin E Controversy vs Answer?
50% of patients do not respond
Increased mortality?
Prostate cancer risk (1.6 per 1,000 person years)
Long term safety a question
Some observational studies showing increase in all cause mortality if >400 IU used
AALSD, ACG, AGA joint 2012 guideline recommends Vitamin E at 800 IU/day in those non diabetic pts with biopsy proven NASH
Some advise treating if no CAD/DM and ONLY IF FIBROSIS IS PRESENT

39. Other therapies Metformin has not been shown to change histology
TZD’s improve steatosis, insulin sensitivity, and inflammation in meta analysis (Boettcher E et al. Aliment Pharmacol Ther. 2012;35(1):66
TZD’s however need long term use and cause weight gain, cardiac toxicity and fracture risk
Obeticholic acid (OCA) - FLINT trial ( Neuschwander-Tetri BA, et al. Lancet 2014)
Synthetic variant of natural bile acids and acts to promote insulin sensitivity
141 pts randomly assigned to OCA vs placebo
45% vs 21% improved liver histology

40. Other drug therapies
Urso- No benefit after 18 mos in RCT after initial early studies showed some possible benefit
Pentoxifylline- improved ALT and steatosis- more studies needed- phase 2
Antifibrotics such as Simtuzumab being studied in phase 2

41. Ezetimibe and Probiotics
MOZART Trial
50 pts with bx proven NASH randomized to 10 mg ezetimibe vs placebo for 24 weeks
Ezetimibe did not reduce liver fat in NASH
Probiotics studied in double blind RCT of VSL#3 in obese children with biopsy proven NAFLD
Change in fatty liver severity at 4 mos by US
21% no fat, 70% light fat, 9 % moderate fat and 0% severe vs placebo where 0% none, 7 % had light, 76% moderate, 17% severe

42. Drugs in Phase 2 Race

43. Summary NAFLD and NASH are alarmingly increasing in prevalence
Most patients with NASH succumb to CV disease, malignancy, liver disease respectively
Becoming a leading cause of liver transplantation
Not everyone needs a biopsy, consider risk factors and NAFLD score
More work is needed with dietary advice to guide patients and clinicians
Ongoing trials appear promising, Vitamin E can be used in the right setting

44. Questions?

45. QUESTION

46. QUESTION

47. AASLD,ACG,AGA 2012 Joint Guideline
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107: