Risk if Non-Alcoholic Fatty Liver Disease (NAFLD) in relation to changes in body weight and shape in a life-course perspective in general populations

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1 Synopsis of proposal February, 2012 Thorkild IA Sørensen Institute of Preventive Medicine (IPM) Copenhagen University Hospitals Risk if Non-Alcoholic Fatty Liver Disease (NAFLD) in relation to changes in body weight and shape in a life-course perspective in general populations Background Non-alcoholic fatty liver disease, which includes a complex of stages of liver pathology ranging from steatosis, steatohepatitis (NASH), fibrosis and cirrhosis and possibly also primary liver cancer, has received increasing attention the recent decades. NAFLD is strongly related to concomitant obesity and metabolic syndrome ( and it is likely to be primarily based on the relationship to abdominal obesity ( However, it remains unknown how this relationship is established during the life course starting at birth and running throughout adult life. Deducted from the findings with metabolic syndrome, it would be expected that low birth weight combined with later excessive increase in weight would be particularly prone to NAFLD. High birth weight is associated with later obesity and would therefore also be expected to be associated with increased risk of NAFLD. In the short-term clinical setting, it is well known that fatty liver and non-alcoholic steatohepatitis (NASH) can be induced by excessive calories, and that reduced calorie intake can reduce the fat content of the liver. Lipotoxicity may be the biological mechanism behind these changes, originating from overloading with toxic free fatty acids occurring when the triglyceride storage capacity is exceeded ( By increasing burning of calories and especially beta-oxidation of fatty acids, physical activity may prevent and alleviate NAFLD. On the other hand, the very rapid weight loss induced by intestinal bypass surgery may also induce fatty liver and NASH, possibly due to protein deficiency. On this background, we hypothesize that throughout life changes in body weight and shape and possibly dependent on birth weight and later physical activity has an influence on the risk that is independent of the concomitant association with obesity. Objectives To investigate the influence of body weight and body weight changes on risk of development and progression of NAFLD at individual level in a life course perspective. To investigate the influence of body shape and changes in body shape on risk of development and progression of NAFLD at individual level in a life course perspective. To investigate the influence of physical activity habits on risk of development and progression of NAFLD at individual level. Populations and methods The work is based on access to cohorts with info about repeated weight and height over long time periods (some with body shape and composition). By the unique personal ID# (in Denmark, the CPR number) assigned to each participant in the cohorts, they can be linked to outcome registers. The Danish / Finnish cohorts of relevance are the following (contact persons in parentheses): 1

2 The Copenhagen School Health Record Register (Thorkild IA Sørensen et al) The Danish Obesity Draft Board Cohort (Thorkild IA Sørensen) Copenhagen City Heart Study (Gorm B Jensen & Peter Schnohr) Diet, Cancer and Health Cohort (Kim Overvad & Anne Tjønneland) Twin Omnibus 1-2 Cohort (Kirsten Ohm Kyvik) Mothers in the Danish National Birth Cohort (Jørn Olsen & Ellen Nøhr) The Helsinki Birth Cohorts (Johan Eriksson) National registers with clinically collected end-point information on NAFLD: Cause-of-death register Hospital discharge register Pathology Register Cancer register The ICD codes used to identify cases of NAFLD and respectively exclude other liver disease of other aetiology are listed in the Annex. The information in the Pathology Register on the same conditions as defined by the histological examinations of liver biopsies is extracted by an elaborate algorithm from the output from records linkages. Record linkage to the Psychiatry Register may be used to exclude alcoholic etiology. Record linkage to the Diabetes Register may be used to identify diabetes cases as an intermediate risk factor. Statistical analyses Information needed from the cohorts is sex, age, time of examinations, any available anthropometrics including birth weight, height, weight, and waist and hip circumference, and any information describing physical activity and alcohol consumption, and as confounders, also smoking, which may influence body weight at any of the examinations. Available information about any liver disease and diabetes will also be relevant. The Copenhagen School Health Record Register includes data on birth weight and anthropometrics in childhood and will be used to analyse this phase of the life course. The other Danish cohorts are all related to adult life course. Subsets of these cohorts overlap with the school-based register, and in these combined cohorts, analyses of the life course associations from birth and childhood through adulthood will be conducted. The statistical analyses will be based on Cox proportional hazards regression models with age as underlying time scale, time of diagnosis of NAFLD and of its individual components as end-points, taking into account competing end-points (occurrence of other liver diseases, especially alcoholic, death from other causes) measures of body weight and shape as exposure possible time-dependent variables, including their changes over time, and with the various other factors added as appropriate to the model either as covariates or used as stratifying variables allowing different non-parametric underlying hazard functions. Meta-analyses or meta-regression of the estimates of the associations between the body weight and shape and physical activity variables will be considered where feasible. FLIP relationship The studies is an integrated part of the EU FP7 project entitled Fatty Liver Inhibition of Progression (FLIP), which is co-ordinated by the clinical hepatologist, Prof Vlad Ratziu, Paris, and in which IPM is responsible for the epidemiological work package (see 2

3 Collaborative agreements Agreements will be made with each individual cohort group and co-authorship arrangement will aim at complying with the Vancouver rules to be followed by agreements about the practical implementation about data extraction and analyses, including where and by whom and when it is to be done. Work-plan 1. Making agreements, including forming working groups 2. Record linkages (first priority is National Patient Register to generate case numbers) 3. Tabular and graphical data overview 4. Detailed analysis plan 5. Implementation of the plan 6. Writing manuscripts 3

4 NAFLD diagnoser i LPR Diagnostic category ICD 8/10 codes HCC : Neoplasma malignum primarium hepatis NA Steatosis NA Steatohepatitis C22.0: Neoplasma malignum hepatocellulare : Steatosis hepatis non alcoholica : Steatosis hepatis K76.0: Degeneratio hepatis steatosa ikke klassificeret andetsteds 570.xx: : Hepatitis acuta : Hepatitis subacuta : Hepatitis et subacuta alia definita : Hepatitis et subacuta : Hepatitis non specificata NA Fibrosis NA Cirrhosis K73.xx K73.0: Hepatitis chronica persistens ikke klassificeret andetsteds K73.1: Hepatitis chronica lobularis ikke klassificeret andetsteds K73.2: Hepatitis chronica activa ikke klassificeret andetsteds K73.8: Anden form for kronisk hepatit ikke klassificeret andetsteds K73.9: Kronisk hepatit uden specifikation : Degeneratio hepatis non specificata K74.0: Fibrosis hepatis K74.1: Sclerosis hepatis K74.2: Fibrosis hepatis med sklerose : Cirrhosis non specificata : Cirrhosis hepatis alia (alcoholisimo non indicato) K74.6: Anden og ikke specificeret cirrhosis hepatis 4

5 Viral, biliary liver disease and alcohol related diagnoses used for exclusions as competing end-points Diagnostic category Viral hepatitis Alcohol related ICD xx: Hepatitis viralis acuta 291.xx: Psycosis alcoholica 303.xx: Alcoholismus : Cirrhosis hepatis ex alcoholism (Laënnec) : Steatosis hepatis alcoholica Biliary liver disease : Pancreatitis chronica alcoholic : Cirrhosis biliiaris primaria : Cirrhosis biliiaris secundaria ICD10 Viral hepatites Alcohol related B15-B19: Viral lever betændelse F10.x: Psykiske lidelser og adfærdsforstyrrelser som af alkoholbrug F10.0: Akut alkohol forgifning F10.1: Skadeligt brug af alkohol F10.3: Abstinenstilstand som følge af alkoholforbrug F10.4: Delirøs abstinenstilstand som følge af alkoholforbrug F10.5: Alkoholpsykose F10.6: Amnestisk syndrom som følge af alkoholforbrug F10.7: Sent indsættende eller residual psykotisk tilstand som følge af alkoholforbrug F10.8: Andre psykiske og adfærdmæssige forstyrelser som følge af alkoholforbrug F10.9: Psykisk eller og adfærdmæssig lidelse uden specifikation som følge af alkoholforbrug G62.1: Polyneuropathia alcoholica K70.x: Alkoholisk leversygdom K70.0 Steatosis hepatis alcoholica K70.1 Hepatitis alcoholica K70.2 Fibrosis hepatis alcoholica K70.3 Cirrhosis hepatis alcoholica K70.4 Insufficientia hepatis alcoholica K70.9 Alkoholisk leversygdom uden specifikation K86.0: Pancreatitis chronica alcoholica 5

6 Biliary liver disease K74.3: Cirrhosis biliiaris primaria K74.4: Cirrhosis biliiaris secundaria 6