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

Natural Progression of NAFLD

Etiology

Non alcohol vs alcohol

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

Prevalence

Prevalence among races etc

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

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 1988- prevalence 12% now 28 %• USA 30-45%

Lee Ys, et al. DDW 2012: Abstract 1054.

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. 2009:1236-43

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

Major Indicators for NASH

• Age• Hispanic• HTN• Obese• Diabetes• ALT and AST elevation• Insulin resistance

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

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

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)

Biopsy or Not

• Stages Fibrosis

• Coexisting liver disease excluded

• No improvement in liver tests with lifestyle changes- ?alternate etiology

• Before drug treatment initiation

• Prognostics

NAFLD Fibrosis Score

• NAFLDSCORE.COM

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% • http://www.nafldscore.com/

Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007.

Biopsy algorithm

Stal, P. World J Gastroenterol. 2015 Oct 21;21(39):11077-87. doi: 10.3748/wjg.v21.i39.11077.

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

Secondary Causes of Fatty Liver

Treatments

• Lifestyle modification• No FDA approved therapies • Multiple compounds and existing drugs being

studied• Vitamin E, TZD’s, Experimental

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

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

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

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;6:209–216.6. Kuo CS, Lai NS, Ho LT, Lin CL. Insulin sensitivity in Chinese ovo–lactovegetarians compared with omnivores. Eur J Clin Nutr. 2004;58:312–316.7. Szeto YT, Kwok TC, Benzie IF. Effects of a long–term vegetarian diet on biomarkers of antioxidant status and cardiovascular disease risk. Nutrition. 2004;20:863–866.8. Gawrieh S, Opara EC, Koch TR. Oxidative stress in nonalcoholic fatty liver disease: pathogenesis and antioxidant therapies. J Investig Med. 2004;52:506–514.9. Hua NW, Stoohs RA, Facchini FS. Low iron status and enhanced insulin sensitivity in lacto–ovo vegetarians. Br J Nutr. 2001;86:515–519.

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

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

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

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

Vitamin E

• Arendt 2011- 80 patients 1000 IU/day- improved steatosis on CT scan vs placebo

• Sanyal 2010- 247 patients, 800 IU/day, improved steatosis, inflammation,and ballooning vs placebo and vs TZD- PIVENS STUDY

• Lavine 2011- 173 pts, 800 IU/day, improved steatohepatitis and ballooning vs placebo

• Sanyal 2004- 20 patients, 400 IU/day, improved steatosis vs baseline

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

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

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

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

Drugs in Phase 2 Race

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

Questions?

QUESTION

QUESTION

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;107:811-826.

AASLD,ACG,AGA 2012 Joint Guideline