NAFLD & NASH: Russian perspective

Transcription

1 NAFLD & NASH: Russian perspective Vasily Isakov, MD, PhD Professor, Chief, Department Gastroenterology & Hepatology, Federal Research Center of nutrition, biotechnology and food safety

2 Disclosures Received funding from Gilead, Merck, BMS, Roche, Novartis, AstraZeneca, R-pharm, Abbvie Advisory committees for Gilead, R-pharm, Merck, Abbvie, Nutrilite (Amway), Janssen Consultant/Speaker for Gilead, Merck, BMS, Nutrilite (Amway), AstraZeneca, R-pharm, Abbvie and Janssen Inc.

3 A piece of history Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy. Ludwig J, Viggiano TR, McGill DB, et al. Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic Proceedings 1980; 55(7):434-8.

4 NAFLD - Prevalence Prevalence? Biopsy diagnostic Controversy of normal ALT levels NAFLD spectrum of disease seen with normal LFTs from postmortem studies. Cryptogenic cirrhosis

5 Prevalence of NAFLD in Russia Age (years) ,158 (16.8) ,062 (16.5) ,520 (21.2) ,469 (21.0) ,825 (12.4) ,693 (8.8) Obesity Nil 17,975 (58.4) Stage 1 4,827 (15.7) Stage 2 1,869 (4.1) Stage (2.1) Coexistent diseases Number of participants (% of total) The open multicenter prospective screening study, DIREG 1, 208 primary care centers US Blood chemistry Arterial hypertension 12,864 (41.8) Dyslipidemia 9,967 (32.4) Type 2 diabetes mellitus 2,755 (9.0) Drapkina et al., 2015

6 Prevalence of NAFLD in Russia Number of participants (% of total) Yes No Enlarged liver 5,017 (16.3) 20,482 (66.6) Heterogeneous structure of the liver 7,590 (24.7) 16,788 (54.6) Increased diameter of the portal vein 398 (1.3) 22,044 (72.9) Enlarged pancreas 998 (3.2) 22,426 (2.1) Disturbed structure of the pancreas 4,363 (14.2) 19,209 (62.5) Enlarged spleen 387 (1.3) 22,853 (74.3) Increased diameter of the splenic vein 392 (1.3) 21,804 (70.9) Liver steatosis 7,456 (24.2) 14,492 (47.1) Liver fibrosis 692 (2.3) 19,877 (64.6) Liver cirrhosis 243 (0.8) 20,308 (66.0) Signs of pancreatic steatosis 622 (2.0) 19,901 (64.7) Signs of pancreatic fibrosis 2,983 (9.7) 17,741 (57.7) Signs of portal hypertension 288 (0.9) 20,147 (65.5) Drapkina et al., 2015

7 Prevalence of NAFLD in Russia NAFLD was observed in 8,315/30,754 (27.0%) of subjects in the study population, with only 297 (3.6%) subjects having a diagnosis of NAFLD established before the screening study was initiated. Steatosis was diagnosed in 80.3% of those with NAFLD (6,680/8,315) and was established in only 3.0% (253/8,315) subjects before the screening study. In the course of screening, steatohepatitis was detected in 16.5% of NAFLD patients (1,375/8,315); according to anamnestic data, steatohepatitis was already established in 0.5% of subjects before screening (44/8,315). In the NAFLD population, the disease at the non-cirrhotic stage was noted in the majority (8,078/8,315; 97.1%) of patients. The disease at the cirrhotic stage was observed in 2.9% (237/8,315) of NAFLD patients. Alcoholic liver disease (ALD) or alcohol use in dangerous doses (medical history) was noted in 5.2% of the study population (1,608/30,754) and viral hepatitis/virus carrier status was observed in 5.3% of subjects (1,617/30,754). Drapkina et al., 2015

8 Why these data are erroneous? Viral hepatitis prevalence in general population is 2,8-3,6% as maximum In 2007 consumption of alcohol in Russia was 12,4 L per capita (age 15+), which means 34 ml pure alcohol per day US equipment were different in all centers Normal lab values were different

9 Does normal BMI guarantee the protection against NAFLD/NASH? 25 NASH patients were mostly characterized by a mild to moderate degree of inflammation and fibrosis and were free of hyperlipidemia, diabetes and obesity, conditions known to entail abnormal dietary and metabolic profiles and to carry an increased risk of advanced liver disease and cirrhosis. Musso et al., Hepatology 2003

10 Does normal BMI guarantee the protection against NAFLD/NASH? Dietary habits of NASH patients are characterized by striking differences in the quality of fat and vitamins compared with controls, despite similar intakes in calories and macronutrients. Musso et al., Hepatology 2003

11 Does normal BMI guarantee the protection against NAFLD/NASH? The insulin sensitivity index (ISI) of patients with NASH was nearly half that of controls, and the different features of the metabolic syndrome were evident in many patients. The ISI and the presence of the features of the metabolic syndrome correlated significantly with saturated fat intake but not with BMI or waist circumference; therefore, the effect of the different types of fatty acids on insulin sensitivity would not seem to be mediated by body or abdominal fat accumulation. Musso et al., Hepatology 2003

12 Lipotoxicity is a key factor in liver damage Neuschwander-Tetri Hepatology 2010

13 It seems that there are different injury mechanisms act in different steatohepatitis Methods: HETE were studied in blood samples obtained from patients with ASH (30) and NASH (39). Alcohol consumption was confirmed/excluded using CAGE and AUDIT scores. The identification and quantitation of 5(S) hydroxyeicosatetraenoic acid (5 HETE), 15 HETE and also non enzymatic oxidation product 11 HETE were carried out by HPLC MS with using 2 hydroxyoctanoic acid as internal standard. The HPLC system was coupled to mass selective detector (MS TOF). The position of hydroxyl group in HETE was elucidated by HPLC MS/MS. The MS/MS transitions were for 15 HETE m/z 319 m/z 219; for 11 HETE m/z 319 m/z 167; for 5 HETE m/z 319 m/z 115. Results: Mean age, BMI and ALT serum level were similar in patients from ASH and NASH groups. Blood 5 HETE concentration was also similar in both groups of patients, but concentration of 15 HETE and 11 HETE was significantly higher in NASH patients (table 1). NASH n=39 ASH n=30 P Age, yrs (M±SD) 47,8±13,7 45,1±10,4 NS BMI kg/m3 (M±SD) 36,6±7,1 35,3±6,5 NS ALT, IU/l (M±SD) 77,7±51,4 82,3±48,3 NS 15 HETE, ng/g (M±SD) 21,6±20,2 11,9±13,7 0,02 11 HETE, ng/g (M±SD) 20,8±21,3 11,2±12,9 0,03 5 HETE, ng/g (M±SD) 23,8±24,4 16,4±21,4 0,36 [Table 1] Conclusions: Rate of production of eicosatetraenoic acid metabolites by lipoxygenase pathway is different in NASH and ALD overweight patients. It means that different mechanisms are responsible for formation of potentially toxic fatty acids metabolites in these two types of patients. rence: 2014 International Liver Congress TM Abstract: A Status: Draft Selezneva et al., J Hepatol 2014

14 Mortality in NAFLD & AFLD FU 16,7 (0,2-21.9) yrs in NAFLD and 9,2 (0,6-23,1) yrs in AFLD Dam-Larsen S., et al., 2004

15 NAFLD - Prognosis Increased overall mortality compared to matched control populations. Commonest cause of death in patients with NAFLD, NAFL and NASH is cardiovascular disease. Increased liver-related mortality rate increasingly common indication for liver transplantation (15-20%). Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC. American Journal of Gastroenterology doi: /ajg

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20 Low-caloric or isocaloric diet? 174 NASH patients (f:m=86:88) were randomly assigned (as 1:2) for LCD ( kcal/day) or ICD ( kcal/day) calculated according to patients' sex, age, resting energy expenditures and daily physical activity. Caloric restriction was achieved by decreasing consumption of carbohydrates and fat in LCD, whereas for ICD the caloric consumption was established according to the recommended daily values for proteins, fat and carbohydrates for ideal BMI for every patient. Selezneva K. et al., J Hepatol, 2014

21 Different approach to the medical treatment Guideline Whom to treat? Metformin Glitazones Vit E UDCA / Omega-3 AASLD NASH NO YES* YES + NO / NO WGO NASH NO NO NO NO / NO EASL NASH >F2 NO YES YES NO/NO * 20. Pioglitazone can be used to treat steatohepatitis in patients with biopsy-proven NASH. However, it should be noted that majority of the patients who participated in clinical trials that investigated pioglitazone for NASH were non-diabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established. (Strength 1, Evidence - B) Vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population. (Strength - 1, Quality - B) 22. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis (Strength - 1, Quality - C)

22 Conclusion 1 Real prevalence of NAFLD/NASH is Russia is unknown, but expect to be high and increasing due to increase the prevalence of obesity and metabolic syndrome during the last two decades Being lean is not a guarantee do not have NASH, but controlling the weight and waist circumference are associated with decrease of liver fibrosis and non-progression of NASH Progression of NASH will increase mortality but firstly due to other reasons than cirrhosis itself

23 Conclusion 2 J. Ludwig : Currently, we know of no effective therapy Diet & Exercises are quite effective, but expensive and not totally accepted by patients and doctors. Old drugs (compounds) are not proved to be effective according to evidence-based medicine principles (we need new ideas how to prove!) New drugs are on the way