Misclassified Alcohol-related Liver Disease is Common in Presumed Metabolic Dysfunction-associated Steatotic Liver Disease and Highly Increases Risk for Future Cirrhosis.

BACKGROUND & AIMS: Alcohol overconsumption is a risk factor for disease progression in patients with presumed metabolic dysfunction-associated steatotic liver disease (MASLD). How commonly this occurs and how it affects progression to major adverse liver outcomes (MALOs) is not well known. METHODS: We did a register-based cohort study, including all patients with a diagnosis of MASLD in Sweden between 1987 and 2020. Patients were stratified on co-occurrence of diagnoses of alcohol-related liver disease (ALD) or alcohol use disorder (AUD) prior to MASLD diagnosis. Incident MALOs were derived from national registers. Cox regression was used to calculate hazard ratios (HRs) for incident MALO. RESULTS: A total of 15,107 patients with MASLD were identified. The median age was 55 years, and 52% were female. Of the patients, 1843 (12%) had a prior diagnosis of ALD or AUD. During follow-up, a further 787 patients (5.2%) received a diagnosis of ALD or AUD. Patients with previous ALD or AUD diagnoses at or before baseline had considerably higher rates of MALOs compared with patients without (19.5% vs 7.8%; adjusted HR, 3.12; 95% confidence interval, 2.74-3.55). Acquiring an ALD or AUD diagnosis after MASLD diagnosis was associated with higher rates of MALOs (adjusted HR, 5.81; 95% confidence interval, 4.90-6.88). CONCLUSIONS: ALD or AUD is commonly diagnosed prior to or after MASLD diagnosis. Such patients have considerably higher rates of progression to MALOs. Correctly separating between MASLD and ALD is vital to assess prognosis.

The association of short and long sleep with mortality in men and women.

Both short (< 6 hr) and long (> 8 hr) sleep are associated with increased mortality. We here investigated whether the association between sleep duration and all-cause, cardiovascular disease and cancer mortality differs between men and women. A cohort of 34,311 participants (mean age and standard deviation = 50.5 ± 15.5 years, 65% women), with detailed assessment of sleep at baseline and up to 20.5 years of follow-up (18 years for cause-specific mortality), was analysed using Cox proportional hazards model to estimate HRs with 95% confidence intervals. After adjustment for covariates, all-cause, cardiovascular disease and cancer mortalities were increased for both < 5 hr and ≥ 9 hr sleep durations (with 6 hr as reference). For all-cause mortality, women who slept < 5 hr had a hazard ratio = 1.54 (95% confidence interval = 1.32-1.80), while the corresponding hazard ratio was 1.05 (95% confidence interval = 0.88-1.27) for men, the interaction being significant (p < 0.05). For cardiovascular disease mortality, exclusion of the first 2 years of exposure, as well as competing risk analysis eliminated the originally significant interaction. Cancer mortality did not show any significant interaction. Survival analysis of the difference between the reference duration (6 hr) and the short duration (< 5 hr) during follow-up showed a gradually steeper reduction of survival time for women than for men for all-cause mortality. We also observed that the lowest cancer mortality appeared for the 5-hr sleep duration. In conclusion, the pattern of association between short sleep duration and all-cause mortality differed between women and men, and the difference between men and women increased with follow-up time.

Disentangling the contributions of alcohol use disorder and alcohol-related liver disease towards dementia: A population-based cohort study.

AIMS: The aim of the study was to disentangle the contributions of alcohol and alcohol-related liver disease (ALD) towards dementia by independently measuring the association between alcohol use disorder (AUD) alone and ALD with dementia. DESIGN: This was a nation-wide cohort study. SETTING: The study was conducted in Sweden from 1987 to 2020. PARTICIPANTS: DELIVER (DEcoding the epidemiology of LIVER disease in Sweden) cohort, containing administrative codes on patients with chronic liver disease from the National Patient Register and other registers between 1987 and 2020. MEASUREMENTS: International Classification of Disease 9th (ICD-9) and 10th (ICD-10) version codes were used to define the presence of AUD, ALD and dementia. The associations of AUD alone and ALD with incident dementia were estimated using Cox regression models adjusting for potential confounders. Cumulative incidences were also calculated accounting for competing risks of death. FINDINGS: A total of 128 884 individuals with AUD alone, 17 754 with ALD and 2 479 049 controls were identified. During a median follow-up of 8.9 years, 13 395 (10.4%), 2187 (12.3%) and 138 925 (5.6%) dementia cases were identified in these groups, respectively. Dementia rates were increased in AUD alone [adjusted hazard ratio (aHR) = 4.6, 95% confidence interval (CI) = 4.5-4.6] and in ALD (aHR = 8.6, 95% CI = 8.3-9.0) compared with controls. AUD alone was also associated with increased rates of vascular dementia (aHR = 2.3, 95% CI = 2.2-2.5) and Alzheimer's disease (aHR = 1.4, 95% CI = 1.3-1.4), while ALD was only associated with vascular dementia (aHR = 2.7, 95% CI = 2.3-3.2). The median age at dementia diagnosis was 67 years [interquartile range (IQR) = 56-76] in AUD alone and 63 years (IQR = 56-71) in ALD compared with 85 years (IQR = 79-89) in controls. CONCLUSION: In Sweden, patients with alcohol use disorder (AUD) appear to have increased rates of dementia and diagnosis at a younger age, compared with patients without AUD. Concurrent alcohol-related liver disease appears to increase the diagnosis rate and lower the median age further.

Post-colonoscopy rectal cancer in Swedish patients with Crohn's disease 2001-2015: a population-based case review study.

OBJECTIVE: Post-colonoscopy colorectal cancer (PCCRC) is a key quality indicator of colonoscopy, and PCCRC rates are high in the IBD population. Rectal cancer, an important risk factor for PCCRC among patients with Crohn's disease (CD), has not previously been examined. METHODS: Swedish adult patients with CD who underwent a colonoscopy within 36 months before a rectal cancer diagnosis between 2001 and 2015 were identified through the National Patient and Cancer registers. Their medical records were reviewed and a root-cause analysis and a sub-categorization according to the World Endoscopic Organization (WEO) were performed. RESULTS: Of 24 patients with CD and PCCRC in the rectum, 79% were men and the median age was 50 (IQR 45-59) years. The median disease duration was 21.5 (IQR 19-30) years. The cancer was located in the distal 5 cm of the rectum in 63% of the cases. Retroversion in the rectum was reported in only one case. The most common plausible explanation for PCCRC was 'possible missed lesion, prior examination adequate' (63%); when adding retroversion in the rectum, instead 77% of examinations were considered negative but deemed as inadequate. The most common PCCRC sub-category was non-interval type C (54%) and B (37%). Among those with type C, 38% should have been included in surveillance according to present guidelines. CONCLUSION: Better adherence to surveillance guidelines and more meticulous follow-up is warranted. The importance of performing rectal palpation and retroversion in the rectum is underscored and we suggest that this is included in the WEO algorithm.

Four-fold increased mortality rate in patients with Wilson's disease: A population-based cohort study of 151 patients.

BACKGROUND AND AIMS: Few studies have investigated mortality rates in patients with Wilson's disease and compared these to the general population. Here, we examined several clinical outcomes (including cardiovascular, psychiatric, neurologic conditions) in a population-based study of patients with Wilson's disease. METHOD: We used nationwide registers to identify all patients with a first diagnosis of Wilson's disease between 2002 and 2020 in Sweden. Each patient was matched by age, sex, and municipality with up to 10 reference individuals from the general population. Validated registers were used to investigate outcomes up to 19 years after baseline in patients and reference individuals. RESULTS: We identified 151 patients with Wilson's disease matched with 1441 reference individuals. Median age at baseline was 26 years (IQR 17-42) and 50% were males. During a median follow-up of 6.6 years (IQR 2.9-12.9), 10 (6.6%) patients with Wilson's disease died compared with 31 (2.2%) reference individuals. This translated to a hazard ratio (HR) of 3.8 (95%CI = 1.8-8.1). Mortality was higher among Wilson's disease patients with baseline neuropsychiatric diagnoses (HR 7.9, 95%CI = 2.9-21.8). Cumulative mortality over 10 years was 9.3% (95%CI = 5.0-16.8) in Wilson's disease, compared to 2.4% (95%CI = 1.6-3.6) in reference individuals. We observed significantly elevated risks in the Wilson's disease group for incident cardiovascular disease, and incident psychiatric and neurological conditions when considering liver transplantation or death from other causes as competing events. CONCLUSION: In this large population-based cohort study, patients with Wilson's disease had an almost four-fold increased mortality rate compared with matched individuals from the general population.

Risk of infections in non-alcoholic fatty liver disease: A nationwide population-based cohort study.

BACKGROUND AND AIMS: Previous literature suggests an association between non-alcoholic fatty liver disease (NAFLD) and infections. We aimed to determine the rate and risk of severe infections in NAFLD compared to the general population. METHODS: In this population-based cohort study, we used national registers to identify all patients with a hospital-based diagnosis of NAFLD in Sweden 1987-2020 (n = 14 869). The patients were matched with ≤10 comparators from the general population for age, sex, municipality, and calendar year (n = 137 145). Cox regression was used to estimate hazard ratios (HR) for infections in patients with NAFLD compared to comparators. Cumulative incidences were calculated while accounting for competing risks (non-infection death and liver transplantation). RESULTS: Severe infections leading to death or hospitalization occurred in 1990 (13.4%) patients with NAFLD and 9899 (7.2%) comparators during a median of 4.5 and 6.1 years of follow-up, respectively. The rate of severe infections per 1000 person-years was higher in patients with NAFLD (21.0) than comparators (9.1) independently of components related to the metabolic syndrome (adjusted HR 1.9, 95% CI = 1.8-2.0). Infection-related mortality was also higher in NAFLD compared to comparators (adjusted HR 1.8, 95% CI = 1.6-2.2). The 10-year cumulative incidence of severe infections was 16.6% (95% CI = 15.8-17.4) in NAFLD and 8.0% (95% CI = 7.8-8.2) in comparators. CONCLUSION: NAFLD was associated with severe infections and infection-related mortality, independently of components associated with the metabolic syndrome. Increased clinical vigilance of severe infections in NAFLD may diminish the risk of premature death.

Increased risk for microvascular outcomes in NAFLD-A nationwide, population-based cohort study.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is considered a multisystem disease, as it is bidirectionally linked to other cardiometabolic disorders, such as type 2 diabetes (T2D). However, the long-term risk for microvascular outcomes in NAFLD is unclear. METHODS: Using the outpatient part of the nationwide Swedish Patient Register in the time period between 01/01/2002 and 12/31/2019, we identified all individuals with a first NAFLD diagnosis (N = 6785) and matched these (age, sex, and municipality) with up to 10 reference individuals from the general population (N = 61,136). Using population-based registers, we ascertained the development of microvascular diseases. The primary outcome was defined as a composite outcome of any diagnosis representative of microvascular disease (chronic kidney disease, retinopathy, or neuropathy). As secondary outcomes, we separately examined the risk of each specific microvascular outcome. Hazard ratios (aHR, adjusted for cirrhosis and time-varying T2D, hypertension, and hyperlipidemia) for the outcomes were calculated by Cox proportional-hazards models. RESULTS: Median follow-up was 5.7 years. The incidence rate of microvascular diseases was >twofold higher in patients with NAFLD (10.8 per 1000 person-years [95% confidence interval (CI) = 9.9-11.8]) versus reference individuals (4.7 per 1000 person-years [95%CI = 4.5-4.9]). NAFLD was independently and positively associated with the development of microvascular diseases compared to non-NAFLD subjects (aHR = 1.45 [95%CI = 1.28-1.63]). When stratifying the analysis by follow-up time, sex, or age categories, results remain virtually unchanged. CONCLUSIONS: NAFLD is positively and independently associated with the development of microvascular diseases. The risk for development of microvascular diseases should be taken into account in the personalized risk assessment of individuals with NAFLD.

Secondary Prevention of Esophageal Variceal Bleeding Is Often Imperfect: A National, Population-Based Cohort Study of 3592 Patients.

BACKGROUND AND AIMS: Secondary prevention of esophageal variceal bleeding is important to improve prognosis, but uptake of guidelines is unknown in a real-world setting. Here, we determined the proportion of patients receiving appropriate nonselective beta-blocker treatment and repeat upper endoscopy after a first episode of esophageal variceal bleeding within a reasonable time frame. METHODS: Population-based registers were used to identify all patients with a first episode of esophageal variceal bleeding in Sweden from 2006 to 2020. Crosslinkage between registers was performed to receive information on the cumulative incidence of patients with a dispensation of nonselective beta-blockers and repeat upper endoscopy within 120 days from baseline. Overall mortality was investigated using Cox regression. RESULTS: In total, 3592 patients were identified, with a median age of 63 (interquartile range, 54-71) years. The cumulative incidence of a dispensation of nonselective beta-blockers and a repeat endoscopy within 120 days was 33%. A total of 77% received either of these treatments. Overall mortality was high, with 65% of patients dying after esophageal variceal bleeding during the full follow-up period (median 1.7 years). We observed an improved overall mortality during the later years of the study period (adjusted hazard ratio for the 2016-2020 period compared with the 2006-2010 period, 0.80; 95% confidence interval, 0.71-0.89). Patients with receipt of nonselective beta-blockers and repeat upper endoscopy had better overall survival compared with those without (adjusted hazard ratio, 0.80; 95% confidence interval, 0.72-0.90). CONCLUSIONS: Secondary prevention of esophageal variceal bleeding has not been widely undertaken, with many patients not receiving guideline-supported interventions within a reasonable time frame. This highlights a need to raise awareness on appropriate prevention strategies to clinicians and patients.

Post-endoscopy colorectal cancer after colectomy in inflammatory bowel disease patients: a population-based register study.

OBJECTIVES: Long-standing inflammatory bowel disease (IBD) colitis is an indication for endoscopic surveillance. Postcolonoscopy colorectal cancer (PCCRC), cancer detected after a negative colonoscopy, is a quality indicator for colonoscopy. In analogy with PCCRC, we aimed to assess postendoscopy CRC (PECRC) in individuals with IBD who had undergone colectomy. METHODS: This register study included Swedish adults with an IBD diagnosis who had undergone colectomy and later were examined by either colonoscopy or sigmoidoscopy during 2001-2012. The final study population had a CRC diagnosis within 36 months of the index examination. Poisson regression was used to assess the relative risks (RR) of PECRC. RESULTS: A total of 33 individuals, 12 with an ileorectal anastomosis and 21 with a rectal remnant, had a CRC diagnosis within 36 months of the index endoscopy. Eleven cancers were detected as CRCs, and 22 (67%) were PECRCs. Compared with individuals aged >70 years, individuals aged <30 years had an RR of 3.1 (P = 0.054) and individuals aged 30-50 years had a RR of 2.6 (P = 0.030). A longer interval between colectomy and index endoscopy (>10 vs. <10 years) was associated with a lower risk of PCCRC (RR = 0.5; P = 0.007). There was no significant difference between the risk for Crohn's disease vs. ulcerative colitis, or between ileorectal anastomosis and rectal remnant risks. CONCLUSIONS: Continuous surveillance of IBD patients after colectomy is important. In the postcolectomy context, PECRC may be used as a quality indicator.

Three-fold Increased Risk of Death in Budd-Chiari Syndrome Compared to Matched Controls: A Population-based Cohort Study.

BACKGROUND & AIMS: Patients with Budd-Chiari syndrome (BCS) have an elevated risk of overall and liver-specific mortality, but this has not been quantified on a population level nor compared against a matched general population cohort. METHODS: We identified all patients in Sweden with a recorded diagnosis of BCS in the Swedish National Patient Register between 1987 and 2016. Patients with BCS were matched for age, sex, and municipality at baseline with up to 10 reference individuals from the general population. Data on cause-specific mortality were obtained from the Causes of Death Register. A Cox regression model was performed to investigate rates of all-cause and cause-specific mortality. RESULTS: A total of 478 patients with BCS were matched with 4603 reference individuals. Of the patients with BCS, 43% were men, the median age was 58 years, 39% had a recorded diagnosis of a precipitating risk factor, and 13% had underlying liver disease. During a follow-up of up to 29 years, 243 (51%) of the patients with BCS died compared with 1346 (29%) of the reference individuals. Overall mortality was 70 per 1000 person-years in patients with BCS compared with 28 per 1000 person-years in reference individuals, translating into an adjusted hazard ratio (aHR) of 3.1 (95% confidence interval [CI], 2.6-3.6). Although liver-related mortality was particularly high (aHR, 47.6; 95% CI, 16.5-137.4), liver disease accounted for only 10% of deaths in BCS. The most common cause of death was cardiovascular disease (aHR, 2.2; 95% CI, 1.7-2.9). CONCLUSIONS: Patients with BCS in Sweden had a 3-fold higher risk of death compared with general population reference individuals. Although mortality from liver diseases was high in relative terms, most patients died from cardiovascular causes.

Nonalcoholic Fatty Liver Disease and Risk of Dementia: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) and dementia share common risk factors including metabolic disorders. However, whether NAFLD is associated with dementia risk is unclear. We investigated the association between NAFLD and dementia risk as well as the role of cardiovascular complications including heart disease and stroke. METHODS: In this population-based matched cohort study, we identified all Swedish patients aged 65 years or older with NAFLD identified from the National Patient Register (NPR) between 1987 and 2016. These were matched with up to 10 reference individuals from the general population on age, sex, and municipality at the year of diagnosis. Incident dementia diagnosis was derived from the NPR or the Cause of Death Register until 2016. Adjusted hazard ratios (aHRs) and 95% CIs were estimated with Cox regression models. RESULTS: A total of 2,898 patients with NAFLD and 28,357 matched controls were identified (median age at entry, interquartile range [IQR], 70 [8]; 55.1% female). During a median follow-up of 5.5 years (IQR: 8.5 years), 145 (5.0%) patients with NAFLD and 1,291 (4.6%) reference individuals were diagnosed with dementia. Compared with the reference individuals, patients with NAFLD had higher rates of dementia (aHR 1.38, 95% CI 1.10-1.72) and vascular dementia (aHR 1.44, 95% CI 0.96-2.23, p = 0.07). Comorbid NAFLD and either heart disease (aHR 1.50 95% 1.08-2.05) or stroke (aHR 2.60 95% CI 1.95-3.47) conferred a greater risk of dementia. DISCUSSION: NAFLD had a modest association with increased rates of dementia. This was stronger among patients with NAFLD diagnosed with cardiovascular comorbidities. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that nonalcoholic fatty liver disease is associated with the development of vascular and nonvascular dementia.

The risk of hepatocellular carcinoma in cirrhosis differs by etiology, age and sex: A Swedish nationwide population-based cohort study.

BACKGROUND: Current risk estimates for hepatocellular carcinoma (HCC) in individuals with cirrhosis vary between studies. The risk has mostly been evaluated for single etiologies separately. OBJECTIVES: We examined the risk of HCC in Swedish outpatients with a new diagnosis of cirrhosis, aiming to identify subgroups with a particularly high risk for incident HCC. METHODS: All patients with a first diagnosis of cirrhosis in the National Outpatient Register for whom the etiology of cirrhosis could be estimated were identified. Incident cases of HCC were ascertained until the end of 2016 using record linkage to national registers. The cumulative incidence of HCC across etiologies of cirrhosis, sex and age was calculated considering non-HCC death as a competing risk. RESULTS: We identified 15,215 individuals with cirrhosis. The incidence rate for HCC in cirrhosis was 23/1000 person-years (95%CI = 22-24). Stratified on gender, it was 29/1000 person-years (95%CI = 27-31) in men versus 14/1000 person-years (95%CI = 13-16) in women. The cumulative incidence of HCC in cirrhosis was 8.3% (95%CI = 7.8-8.8) at 5 years and 12.2% (95%CI = 11.6-13.0) at 10 years. At 10 years, the lowest cumulative incidence was seen in women with alcohol-related liver disease (4.3%) and the highest in men with viral hepatitis (26.6%). These figures also varied by age. CONCLUSIONS: The risk of HCC differs extensively across subgroups of etiologies of cirrhosis, age and sex, suggesting that initiation of HCC surveillance could be individually tailored.

Risk of cardiovascular disease and loss in life expectancy in NAFLD.

BACKGROUND AND AIMS: Conflicting evidence exists on cardiovascular disease (CVD) risk in patients with NAFLD, and data are lacking on whether NAFLD increases mortality after a CVD event. Moreover, life expectancy in NAFLD has not been studied. We therefore examined CVD risk and life expectancy in patients with NAFLD compared with the general population. APPROACH AND RESULTS: In this nationwide population-based cohort, all patients with NAFLD diagnosis and without baseline CVD (ascertaining from the Swedish National Patient Register from 1987 to 2016, n = 10,023) were matched 10:1 on age, sex, and municipality to individuals from the general population (controls, n = 96,313). CVD diagnosis and mortality were derived from national registers. Multistate models and flexible parametric survival models were used to estimate adjusted hazard ratios (aHRs) for CVD risk and loss in life expectancy due to NAFLD. We identified 1037 (10.3%) CVD events in patients with NAFLD and 4041 (4.2%) in controls. CVD risk was 2.6-fold higher in NAFLD compared with controls (aHR = 2.61, 95% CI = 2.36-2.88) and was strongest for nonfatal CVD (aHR = 3.71, 95% CI = 3.29-4.17). After a nonfatal CVD event, the risk for all-cause mortality was similar between patients with NAFLD and controls (aHR = 0.89, 95% CI = 0.64-1.25). Life expectancy in patients with NAFLD was, on average, 2.8 years lower than controls, with the highest loss of life-years when NAFLD was diagnosed in middle age (40-60 years). CONCLUSIONS: NAFLD was associated with a higher risk of nonfatal CVD but did not affect post-CVD mortality risk. Patients diagnosed with NAFLD have a lower life expectancy than the general population.

Cohort profile: decoding the epidemiology of liver disease in Sweden (DELIVER).

BACKGROUND AND AIMS: Swedish nationwide registries can be used to identify patients with a wide range of diagnoses. This information can be used to construct cohorts useful to determine prognosis and identify risk factors for disease progression. Here, we describe a new register-based cohort of patients with a diverse set of chronic liver disease diagnoses in Sweden. METHODS: The DELIVER (DEcoding the epidemiology of LIVER disease in sweden) was constructed using extensive data linkages between different Swedish registers, diagnosed between 1964 and 2016. Patients in DELIVER are matched 1:10 to reference individuals from the general population on age, sex, municipality and calendar year of first liver disease diagnosis. Longitudinal cross-linked data from several registers allow for identification of outcomes occurring before or after liver disease diagnosis. Further, since July 2005 all dispensed drugs can be identified. RESULTS: In total, 307 768 unique individuals with a diagnosis of a chronic liver disease since 1964 were identified, and these were matched with 3 067 714 reference individuals from the general population. As examples, DELIVER contains data on 90 948 patients with a diagnosis of viral hepatitis; 50 593 patients with alcohol-related liver disease and 13 242 patients with non-alcoholic fatty liver disease. CONCLUSIONS: The DELIVER cohort can be used to examine several important research questions. Long-term outcomes of chronic liver diseases, risk factors for disease progression, impact of dispensed drugs, disease panorama and time trends are examples. Here we describe the construction and data availability of DELIVER.

Plasmodium falciparum-Specific Memory B-Cell and Antibody Responses Are Associated With Immunity in Children Living in an Endemic Area of Kenya.

Identifying the mechanism of naturally acquired immunity against Plasmodium falciparum malaria could contribute to the design of effective malaria vaccines. Using a recently developed multiplexed FluoroSpot assay, we assessed cross-sectional pre-existing memory B-cells (MBCs) and antibody responses against six well known P. falciparum antigens (MSP-119, MSP-2 (3D7), MSP-2 (FC27), MSP-3, AMA-1 and CSP) and measured their associations with previous infections and time to clinical malaria in the ensuing malaria season in Kenyan children. These children were under active weekly surveillance for malaria as part of a long-term longitudinal malaria immunology cohort study, where they are recruited from birth. After performing Cox regression analysis, we found that children with a breadth of three or more antigen-specific MBC or antibody responses at the baseline had a reduced risk for malaria in the ensuing P. falciparum transmission season. Specifically, MBC responses against AMA-1, MSP-2 (3D7) and MSP-3, as well as antibody responses to MSP-2 (3D7) and MSP-3 were prospectively associated with a reduced risk for malaria. The magnitude or breadth of MBC responses were however not correlated with the cumulative number of malaria episodes since birth. We conclude that increased breadth for merozoite antigen-specific MBC and antibody responses is associated with protection against malaria.

Risk of hepatic and extrahepatic cancer in NAFLD: A population-based cohort study.

BACKGROUND AND AIMS: Individuals with non-alcoholic fatty liver disease (NAFLD) may be at greater risk of cancer. This study aimed to investigate the risk of hepatic and extrahepatic cancer compared to the general population in a population-based cohort of patients with NAFLD. METHODS: We used the Swedish National Patient Registry from 1987 to 2016 to identify patients with a NAFLD diagnosis and no prior cancer. All patients with NAFLD were compared to up to 10 controls matched for age, sex and living location. The primary outcome was the first occurrence of any cancer as ascertained from national registries. As secondary outcomes, we analysed the risk of pre-specified cancer subtypes. Cox regression models, adjusted for baseline diabetes, hypertension, hyperlipidaemia and chronic obstructive pulmonary disease were applied. RESULTS: We identified 8415 patients with NAFLD. Over a median follow-up of 6.0 years (IQR 2.5-11.2 years), an increased risk for any cancer was found in patients with NAFLD compared to controls (9.7 vs. 8.6 cases per 1000 person-years): hazard ratio (HR) = 1.22 (95% confidence interval, CI = 1.12-1.33). The risk for hepatocellular carcinoma (HCC) was particularly high (adjusted HR, aHR = 12.18, 95% CI = 7.15-20.79). The risk for some other cancer subtypes increased (colorectal [aHR 1.38], kidney [aHR 2.12], bladder [aHR 2.51] and uterine [aHR 1.78]), but was low in absolute terms. CONCLUSION: In this population-based cohort, NAFLD was associated with an increased risk of developing cancer (especially HCC). The absolute risk for other forms of cancer was generally comparable to the control population.

Sleep duration and mortality, influence of age, retirement, and occupational group.

Previous work has shown that both long and short sleep duration is associated with increased mortality, with lowest risk around 7 hr. This has had widespread impact on views on the optimal sleep duration. However, age, being employed/retired, and blue-/white-collar status, may influence the time available for sleep and thus, confound the association. We investigated the role of these factors on the association between sleep duration and mortality. We used employed and retired participants (N = 25,430) from the Swedish National March Cohort and Cox proportional hazards regression to model the shape of the association. We found a significant U-shaped association in a multivariable model with a hazard ratio (HR) of 1.24 (95% confidence interval [CI] 1.10, 1.39) for <5-hr sleep duration, and a HR of 1.30 (95% CI 1.12, 1.51) for ≥9-hr sleep duration, with the lowest HR for 7 hr, but with a span of low HRs from 5 to 8 hr. Unadjusted values showed a pronounced U-shape. Adjusting for age accounted for most of the attenuation in the multivariable model. Stratification into five age groups showed a significant U-shape only in those aged >60.3 years at baseline. The shape of the association did not differ between blue-/white-collar workers, nor between employed and retired groups. We conclude that the U-shaped association between sleep duration and mortality is present only in older individuals.

Replication of Oncology Randomized Trial Results using Swedish Registry Real World-Data: A Feasibility Study.

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology.

Non-alcoholic fatty liver disease does not increase dementia risk although histology data might improve risk prediction.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is common in the general population, but its association with dementia is unclear. We aimed to assess the risk of dementia related to NAFLD, and to determine whether histological parameters could improve the predictive capacity of a conventional risk model for dementia in patients with biopsy-proven NAFLD. METHODS: A retrospective matched cohort study of 656 NAFLD patients underwent liver biopsy at 2 hospitals between 1971 and 2009. Up to 10 individuals (controls) from the general population (n = 6,436) were matched for age, sex, and municipality to each patient. Dementia was ascertained from National registers until 2014. Using Cox regression, we estimated hazard ratios for dementia with 95% confidence intervals. In the biopsy cohort, the discriminative power of adding histological markers to a conventional risk model was assessed by Harrell's C-index and compared with a likelihood-ratio test. RESULTS: During a mean follow-up of 19.7 ± 8.7 years, 3.3% of the NAFLD patients and 4.9% of the controls developed dementia (p = 0.07). Overall, NAFLD was not significantly associated with incident dementia. In the biopsy cohort, the model of conventional risk factors (age, sex, hypertension, and cardiovascular diseases) had a C-index of 0.912 to predict incident dementia. Adding individual histological parameters significantly increased the prediction of dementia, with the most pronounced improvement for fibrosis stage (C-index = 0.938, p <0.05). CONCLUSIONS: Although NAFLD was not associated with the risk of dementia, we found that adding histological markers to a conventional risk model for dementia enhanced the predictive capacity, indicating a shared metabolic origin. LAY SUMMARY: Both non-alcoholic fatty liver disease (NAFLD) and dementia are increasing in prevalence because of a more sedentary lifestyle, increased prevalence of obesity and population ageing. However, the link between these 2 diseases is not well studied. We investigated the association between NAFLD and the risk of dementia and found no association. However, liver histology parameters, especially fibrosis, could significantly improve the prediction of dementia risk.