Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population.

BACKGROUND & AIMS: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. METHODS: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. RESULTS: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. CONCLUSION: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Work ability trends 2000-2020 and birth-cohort projections until 2040 in Finland.

Aims: To examine age-group and birth-cohort trends in perceived work ability in Finland in 2000-2020 and make projections of perceived work ability up to 2040 based on the observed birth-cohort development. Methods: Ten population-representative cross-sectional surveys conducted in Finland between 2000 and 2020 were used (overall N = 61,087, range 817-18,956). Self-reported estimates of current work ability in relation to the person's lifetime best on a scale from zero to ten (0-10) were classified into three groups: limited (0-5), intermediate (6-7), and good (8-10). Multiple imputation was used in projecting work ability. Results: Examining past trends by 5-year birth-cohorts born between 1961 and 1995 showed that work ability has declined steadily over time among older birth-cohorts, while in the two younger cohorts a stable development before 2017 and a steep decline between 2017 and 2020 was seen. Trends by 5-year age groups showed a declining trend of good work ability among 20-44-year-olds, a stable trend among 45-54-year-olds, and an improving trend among 55-year-olds and older was observed for the period 2000-2020. Among the under 55-year-olds the prevalence of good work ability ended up around 75% and at 68% among the 55-59-year-olds, 58% among the 60-69-year-olds and 49% among the 70-74-year-olds in 2020. Birth-cohort projections suggested a declining work ability in the future among all age groups included (30-74 years). By 2040, the prevalence of good work ability is projected to decline by 10 to 15 percentage points among 45-74-year-olds. Conclusions: The projections suggest declining work ability in the future. Efforts to counteract the decline in work ability are needed.

Association between physical fitness and perceived work ability among Finnish population: a cross-sectional study.

OBJECTIVE: This cross-sectional study aims to examine association between different components of physical fitness and perceived work ability among working age population. METHODS: The population-based study sample included 2050 participants aged 18-74 from the Finnish national Health 2011 study. Physical fitness was assessed by the single leg stand test, the modified push-up test, the vertical jump test and the six-minute walk test, and perceived work ability was assessed via interview. Logistic regression was used for examining the associations between physical fitness and work ability. RESULTS: After adjusting for potential confounders (age, sex, marital status, educational level, work characteristics, total physical activity, daily smoking, BMI and number of diseases), odds ratios indicated that good work ability was more likely among those who had better balance in single leg stand test (OR = 1.54; 95% CI 1.07-2.24), and who belonged in the high fitness thirds in six-minute walking test (OR = 2.08; 95% CI 1.24-3.49) and in vertical jump test (OR = 2.51; 95% CI 1.23-5.12) compared to lowest third. Moreover, moderate (OR = 1.76; 95% CI 1.02-3.05) to high fitness (OR = 2.87; 95% CI 1.40-5.92) in modified push-up test increased the likelihood of good work ability compared to lowest third. CONCLUSION: These study results indicate that good musculoskeletal as well as cardiorespiratory fitness are associated with better perceived work ability. Promoting physical fitness in individual and societal level may be potential targets for maintaining good work ability in working age population.

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. METHODS: Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. RESULTS: Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. CONCLUSIONS: The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Combined use of the ELF test and CLivD score improves prediction of liver-related outcomes in the general population.

BACKGROUND AND AIMS: Effective and feasible population screening strategies are needed for the early detection of individuals at high risk of future severe liver-related outcomes. We evaluated the predictive performance of the combination of liver fibrosis assessment, phenotype profile, and genetic risk. METHODS: Data from 5795 adults attending the Finnish Health 2000 Survey were linked with healthcare registers for liver-related outcomes (hospitalization, hepatocellular cancer, and death). Fibrosis was assessed using the enhanced liver fibrosis (ELF) test, phenotype profile by the chronic liver disease (CLivD) risk score, and genetic risk by a validated Polygenic Risk Score (PRS-5). Predictive performance was assessed by competing-risk analyses. RESULTS: During a median 13-year follow-up, 64 liver-related outcome events were recorded. ELF, CLivD score, and PRS-5 were independently associated with liver-related outcomes. The absolute 10-year risk of liver-related outcomes at an ELF value of 11.3 ranged from 0.3% to 33% depending on the CLivD score. The CLivD score added 51% of new predictive information to the ELF test and improved areas under the curve (AUCs) from 0.91, 0.81, and 0.71 for ELF alone to 0.95, 0.85, and 0.80, respectively, for ELF combined with the CLivD score at 1, 5, and 10 years. The greatest improvement was for 10-year predictions (delta-AUC 0.097, p < .0001). Adding PRS-5 did not significantly increase predictive performance. Findings were consistent in individuals with obesity, diabetes, or alcohol risk use, and regardless of whether gamma-glutamyltransferase was used in the CLivD score. CONCLUSION: A combination of ELF and CLivD score predicts liver-related outcomes significantly better than the ELF test alone.

Persistent organic pollutants associate with liver disease in a Finnish general population sample.

BACKGROUND AND AIMS: Persistent organic pollutants (POPs) have multiple adverse effects on human health. Recent studies show a possible association with liver disease, but population-based data are scarce. In this population-based study, we studied the associations between POPs and biomarkers of liver disease and incident liver disease. METHODS: This study consisted of 2789 adults that participated in the environmental toxin subset of the Finnish health-examination survey, FINRISK 2007. Toxins were measured from serum samples, and standard liver tests and dynamic aspartate aminotransferase-alanine aminotransferase ratio (dAAR) were measured as biomarkers of liver function. Associations between POPs and the biomarkers were then analysed using linear regression. Associations between POPs and incident liver disease (n = 36) were analysed by Cox regression. RESULTS: Organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and several perfluorinated alkyl substances exhibited statistically significant positive associations with several biomarkers of liver injury (betacoefficient per SD 0.04-0.14, p < 0.05). These associations were stronger in subgroups of individuals with obesity or non-alcoholic fatty liver disease. OCPs, PCBs and perfluoro-octanoic acid also had significant positive associations with dAAR, which can be used to predict risk of incident severe liver outcomes (beta coefficient per SD 0.05-0.08, p < 0.05). OCPs and PCBs were also significantly and positively associated with incident liver disease (hazard ratio per SD 1.82 95% CI 1.21-2.73, p < 0.01 and hazard ratio per SD 1.69, 95% CI 1.07-2.68, p < 0.05 respectively). CONCLUSIONS: Several POPs show positive associations with markers of liver injury and incident liver disease, suggesting that environmental toxins are important risk factors for chronic liver disease.

Probable Sarcopenia, Obesity, and Risk of All-Cause Mortality: A Pooled Analysis of 4,612 Participants.

INTRODUCTION: Conflicting evidence exists concerning whether having sarcopenic obesity has additive mortality risk over having only sarcopenia or obesity. We examined the independent and combined associations of obesity and probable sarcopenia with all-cause mortality. METHODS: The pooled analysis included three large, harmonized datasets (Health 2000 Survey; Health, Aging and Body Composition Study; Longitudinal Aging Study Amsterdam) with mortality follow-up data on individuals aged 70 years and over at baseline (n = 4,612). Obesity indicators included body mass index and waist circumference, and probable sarcopenia was defined based on grip strength. The mixed effects Cox model was used for statistical analyses, adjusting for age, sex, marital status, education, race, physical activity, alcohol consumption, smoking, and baseline diseases. RESULTS: Risk of death increased for those having probable sarcopenia only (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.39-1.85) or probable sarcopenia with obesity (HR: 1.36, 95% CI: 1.13-1.64) but not for the obese-only group (HR: 0.92, 95% CI: 0.85-1.01), when compared to non-obese non-sarcopenic individuals. The results were similar regardless of adjustments for covariates or different obesity criteria applied. CONCLUSION: Probable sarcopenia, whether combined with obesity or not, is associated with increased mortality. Obesity did not increase mortality among older adults. Maintaining muscle strength and identifying older adults at risk of sarcopenia is important for the prevention of premature mortality.

Poor health status before the COVID-19 pandemic is associated with unfavourable changes in health-related lifestyle.

AIMS: The effects of COVID-19 containment measures on health-related lifestyle have been both favourable and unfavourable for health. Factors predisposing to unfavourable changes are still poorly known. In this short communication, we aimed to examine which socioeconomic and health-related factors predicted unfavourable lifestyle changes based on data from the same individuals before (2017) the pandemic and during the second wave (2020) of the pandemic in Finland. METHODS: This individual-level follow-up study was based on a nationally representative, two-stage stratified cluster sample of Finnish adults from the FinHealth 2017 Study, conducted in Spring 2017, and its follow-up survey, conducted in Autumn 2020. A total of 3834 men and women aged 25-69 years at baseline had information of selected lifestyle factors (vegetable consumption, leisure-time physical activity, sleeping problems and nightmares) available at both time points. Odds ratios and 95% confidence intervals for unfavourable lifestyle changes (yes/no) according to socioeconomic and health-related factors were calculated using logistic regression models taking into account the sampling design and non-response. RESULTS: We found that those having poor health (i.e. psychological distress, poor self-rated health or chronic diseases) or disadvantaged socioeconomic background before the pandemic were prone to unfavourable lifestyle changes during the follow-up. CONCLUSIONS: Observed unfavourable lifestyle changes in vulnerable population groups may accelerate health inequalities. Targeted health promotion actions are needed to prevent this unfavourable development.

Development of non-communicable disease risk factors in Finland: projections up to 2040.

BACKGROUND: Non-communicable diseases are a major cause of mortality and morbidity worldwide. They share the same behavioural risk factors (smoking, sedentary behaviour, alcohol consumption and an unhealthy diet), all of which are modifiable risk factors, and biological consequences (hypertension, elevated total cholesterol, obesity and diabetes). METHODS: Using data from a series of cross-sectional health examination surveys conducted among the adult population in Finland from 1997 to 2017, a projection of risk factor development (smoking, leisure time sedentary behaviour, hypertension, elevated total cholesterol, overweight and obesity, and diabetes) up to the year 2040 was made. The projections were estimated using a multiple imputation method. RESULTS: Smoking prevalence is estimated to continue to decline up to 2040, similar to hypertension and elevated total cholesterol. By contrast, obesity and diabetes will develop unfavourably, with an increase in prevalence. The increase in obesity is mainly due to polarisation - that is, normal-weight people remain of a normal weight, but overweight people tend to gain more weight and become obese. The observed and estimated changes for leisure time sedentary lifestyle were not statistically significant. CONCLUSIONS: Projections of risk factors for non-communicable diseases are needed to guide public health policies and programmes, decision-making and the allocation of health care resources for prevention and care. In Finland, favourable developments have been seen in many of the risk factors, but obesity and diabetes show unfavourable development. There is a need to continue regular, systematic monitoring of the development of risk factors through health examination surveys and to set national goals and programmes to tackle the existing problems.

Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score.

BACKGROUND & AIMS: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors. METHODS: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. RESULTS: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. CONCLUSIONS: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. LAY SUMMARY: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.

The association of high-sensitivity C-reactive protein with future weight gain in adults.

BACKGROUND: Obesity is associated with low-grade systemic inflammation, and it has been suggested that increased inflammation markers could predict future weight gain. Our aim was to investigate the associations of high-sensitivity C-reactive protein (hs-CRP) concentration with changes in weight and waist circumference in adults during 11 years of follow-up. METHODS: We used data from the Health 2000 and Health 2011 surveys consisting of a population-based sample of Finnish adults. We included those 3143 participants, aged 30-75 years at baseline, whose baseline hs-CRP was measured, and who had information on measured weight and height at both time points. Associations between baseline hs-CRP and changes in weight and waist circumference were analyzed using multinomial logistic regression, adjusted for sociodemographic factors (age, sex, marital status, and educational status), lifestyle factors (smoking, alcohol consumption, leisure-time physical activity, sitting time, sleeping time, and psychological distress), and baseline values of BMI and waist circumference. RESULTS: Hs-CRP was not associated with weight gain (≥5%) when adjusted for potential confounders (OR 0.99, 95% CI 0.96-1.01), compared to stable weight (change <±5%). Higher baseline hs-CRP was associated with decrease in weight (≤-5%) in the unadjusted (OR 1.03, 1.01-1.05), but not in the adjusted (OR 1.01, 0.99-1.03) model. No association was observed between hs-CRP and waist circumference. CONCLUSIONS: Hs-CRP was not associated with future changes in weight or waist circumference in adults. These findings suggest that hs-CRP concentration does not predict future weight gain.

Attribution of diabetes to the development of severe liver disease in the general population.

BACKGROUND AND AIMS: Diabetes is associated with advanced liver disease and predicts mortality regardless of the primary aetiology of the liver disease. Even a family history of diabetes has been linked to advanced liver fibrosis in non-alcoholic fatty liver disease (NAFLD). However, the fraction of liver-related outcomes in the general population that are attributable to diabetes remains unclear. METHODS: The population attributable fraction (PAF) of diabetes for liver disease as a time-dependent exposure was estimated in the Finnish FINRISK study (n = 28 787) and the British Whitehall II study (n = 7855). We also assessed the predictive ability of a family history of diabetes for liver-related outcomes. Incident diabetes data were from drug purchase/reimbursement and healthcare registries (FINRISK) or follow-up examinations (Whitehall II). Incident severe liver outcomes were identified through linkage with national healthcare registries. RESULTS: Diabetes was associated with a two-fold risk of liver-related outcomes in both the FINRISK (HR, 1.92; p < .001) and Whitehall II (HR, 2.37; p < .001) cohorts, and this remained significant after adjusting for multiple confounders. PAF analyses demonstrated that diabetes explained 12-14% of the risk for severe liver-related outcomes after 10 and 20 years of follow-up. Also, maternal diabetes increased the risk of liver-related outcomes in the FINRISK (HR, 1.43; p = .044) and Whitehall II (HR, 2.04; p = .051) cohorts. CONCLUSION: Approximately 12%-14% of severe liver-related outcomes are attributable to diabetes at the population level. The association between maternal diabetes and liver disease might suggest a mitochondrial genetic mechanism.

The association of body mass index with quality of life and working ability: a Finnish population-based study.

PURPOSE: The impact of obesity on quality of life (QoL) and working ability vary in different dimensions. This study investigated the association of obesity with QoL and working ability in Finnish adults. Comorbidities as associative factors were also characterised. METHODS: This cross-sectional study included 4956 randomly selected adults. QoL (EUROHIS-QOL 8 total score and individual components), perceived physical and psychological working ability, and sick leave days were analysed in different body mass index (BMI) groups. Regression models were used to study the role of comorbidities as associative factors. RESULTS: EUROHIS-QOL 8 total score was significantly lower in BMI group 25.0-29.9 kg/m2 (4.01; 95% confidence interval 3.97-4.05), BMI 30.0-34.9 kg/m2 (3.85; 3.79-3.91), BMI 35.0-39.9 kg/m2 (3.75; 3.66-3.85), and BMI ≥ 40.0 kg/m2 (3.73; 3.46-4.00) compared to individuals with normal (18.5-24.9 kg/m2) BMI (4.08; 4.04-4.12). Individuals with obesity (BMI ≥ 30.0 kg/m2) rated their QoL lower than individuals with normal BMI in seven of the eight EUROHIS-QOL 8 components. A lesser proportion of individuals (53-73%) with obesity rated their physical working ability as very or fairly good compared to individuals with normal BMI (90%, p values < 0.001). The psychological working ability was rated as very or fairly good by 71-75% of individuals with obesity compared to 85% of individuals with normal BMI (p = 0.008 and p = 0.001 in individuals with BMI 30.0-34.9 and BMI 35.0-39.9 kg/m2, respectively). CONCLUSIONS: Obesity was negatively associated with both physical and psychological components of QoL, even after accounting for obesity-related comorbidities. Obesity treatment can benefit from a holistic approach that considers these multifaceted associations.

Lifestyle factors and obesity in young adults - changes in the 2000s in Finland.

AIMS: Young adulthood is a life stage that is vulnerable to detrimental lifestyle changes and excessive weight gain, which may have major effects on health later in life. This study aimed to examine the changes in lifestyle-related factors in the 2000s and sociodemographic differences in lifestyle in Finnish young adults. METHODS: The study was based on the cross-sectional data from two representative samples of Finnish young adults aged 18-29 years from the Health 2000 Survey (n = 1894; 90% participated) and the FinHealth 2017 Study (n = 1162; 54% participated). Sociodemographic factors, lifestyle choices (smoking, alcohol consumption, intake of vegetables, physical activity), and anthropometrics were self-reported. Weighted prevalence based on predictive margins and odds ratios were analyzed using logistic regression, taking into account the sampling design and non-response. RESULTS: The prevalence of daily cigarette smoking decreased between the years 2000 and 2017 from 34% to 12% (p < 0.01) and from 23% to 11% (p < 0.01) in men and women, respectively. There was a decline in the prevalence of daily intake of fresh vegetables, especially in men. The prevalence of obesity (BMI ⩾ 30 kg/m2) doubled being 15% in men and 18% in women in 2017. Health-endangering lifestyles, measured by a lifestyle sum score, were more common among young adults with lower education compared to those with higher. CONCLUSIONS: This study showed both favorable and unfavorable changes in the lifestyles of Finnish young adults in the 2000s. Health-endangering lifestyles were more common among young adults with lower education, suggesting the need for tailored health-promoting actions. Special attention should be given to obesity prevention.

Temporal changes in health-related lifestyle during the COVID-19 epidemic in Finland - a series of cross-sectional surveys.

BACKGROUND: Public health recommendations and governmental restrictions during the COVID-19 epidemic have affect everyday life. This study aimed to examine temporal changes in health-related lifestyle and the accumulation of positive and negative changes in the key lifestyle factors (vegetable consumption, leisure-time physical activity, sleeping, alcohol consumption, smoking) in the same individuals among Finnish adults during the epidemic. METHODS: This study was based on a series of cross-sectional surveys conducted between April 2020 and June 2021 to investigate antibody levels for the new coronavirus in the population. In each survey, a random sample of adults (18 to 69 years) from five university hospital regions were invited. A total of 5655 (response rate 32%) responded to the questionnaire including questions on lifestyle changes during epidemic. RESULTS: On average one-sixth of respondents (17%) reported at least two negative changes in the key lifestyle factors during the study period. An increase in snacking and sleep problems and decrease in leisure-time physical activity and active commuting to work were the most common of individual negative changes. The proportion of negative changes in physical activity increased as the epidemic drags on. In contrast, on average every seventh of the respondents (14%) reported at least two positive lifestyle changes in the key lifestyle factors. The most common individual positive changes were increased consumption of fruit, berries and vegetables and decreased consumption of alcohol. More negative changes were reported on average, when both negative and positive changes in the key lifestyle factors were summed. The most negative changes were reported in the late 2020. CONCLUSION: The results of the present study suggest that the lifestyle changes during the COVID-19 epidemic have been diverse being on average more commonly unfavorable than favorable for health. The deteriorated epidemic situation in the late 2020 and, on the other hand, prolonged epidemic predisposed to negative lifestyle changes. Further studies are important to examine whether these changes are maintained over time and to identify the factors that contribute to changes and their accumulation in the same individuals. Health promotion actions are needed to prevent the long-term effects of the epidemic on health and welfare.

Risks of Light and Moderate Alcohol Use in Fatty Liver Disease: Follow-Up of Population Cohorts.

BACKGROUND AND AIMS: The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and malignant disease, as well as death. APPROACH AND RESULTS: Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all-cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose-dependent risk increase for incident advanced liver disease and malignancies. Consuming 10-19 g/day of alcohol in general or 0-9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%-40% reduction of incident cardiovascular disease (CVD). We observed a J-shaped association between alcohol intake and all-cause death with a maximal risk reduction of 21% (95% confidence interval, 5%-34%) at alcohol intake of 0-9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects. CONCLUSIONS: Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.

Genetic Risk Score for Serum 25-Hydroxyvitamin D Concentration Helps to Guide Personalized Vitamin D Supplementation in Healthy Finnish Adults.

BACKGROUND: Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D. OBJECTIVES: We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration. METHODS: We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere. RESULTS: GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 × 10-6) and serum 25(OH)D concentration from 64.4 ± 20.9 nmol/L to 68.5 ± 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063). CONCLUSIONS: We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries.

Incidence of liver-related morbidity and mortality in a population cohort of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) increases morbidity and mortality. However, patients in biopsy-based cohorts are highly selected and the absolute risks of liver- and non-liver outcomes in NAFLD in population remains undefined. We analysed both liver-related and non-liver-related outcomes in Finnish population cohorts of NAFLD. METHODS: We included 10 993 individuals (6707 men, mean age 53.3 ± 12.6 years) with NAFLD (fatty liver index ≥60) from the Finnish population-based FINRISK and Health 2000 studies. Liver fibrosis was assessed by the dAAR score, and genetic risk by a recent polygenic risk score (PRS-5). Incident liver-related outcomes, cardiovascular disease (CVD), cancer and chronic kidney disease (CKD) were identified through linkage with national registries. RESULTS: Mean follow-up was 12.1 years (1128 069 person-years). The crude incidence rate of liver-related outcomes in NAFLD was 0.97/1000 person-years. The cumulative incidence increased with age, being respectively 2.4% and 1.5% at 20 years in men and women aged 60 years at baseline, while the relative risks for CVD and cancer were 9-16 times higher. The risk of CKD exceeded that of liver outcomes at a baseline age around 50 years. 20-year cumulative incidence of liver-related outcomes was 4.3% in the high, and 1.5% in the low PRS-5 group. The dAAR score associated with liver outcomes, but not with extra-hepatic outcomes. CONCLUSION: The absolute risk of liver-related outcomes in NAFLD is low, with much higher risk of CVD and cancer, emphasizing the need for more individualized and holistic risk-stratification in NAFLD.

Waist and hip circumference are independently associated with the risk of liver disease in population-based studies.

BACKGROUND & AIMS: While several anthropometric measures predict liver disease, the waist-hip ratio (WHR) has shown superiority in previous studies. We analysed independent and joint associations of waist circumference (WC) and hip circumference (HC) with liver disease and liver-related risk factors. METHODS: Cross-sectional study (n = 6619) and longitudinal cohort (n = 40 923) comprised individuals from Health 2000 and FINRISK 1992-2012 studies. Prevalent and viral liver diseases were excluded. Longitudinal cohort was linked with national healthcare registers for severe incident liver disease. Linear regression and Cox proportional hazards models were used to analyse anthropometric, lifestyle, metabolic and bioimpedance-related parameters; liver enzymes; and 59 liver-related genetic risk variants. RESULTS: WC and HC showed independent and opposite associations with both liver enzymes and incident liver disease among men (HR for liver disease: WC, 1.07, 95% CI 1.03-1.11; HC, 0.96, 95% CI 0.92-0.99; P-range .04 to <.001) and women (HR for liver diseases: WC, 1.06, 95% CI 1.02-1.10; HC, 0.93, 95% CI 0.89-0.98; P-range .005 to .004). HC modified associations between WC and liver enzymes, and between WC and incident liver disease, particularly among men. Liver enzymes and risk of liver disease increased with increasing WC, more so among individuals with high WHR compared to with low WHR. WC and HC jointly reflected both body fat distribution and muscle mass, which was largely mirrored by WHR. CONCLUSIONS: WC and HC exhibit independent and joint associations with liver disease, which are largely reflected by WHR. Both body fat distribution and muscle mass contribute to these anthropometric measures.

Cow's milk allergy in infancy and later development of type 1 diabetes-nationwide case-cohort study.

BAKGROUND: It is suggested that early intake of cow's milk could be a risk factor for type 1 diabetes (T1DM). Further, the different immunological background, gives a suggestion of an inverse relationship for the occurrence of these diseases. The aim of this study was to explore the association between cow's milk allergy (CMA) and the risk of T1DM in a register-based case-cohort study. METHODS: Data were obtained from Finnish nationwide health registers. The study included all children born in Finland between January 01, 1986 and December 31, 2008 and diagnosed with T1DM before the age of 16 years (n = 7754). A 10% random sample from each birth year cohort was selected as a reference cohort (n = 137,798). T1DM, CMA, and asthma were defined based on valid special reimbursements for the costs of drugs/special formulas needed in the treatment of the diseases. Child's sex, birth decade, asthma, maternal diabetes and asthma, smoking during pregnancy, and previous deliveries were considered as confounding factors. Time-dependent, weighted Cox regression was applied for statistical analyses. RESULTS: Children with CMA had an increased risk of developing T1DM in fully adjusted model (HR = 1.17; 95% CI 1.02-1.34), but the association was no longer observed when including the use of special infant formulas in the definition of CMA in the sensitivity analysis (HR = 1.11; 95% CI 0.92-1.32). CMA was associated with an increased risk of T1DM in children without asthma (HR = 1.27; 95%CI 1.10-1.47), but not in children with asthma (HR = 0.80; 95% CI 0.92-1.27). CONCLUSION: Children with CMA may have an increased risk of T1DM.