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Daniel Zimmerman, MD VP and Medical Director, RGA Global

October 2015 To change photo: 1. Delete the current image. This will leave a blank placeholder with a picture icon. 2. Click the icon to add a new image. The photo will be automatically be cropped to fit the placeholder.

NOTE: If you use the “Change Picture” function, the image will be imported in its original proportions and won’t fill the placeholder completely and will need to be cropped. Non-alcoholic Fatty (NAFLD)

Core Principles

2 See for instructions on how to change sidebar photo NAFLD – Non-alcoholic Definitions

. NAFLD • Evidence of hepatic , either by imaging or histology with > 5% steatotic hepatocytes • No identified causes for secondary hepatic accumulation . Causes of secondary hepatic fat accumulation • Excess EtOH, Hep C (genotype 3), Wilson’s disease, lipodystrophy, starvation, , abetalipoproteinemia, medications, (e.g. amiodarone) • Excess EtOH defined as: > 20 gm/d female and >30 gm/d male . NAFLD is a spectrum (steatosis  ) of disease but primarily divided into: • Non-alcoholic fatty liver (NAFL) – no histological evidence of hepatocellular injury • Non-alcoholic steatohepatitis (NASH) – histological evidence of , hepatocellular ballooning (injury) with or without fibrosis – indistinguishable from alcoholic steatohepatitis

3 See Appendix for instructions on how to change sidebar photo NAFLD – Epidemiology and Risk Factors

. Prevalence • Japan: 31-86/1,000 person-years • UK: 29/100,000 • Dallas Heart Study (using MR spectroscopy): 31% of gen pop • Worldwide estimates of 6.3-33% with median of 20% • NASH estimates lower at 3-5% . Risk Factors • : With BMI > 30 the prevalence is > 60%, prevalence increases to > 90% with BMI > 39! • DM-2: up to 69% may have NAFLD • Hyperlipidemia: 50% of dyslipidemia clinic attendees have NAFLD • NAFLD prevalence increases with age • Males > Females

4 See Appendix for instructions on how to change sidebar photo NAFLD – Lab Findings

. Liver Enzymes • ALT and AST may be elevated up to 5x ULN • AST/ALT ratio usually < 1 • Alk phos and GGT may also be elevated • Degree of liver enzyme elevations does not correlate with clinical inflammation or fibrosis • Ferritin > 1.5x ULN may correlate with higher likelihood of NASH being present . Imaging • Liver US is 82-89% sensitive and 93% specific for identifying fatty infiltrate • CT no more sensitive than US, but can identify other pathology • Imaging cannot distinguish steatosis from steatohepatitis

5 See Appendix for instructions on how to change sidebar photo NAFLD – Grade and Stage of Liver

. Grade Grade Grade 1 - mild Steatosis in up to 66% of hepatocytes, occasional ballooned hepatocyte, scattered neutrophils +/- lymphocytes in hepatic lobules, no or mild portal inflammation

Grade 2 – moderate Steatosis of any degree, some ballooned hepatocytes and neutrophils, pericentral fibrosis may be present, mild to moderate portal and lobular inflammation Grade 3 - severe Diffuse lobular steatosis, widespread ballooning and lobular inflammation with pericentral vein fibrosis, mild to moderate portal inflammation . Stage – degree of fibrosis Stage – degree of fibrosis 0 No fibrosis

1 Zone 3 perisinusoidal fibrosis only

2 Zone 3 plus portal/periportal fibrosis

3 As above with bridging fibrosis

4 Cirrhosis

6 See Appendix for instructions on how to change sidebar photo NAFLD – Morbidity and Mortality Risk Multiple studies – somewhat conflicting results

. Issues • Epidemiologic studies are often based on biochemical and imaging studies and not biopsy • Difficult to control for co-variates which may also increase risk of death and CV outcomes • NAFLD may only be a “serious condition” in a sub-group of individuals with NAFLD – the challenge is to identify those individuals. . Morbidity • Large meta-analysis found OR of 1.50 for CV events when other risks controlled. . Mortality • Variable results, but increased MRs in the range of 1.34-1.69, mostly due to CV disease.

7 See Appendix for instructions on how to change sidebar photo NAFLD – Other Points

. Risk factors of progression to advanced fibrosis: • Presence of inflammation on biopsy increases risk 2.5x. • Older age, DM, AST and ALT > 2x ULN, , Mallory hyaline or fibrosis on biopsy, and BMI > 28. . NASH is 3rd most common indication for liver transplant in the U.S. – may become the most common indication in the next 10-20 years. . Risk of hepatocellular carcinoma in individuals with cirrhosis due to NAFLD may be lower than in those with cirrhosis due to C. . Therapeutic interventions to treat or reverse NAFLD: • Effective - Weight loss, bariatric surgery, TZDs, vitamin E (NASH), obeticholic acid • Not effective – metformin, ursodeoxycholic acid, omega-3s

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Core Principles

9 See Appendix for instructions on how to change sidebar photo Ulcerative Colitis – Mortality

. SMRs range from 0.7 – 1.4 depending on study . Mortality highest in first few years after diagnosis and in those with extensive disease . Mortality rates have decreased over time

10 See Appendix for instructions on how to change sidebar photo Ulcerative Colitis – Extra-intestinal manifestations

. 25% of patients develop extra-intestinal manifestations over course of their disease • Arthritis, ankylosing spondylitis (AS), scleritis, iritis, erythema nodosum, pyoderma gangrenosum, primary sclerosing cholangitis (PSC), , thromboembolism . Primary sclerosing cholangitis occurs in 3-7% of those with UC and approximately 2/3 of those with PSC will develop UC • Higher risk of PSC in men and those with pancolitis • Suspect possible PSC in individuals with UC and elevated alkaline phosphatase/GGT . Most extra-intestinal manifestations parallel course of colonic disease activity except for PSC and AS

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See Appendix for instructions on how to change sidebar photo Ulcerative Colitis – Colorectal (CRC) cancer risk

. Two main risk factors for the development of CRC • Duration of disease: Increased risk > 10 years Standardized incidence ratio = 7.0 • Extent of disease: Pancolitis (or > 50% of colon) > . Pancolitis CRC risk • 5-10% after 20 years, 12-20 % after 30 years, 30% after 35 years (varies based on study) . Left-sided colitis CRC risk • Risk increases later than pancolitis: 15-20 years after diagnosis . Ulcerative and proctosigmoiditis CRC risk • No increase risk of CRC . Individuals with both UC and PSC have even higher risk of CRC than those with UC alone

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See Appendix for instructions on how to change sidebar photo Ulcerative Colitis – Surveillance

. Standardized frequency of colonoscopic surveillance not established . Various societies with different recommendations, but in general: • Start surveillance after 8-10 years of disease in those with pancolitis and after 15 years in those with left-sided colitis • Repeat every 1-5 years depending on deemed risk . Dysplasia on random colon

Low Grade Dysplasia High-Grade Dysplasia 19% have CRC at immediate colectomy 40% have CRC at immediate colectomy

34% have CRC at colectomy in 1 year Presence of high-grade dysplasia should lead to immediate colectomy Can regress spontaneously

13 See Appendix for instructions on how to change sidebar photo Crohn’s Disease - Mortality

. Varying results of studies . Large study from 2007 determined overall SMR of 1.29 which was unchanged from the 1970s . MRs decreased with increasing age

14 See Appendix for instructions on how to change sidebar photo Crohn’s disease – CRC cancer risk and surveillance

. Risk of CRC is likely similar to risk in UC . RR of CRC higher in Crohn’s individuals primarily with colonic disease and those diagnosed under age 30 years . Crohn’s may increase risk of small bowel cancer . Most societies recommend the same colonoscopic surveillance protocols for Crohn’s as for UC, although the supportive data is less definitive.

15 See Appendix for instructions on how to change sidebar photo Crohn’s disease – other

. Risk of PSC is slightly lower than with UC – approximately 3.5%

16 See Appendix for instructions on how to change sidebar photo References

. Lu, H, et al. Independent Association between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: A Systematic Review and Meta-Analysis. International Journal of Endocrinology Vol 2013, Article ID 124958.

. Adams, LA, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. , 2005 Jul: 129(1): 113-21.

. Bayard M, et al. Nonalcoholic Fatty Liver Disease. Am Fam Physician 2006;73:1961-8.

. Chalasani, N, 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. Hepatology 2012 Jun, 55(6):2005-23.

. Angulo, P. Long-term mortality in nonalcoholic fatty liver disease: Is liver histology of any prognostic significance? Hepatology, 51:373- 375.

. Wattacheril, Julia, Naga, C. Non-Alcoholic Fatty Liver Disease (NAFLD): Is it really a serious condition? Hepatology 2012 October:56(4):1580-1584.

. www.uptodate.com Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults

. www.uptodate.com Natural history and management of nonalcoholic fatty liver disease in adults

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See Appendix for instructions on how to change sidebar photo References

. Goldman L, Bennett J. Cecil Textbook of Medicine. 2000

. Jess T, et al. Overall and Cause-Specific Mortality in Ulcerative Colitis: Meta-analysis of Population-Based Inception Cohort Studies. American Journal of Gastroenterology 102, 609-617, (1 March 2007).

. www.uptodate.com Colorectal cancer surveillance in inflammatory bowel disease

. Canavan C, et al. Long-Term Prognosis in Crohn’s Disease: An Epidemiological Study of patients Diagnosed More Than 20 years Ago in Cardiff. Aliment Pharmacol Ther. 2007;25(1):59-65.

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