Publications by authors named "Tracey G Simon"

76 Publications

Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort.

Gut 2021 Sep 6. Epub 2021 Sep 6.

Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Objective: Some data suggest a positive association between non-alcoholic fatty liver disease (NAFLD) and incident major adverse cardiovascular events (MACEs). However, data are lacking from large cohorts with liver histology, which remains the gold standard for staging NAFLD severity.

Design: This population-based cohort included all Swedish adults with histologically confirmed NAFLD and without cardiovascular disease (CVD) at baseline (1966-2016, n=10 422). NAFLD was defined from prospectively recorded histopathology and categorised as simple steatosis, non-fibrotic steatohepatitis, non-cirrhotic fibrosis and cirrhosis. Patients with NAFLD were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year and county (n=46 517). Using Cox proportional hazards modelling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs for MACE outcomes (ie, ischaemic heart disease (IHD), stroke, congestive heart failure (CHF) or cardiovascular (CV) mortality).

Results: Over a median of 13.6 years, incident MACE was confirmed in 2850 patients with NAFLD and 10 648 controls. Patients with NAFLD had higher incidence of MACE than controls (24.3 vs 16.0/1000 person-years (PY); difference=8.3/1000 PY; aHR 1.63, 95% CI 1.56 to 1.70), including higher rates of IHD (difference=4.2/1000 PY; aHR 1.64, 95% CI 1.54 to 1.75), CHF (difference=3.3/1000 PY; aHR 1.75, 95% CI 1.63 to 1.87), stroke (difference=2.4/1000 PY; aHR 1.58, 95% CI 1.46 to 1.71) and CV mortality (difference=1.2/1000 PY; aHR 1.37, 95% CI 1.27 to 1.48). Rates of incident MACE increased progressively with worsening NAFLD severity (p=0.02), with the highest incidence observed with cirrhosis (difference vs controls=27.2/1000 PY; aHR 2.15, 95% CI 1.77 to 2.61).

Conclusion: Compared with matched population controls, patients with biopsy-proven NAFLD had significantly higher incidence of MACE, including IHD, stroke, CHF and CV mortality. Excess risk was evident across all stages of NAFLD and increased with worsening disease severity.
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http://dx.doi.org/10.1136/gutjnl-2021-325724DOI Listing
September 2021

Maternal obesity increases the risk and severity of NAFLD in offspring.

J Hepatol 2021 Jul 18. Epub 2021 Jul 18.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Background & Aims: Maternal obesity has been linked to the development of cardiovascular disease and diabetes in offspring, but its relationship to non-alcoholic fatty liver disease (NAFLD) is unclear.

Methods: Through the nationwide ESPRESSO cohort study we identified all individuals ≤25 years of age in Sweden with biopsy-verified NAFLD diagnosed between 1992 and 2016 (n = 165). These were matched by age, sex, and calendar year with up to 5 controls (n = 717). Through linkage with the nationwide Swedish Medical Birth Register (MBR) we retrieved data on maternal early-pregnancy BMI, and possible confounders, in order to calculate adjusted odds ratios (aORs) for NAFLD in offspring.

Results: Maternal BMI was associated with NAFLD in offspring: underweight (aOR 0.84; 95% CI 0.14-5.15), normal weight (reference, aOR 1), overweight (aOR 1.51; 0.95-2.40), and obese (aOR 3.26; 1.72-6.19) women. Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was also more common in offspring of overweight (aOR 1.94; 95% CI 0.96-3.90) and obese (aOR 3.67; 95% CI 1.61-8.38) mothers. Associations were similar after adjusting for maternal pre-eclampsia and gestational diabetes. Socio-economic parameters (smoking, mother born outside the Nordic countries and less than 10 years of basic education) were also associated with NAFLD in offspring but did not materially alter the effect size of maternal BMI in a multivariable model.

Conclusions: This nationwide study found a strong association between maternal overweight/obesity and future NAFLD in offspring. Adjusting for socio-economic and metabolic parameters in the mother did not affect this finding, suggesting that maternal obesity is an independent risk factor for NAFLD in offspring.

Lay Summary: In a study of all young persons in Sweden with a liver biopsy consistent with fatty liver, the authors found that compared to matched controls, the risk of fatty liver was much higher in those with obese mothers. This was independent of available confounders and suggests that the high prevalence of obesity in younger persons might lead to a higher risk of fatty liver in their offspring.
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http://dx.doi.org/10.1016/j.jhep.2021.06.045DOI Listing
July 2021

Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma.

Cancer Prev Res (Phila) 2021 Jul 15. Epub 2021 Jul 15.

Harvard Medical School, Boston, Massachusetts.

Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980-2012) and 48,026 men (1986-2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02-1.09 ( = 0.019), and 1.08; 95% CI = 1.06-1.10 ( = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01-1.08; = 0.010), including after further adjusting for young-adult BMI ( = 0.010) and later-adult BMI ( = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5-<10 kg, 10-<20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67-2.16), 2.09 (95% CI = 1.11-3.95), and 2.61 (95% CI = 1.42-5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk. PREVENTION RELEVANCE: Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0549DOI Listing
July 2021

Glucose-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes.

Clin Gastroenterol Hepatol 2021 Jul 10. Epub 2021 Jul 10.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background & Aims: The study sought to compare the effectiveness of glucose-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors in reducing decompensation events, among patients with cirrhosis and type 2 diabetes.

Methods: This population-based, retrospective cohort study included patients with type 2 diabetes and cirrhosis, in a commercial healthcare database (IBM MarketScan). We constructed 3 pairwise, 1:1 propensity score (PS)-matched cohorts of adults initiating GLP-1RAs or a comparator medication (ie, DPP-4 inhibitors [2006-2020], sulfonylurea [2005-2020], or SGLT-2 inhibitors [2013-2020]). Patients were followed in an as-treated approach for decompensation events (ie, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, or esophageal variceal hemorrhage). Within each PS-matched cohort, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >90 baseline characteristics.

Results: Over 132 days of median follow-up (interquartile range, 73-290 days), PS-matched rates of any decompensation were significantly lower among GLP-1RA initiators, versus DPP-4 inhibitor initiators (105.2 vs 144.0 per 1000 person-years [PY]; HR, 0.68; 95% CI, 0.53-0.88; n = 1431 pairs), and versus sulfonylureas (97.3 vs 144.0 per 1000 PY; HR, 0.64; 95% CI, 0.48-0.84; n = 1246 pairs). Similar, inverse associations were found for individual decompensation events, including ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome (HR, 0.66; 95% CI, 0.45-0.97; and HR, 0.66; 95% CI, 0.46-0.94, respectively); esophageal variceal hemorrhage (HR, 0.62 [95% CI, 0.41-0.92; and HR, 0.59; 95% CI, 0.37-0.92, respectively); and hepatic encephalopathy (HR, 0.76; 95% CI, 0.55-1.06; and HR, 0.60; 95% CI, 0.39-0.92, respectively). Results persisted in subgroups of patients with and without previously decompensated cirrhosis. In contrast, decompensation rates were similar when GLP-1RAs and SGLT-2 inhibitors were directly compared (103.5 vs 112.8 per 1000 PY; HR, 0.89; 95% CI, 0.62-1.28).

Conclusions: Among cirrhotic patients with type 2 diabetes, we find high rates of decompensation, consistent with previous reports; these rates were substantially lower among GLP-1RA initiators compared with DPP-4 inhibitors or sulfonylureas.
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http://dx.doi.org/10.1016/j.cgh.2021.07.010DOI Listing
July 2021

Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality.

J Hepatol 2021 Jul 3. Epub 2021 Jul 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Background & Aims: Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD).

Methods: This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966-2017; n = 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n = 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs.

Results: Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference = 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77-9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference = 6.6%; 95% CI 4.0-9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92-7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18-43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05-9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77-27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97-48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75-98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73-10.79).

Conclusions: Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls.

Lay Summary: Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality.
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http://dx.doi.org/10.1016/j.jhep.2021.06.034DOI Listing
July 2021

Cancer Risk in Patients with Autoimmune Hepatitis: A Nationwide Population-Based Cohort Study with Histopathology.

Am J Epidemiol 2021 Apr 29. Epub 2021 Apr 29.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.

We aimed to determine the risk of incident cancer in autoimmune hepatitis (AIH) compared to the general population and siblings. AIH was defined by the presence of a medical diagnosis of AIH and a liver biopsy in a nationwide Swedish population-based cohort study. We identified 5,268 adults with AIH diagnosed 1969-2016 and 22,996 matched general population reference individuals and 4,170 sibling comparators. Using Cox regression, hazard ratios (HRs) were determined for any incident cancer and sub-types determined from the Swedish Cancer Register. During follow-up, a cancer diagnosis was made in 1,119 individuals with AIH (17.2/1000 person-years) and 4,450 reference individuals (12.0/1000 person-years). This corresponded to an HR of 1.53 (95%CI: 1.42,1.66). Cancer risk was highest in those with cirrhosis. There was a 29.18-fold increased risk of hepatocellular carcinoma (HCC) (95%CI, 17.52,48.61). The annual incidence risk of HCC in individuals with AIH who had cirrhosis was 1.1% per year. AIH was also linked to non-melanoma skin cancer (HR=2.69) and lymphoma (HR=1.89). Sibling analyses yielded similar risk estimates for any cancer (HR=1.84) and HCC (HR=23.10). AIH is associated with an increased risk of any cancer, in particular, HCC and extra-hepatic malignancies. The highest risk for cancer, especially HCC, is in patients with cirrhosis.
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http://dx.doi.org/10.1093/aje/kwab119DOI Listing
April 2021

Body weight variability and the risk of cardiovascular outcomes in patients with nonalcoholic fatty liver disease.

Sci Rep 2021 04 28;11(1):9154. Epub 2021 Apr 28.

Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Republic of Korea.

We investigated the association between body weight variability and the risks of cardiovascular disease and mortality in patients with nonalcoholic fatty liver disease (NAFLD) using large-scale, nationwide cohort data. We included 726,736 individuals with NAFLD who underwent a health examination between 2009 and 2010. NAFLD was defined as a fatty liver index ≥ 60, after excluding significant alcohol intake, viral hepatitis, and liver cirrhosis. Body weight variability was assessed using four indices, including variability independent of the mean (VIM). During a median 8.1-year follow-up, we documented 11,358, 14,714, and 22,164 cases of myocardial infarction (MI), stroke, and all-cause mortality, respectively. Body weight variability was associated with an increased risk of MI, stroke, and mortality after adjusting for confounding variables. The hazard ratios (HRs) (95% confidence intervals) for the highest quartile, compared with the lowest quartile, of VIM for body weight were 1.15 (1.10-1.20), 1.22 (1.18-1.26), and 1.56 (1.53-1.62) for MI, stroke, and all-cause mortality, respectively. Body weight variability was associated with increased risks of MI, stroke, and all-cause mortality in NAFLD patients. Appropriate interventions to maintain a stable weight could positively affect health outcomes in NAFLD patients.
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http://dx.doi.org/10.1038/s41598-021-88733-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080815PMC
April 2021

Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis.

Metabolism 2021 Jul 21;120:154780. Epub 2021 Apr 21.

Harvard Medical School, Boston, MA, United States of America; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, United States of America; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States of America. Electronic address:

Background & Aims: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk.

Methods: We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI).

Results: Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I = 72%).

Conclusions: Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.
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http://dx.doi.org/10.1016/j.metabol.2021.154780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217281PMC
July 2021

Cancer Risk in Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study.

Hepatology 2021 Apr 3. Epub 2021 Apr 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background And Aims: Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity.

Approach And Results: We conducted a population-based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person-years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18-1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56-25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; P  < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers.

Conclusions: Compared with controls, patients with biopsy-proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.
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http://dx.doi.org/10.1002/hep.31845DOI Listing
April 2021

Inflammatory bowel disease and risk of severe COVID-19: A nationwide population-based cohort study in Sweden.

United European Gastroenterol J 2021 03 11;9(2):177-192. Epub 2021 Mar 11.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Background: There are concerns that individuals with chronic immune-mediated diseases are at increased risk of COVID-19 and related severe adverse outcome, including intensive care admission or death. We aimed to explore the absolute and relative risk of severe COVID-19 in inflammatory bowel disease (IBD).

Methods: This population-based cohort study used nationwide registers in Sweden, with 67,292 individuals with a diagnosis of IBD 1969-2017 (Crohn's disease, n = 21,599; ulcerative colitis: n = 43,622; IBD-unclassified: n = 2071) and alive on 1 February 2020. Patients with IBD were matched to up to five controls from the general population (n = 297,910). Cox regression estimated hazard ratios (HRs) for (i) hospital admission with laboratory-confirmed COVID-19 as the primary diagnosis, and (ii) severe COVID-19 (composite outcome consisting of (a) COVID-19 intensive care admission, or (b) death from COVID-19 or (c) death within 30 days of COVID-19 hospital admission), were calculated. Analyses were conditioned on age, sex, calendar period, and county and adjusted for other comorbidities.

Results: Between 1 February and 31 July 2020, 179 (0.27%) IBD patients and 500 (0.17%) general population controls were admitted to hospital with COVID-19 (adjusted HR [aHR] = 1.43; 95% CI = 1.19-1.72). The corresponding numbers for severe COVID-19 was 65 (0.10%) and 183 (0.06%; aHR = 1.11; 95% CI = 0.81-1.52). Adjusted HRs were similar in Crohn's disease and ulcerative colitis. In a propensity score-matched model taking comorbidity into account until 2016, the increased risk for COVID-19 hospital admission remained (aHR = 1.32; 1.12-1.56), but there was no increased risk of severe COVID-19 (aHR = 1.12; 0.85-1.47).

Conclusions: While individuals with IBD were more likely to be admitted to hospital for COVID-19 than the general population, the risk of severe COVID-19 was not higher.
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http://dx.doi.org/10.1002/ueg2.12049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014882PMC
March 2021

Association Between Collagenous and Lymphocytic Colitis and Risk of Severe Coronavirus Disease 2019.

Gastroenterology 2021 06 19;160(7):2585-2587.e3. Epub 2021 Feb 19.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.02.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892313PMC
June 2021

Association Between Liver Fat and Bone Density is Confounded by General and Visceral Adiposity in a Community-Based Cohort.

Obesity (Silver Spring) 2021 03 2;29(3):595-600. Epub 2021 Feb 2.

Section of Gastroenterology, Boston Medical Center, School of Medicine, Boston University, Boston, Massachusetts, USA.

Objective: Nonalcoholic fatty liver disease (NAFLD) is associated with low bone mineral density (BMD); however, it is not known whether early-stage NAFLD may be associated with BMD after accounting for BMI or visceral adipose tissue (VAT).

Methods: This was a cross-sectional study of 3,462 Framingham Heart Study participants who underwent computed tomographic measurement of liver fat, VAT volume, volumetric spine BMD, vertebral cross-sectional area (CSA), and vertebral compressive strength. This study excluded heavy alcohol consumers. Multivariable linear regression models were used to assess the association between NAFLD and volumetric BMD, CSA, and vertebral compressive strength after accounting for covariates, including BMI or VAT.

Results: A total of 2,253 participants (mean age, 51.2  [SD 10.7] years; 51.1% women) were included. In multivariable-adjusted models, positive associations between NAFLD and integral BMD, trabecular BMD, and vertebral compressive strength were observed. However, results were attenuated and no longer significant after additionally adjusting for BMI or VAT. NAFLD was observed to be weakly associated with a lower vertebral CSA in adjusted models.

Conclusions: In a community-based cohort, the associations between NAFLD and BMD and vertebral strength were confounded by BMI and VAT. However, NAFLD was associated with a reduced vertebral CSA in adjusted models.
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http://dx.doi.org/10.1002/oby.23100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904629PMC
March 2021

Association of Inflammatory and Insulinemic Potential of Diet and Lifestyle with Risk of Hepatocellular Carcinoma.

Cancer Epidemiol Biomarkers Prev 2021 04 29;30(4):789-796. Epub 2021 Jan 29.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: We prospectively examined the extent to which greater inflammatory and insulinemic potential of diet and lifestyle are associated with the risk of developing hepatocellular carcinoma (HCC) in two nationwide cohorts.

Methods: Five kinds of pattern scores, including the empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH) and insulin resistance (EDIR), empirical lifestyle pattern score for hyperinsulinemia (ELIH) and insulin resistance (ELIR) were calculated. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression.

Results: After an average follow-up of 25.6 years among 119,316 participants, 142 incident HCC cases were documented. Higher adherence to EDIP (HR by comparing extreme tertiles: 2.03; 95% CI, 1.31-3.16; = 0.001), EDIH (HR, 1.61; 95% CI, 1.06-2.43; = 0.02), and EDIR (HR, 1.62; 95% CI: 1.08-2.42; = 0.02) was associated with increased risk of HCC. Likewise, participants with higher scores of ELIH (HR, 1.89; 95% CI, 1.25-2.87; = 0.001) and ELIR (HR, 2.05; 95% CI, 1.34-3.14, = 0.0004) had higher risk of developing HCC. Additional adjustment for diabetes mellitus and/or body mass index attenuated the magnitude of the associations, indicating that diabetes and/or adiposity may partly mediate the association of these patterns with HCC risk.

Conclusions: Our findings suggest that inflammation and insulin resistance/hyperinsulinemia are potential mechanisms linking dietary or lifestyle factors and HCC development.

Impact: Inflammation and insulin resistance/hyperinsulinemia may partly mediate the association of diet and other lifestyles with HCC development, and interventions to reduce the adverse effect of pro-inflammatory and hyperinsulinemic diet and lifestyle may reduce HCC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026660PMC
April 2021

Administrative Coding in Electronic Health Care Record-Based Research of NAFLD: An Expert Panel Consensus Statement.

Hepatology 2021 Jul 22;74(1):474-482. Epub 2021 Jun 22.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland.

Background And Aims: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach And Results: Researchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions: This expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.
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http://dx.doi.org/10.1002/hep.31726DOI Listing
July 2021

Aspirin Use Is Associated with a Reduced Incidence of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatol Commun 2021 01 13;5(1):133-143. Epub 2020 Nov 13.

Harvard Medical School Boston MA USA.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death worldwide, with a growing incidence and poor prognosis. While some recent studies suggest an inverse association between aspirin use and reduced HCC incidence, other data are conflicting. To date, the precise magnitude of risk reduction-and whether there are dose-dependent and duration-dependent associations-remains unclear. To provide an updated and comprehensive assessment of the association between aspirin use and incident HCC risk, we conducted a systematic review and meta-analysis of all observational studies published through September 2020. Using random-effects meta-analysis, we calculated the pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between aspirin use and incident HCC risk. Where data were available, we evaluated HCC risk according to the defined daily dose of aspirin use. Among 2,389,019 participants, and 20,479 cases of incident HCC, aspirin use was associated with significantly lower HCC risk (adjusted RR, 0.61; 95% CI, 0.51-0.73; ≤ 0.001; I = 90.4%). In subgroup analyses, the magnitude of benefit associated with aspirin was significantly stronger in studies that adjusted for concurrent statin and/or metformin use (RR, 0.45; 95% CI, 0.28-0.64) versus those that did not (  = 0.02), studies that accounted for cirrhosis (RR, 0.49; 95% CI, 0.45-0.52) versus those that did not (  = 0.02), and studies that confirmed HCC through imaging/biopsy (RR, 0.30; 95% CI, 0.15-0.58) compared with billing codes (  < 0.001). In four studies, each defined daily dose was associated with significantly lower HCC risk (RR, 0.98; 95% CI, 0.97-0.98), corresponding to an 8.4% risk reduction per year of aspirin use. In this comprehensive systematic review and meta-analysis, aspirin use was associated with a significant reduction in HCC risk. These benefits appeared to increase with increasing dose and duration of aspirin use.
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http://dx.doi.org/10.1002/hep4.1640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789838PMC
January 2021

Risk of Cancer in Biopsy-Proven Alcohol-Related Liver Disease: A Population-Based Cohort Study of 3410 Persons.

Clin Gastroenterol Hepatol 2021 Jan 7. Epub 2021 Jan 7.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.

Background & Aims: Persons with alcohol-related liver disease (ALD) are at an increased risk of death and liver-related endpoints, but the association with incident cancer is not well understood, and whether it differs across histopathological subgroups is undefined.

Methods: We investigated the risk of cancer in 3,410 persons with a diagnosis of ALD and an available liver biopsy in Sweden between 1969-2016, compared to a matched reference population. Administrative coding from national registers and liver biopsy data were used to define exposure and outcome status. Competing risk regression, adjusted for available confounders and using non-cancer mortality as the competing risk, was used to estimate subdistribution hazard ratios (sHRs) for incident cancer.

Results: At baseline, persons with ALD had a median age of 58.2 years, 67% were men, and 2,042 (60%) had cirrhosis. ALD was not associated with cancer in general (sHR = 1.01, 95%CI = 0.92-1.11), although the risk was increased in persons surviving ≥1 year (sHR = 1.19, 95% CI = 1.08-1.32). The risk of liver cancer was elevated sHR = 12.80, 95%CI = 9.38-17.45). HCC incidence among ALD persons with cirrhosis was 8.6 cases/1,000 person-years, corresponding to a cumulative incidence after 10 years of 5.0%.

Conclusions: Persons with biopsy-proven ALD that survive the initial time after diagnosis are at an elevated risk for cancer, in particular HCC compared with the general population. Although the risk for HCC was elevated, data do not suggest that routine surveillance for HCC in ALD cirrhosis is cost-effective.
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http://dx.doi.org/10.1016/j.cgh.2021.01.005DOI Listing
January 2021

Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.

Gastroenterology 2021 04 11;160(5):1620-1633.e13. Epub 2020 Dec 11.

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.

Methods: We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.

Results: Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P < .001).

Conclusions: Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.
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http://dx.doi.org/10.1053/j.gastro.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035329PMC
April 2021

Microbiome Biomarkers: One Step Closer in NAFLD Cirrhosis.

Hepatology 2021 May 19;73(5):2063-2066. Epub 2021 Apr 19.

Broad Institute, Boston, MA.

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http://dx.doi.org/10.1002/hep.31660DOI Listing
May 2021

Weight gain during early adulthood, trajectory of body shape and the risk of nonalcoholic fatty liver disease: A prospective cohort study among women.

Metabolism 2020 12 12;113:154398. Epub 2020 Oct 12.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America; Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America. Electronic address:

Background & Aims: Obesity is established as a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk remains poorly understood.

Methods: We collected data from 110,054 women enrolled in the Nurses' Health Study II cohort. Early adulthood weight was ascertained at age 18 years, and weight gain since early adulthood was defined prospectively every 2 years. We used a group-based modeling approach to identify five trajectories of body shape from age 5 years up to age 50 years. NAFLD was defined by physician-confirmed diagnoses of fatty liver, after excluding excess alcohol intake and viral hepatitis, using validated approaches.

Results: We documented 3798 NAFLD cases over a total of 20 years of follow-up. Compared to women who maintained stable weight (±2 kg), women with ≥20 kg of adulthood weight gain had the multivariable aHR of 6.96 (95% CI, 5.27-9.18), and this remained significant after further adjusting for early adulthood BMI and updated BMI (both P trend <0.0001). Compared to women with a medium-stable body shape trajectory, the multivariable aHRs for NAFLD were, 2.84 (95% CI, 2.50-3.22) for lean-marked increase, 2.60 (95% CI, 2.27-2.98) for medium-moderate increase, and 3.39 (95% CI, 2.95-3.89) for medium-marked increase.

Conclusions: Both early adulthood weight gain and lifetime body shape trajectory were significantly and independently associated with excess risk of developing NAFLD in mid-life. Maintaining both lean and stable weight throughout life may offer the greatest benefit for the prevention of NAFLD.
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http://dx.doi.org/10.1016/j.metabol.2020.154398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680436PMC
December 2020

Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort.

Gut 2021 Jul 9;70(7):1375-1382. Epub 2020 Oct 9.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden

Objective: Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD).

Design: This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 2017; n=10 568). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, after excluding other etiologies of liver disease, and further categorised as, simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. NAFLD cases were matched to ≤5 general population comparators by age, sex, calendar year and county (n=49 925). Using Cox regression, we estimated multivariable-adjusted HRs (aHRs) and 95% CIs.

Results: Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (16.9 vs 28.6/1000 PY; difference=11.7/1000 PY; aHR=1.93, 95% CI=1.86 to 2.00). Compared with controls, significant excess mortality risk was observed with simple steatosis (8.3/1000 PY, aHR=1.71, 95% CI=1.64 to 1.79), non-fibrotic NASH (13.4/1000 PY, aHR=2.14, 95% CI=1.93 to 2.38), non-cirrhotic fibrosis (18.4/1000 PY, aHR=2.44, 95% CI=2.22 to 2.69) and cirrhosis (53.6/1000 PY, aHR=3.79, 95% CI=3.34 to 4.30)(p <0.01). This dose-dependent gradient was similar when simple steatosis was the reference (p <0.01). The excess mortality associated with NAFLD was primarily from extrahepatic cancer (4.5/1000 PY, aHR=2.16, 95% CI=2.03 to 2.30), followed by cirrhosis (2.7/1000 PY, aHR=18.15, 95% CI=14.78 to 22.30), cardiovascular disease (1.4/1000 PY, aHR=1.35, 95% CI=1.26 to 1.44) and hepatocellular carcinoma (HCC) (1.2/1000 PY, aHR=11.12, 95% CI=8.65 to 14.30).

Conclusion: All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.
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http://dx.doi.org/10.1136/gutjnl-2020-322786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185553PMC
July 2021

Lifestyle and Environmental Approaches for the Primary Prevention of Hepatocellular Carcinoma.

Clin Liver Dis 2020 11 25;24(4):549-576. Epub 2020 Aug 25.

Division of Gastroenterology, GRJ-825C, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Patients with chronic liver disease are at increased risk of developing hepatocellular carcinoma (HCC). Most patients diagnosed with HCC have limited treatment options and a poor overall prognosis, with a 5-year survival less than 15%. Preventing the development of HCC represents the most important strategy. However, current guidelines lack specific recommendations for primary prevention. Lifestyle factors may be central in the pathogenesis of HCC, and primary prevention strategies focused on lifestyle modification could represent an important approach to the prevention of HCC. Both experimental and epidemiologic studies have identified promising chemopreventive agents for the primary prevention of HCC.
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http://dx.doi.org/10.1016/j.cld.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536356PMC
November 2020

Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden.

Lancet Gastroenterol Hepatol 2020 11 17;5(11):986-995. Epub 2020 Aug 17.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, USA. Electronic address:

Background: Use of antibiotics in early life has been linked with childhood inflammatory bowel disease (IBD), but data for adults are mixed, and based on smaller investigations that did not compare risk among siblings with shared genetic or environmental risk factors. We aimed to investigate the association between antibiotic therapy and IBD in a large, population-based study.

Methods: In this prospective case-control study, we identified people living in Sweden aged 16 years or older, with a diagnosis of IBD based on histology and at least one diagnosis code for IBD or its subtypes (ulcerative colitis and Crohn's disease). We identified consecutive patients with incident IBD from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, cross-referenced with the Swedish Patient Register and the Prescribed Drug Register. We accrued data for cumulative antibiotic dispensations until 1 year before time of matching for patients and up to five general population controls per patient (matched on the basis of age, sex, county, and calendar year). We also included unaffected full siblings as a secondary control group. Conditional logistic regression was used to estimate multivariable-adjusted odds ratios (aORs) and 95% CIs for diagnosis of incident IBD.

Findings: We identified 23 982 new patients with IBD (15 951 ulcerative colitis, 7898 Crohn's disease, 133 unclassified IBD) diagnosed between Jan 1, 2007, and Dec 31, 2016. 117 827 matched controls and 28 732 siblings were also identified. After adjusting for several risk factors, aOR in patients who had used antibiotics versus those who had never used antibiotics was 1·88 (95% CI 1·79-1·98) for diagnosis of incident IBD, 1·74 (1·64-1·85) for ulcerative colitis, and 2·27 (2·06-2·49) for Crohn's disease. aOR was higher in patients who had received one antibiotic dispensation (1·11, 1·07-1·15), two antibiotic dispensations (1·38, 1·32-1·44), and three or more antibiotic dispensations (1·55, 1·49-1·61) than patients who had none. Increased risk was noted for ulcerative colitis (aOR with three or more antibiotic dispensations 1·47, 95% CI 1·40-1·54) and Crohn's disease (1·64, 1·53-1·76) with higher estimates corresponding to broad-spectrum antibiotics. Similar but attenuated results were observed when siblings were used as the reference group, with an aOR of 1·35 (95% CI 1·28-1·43) for patients who had received three or more dispensations, compared with general population controls.

Interpretation: Higher cumulative exposure to systemic antibiotic therapy, particularly treatments with greater spectrum of microbial coverage, may be associated with a greater risk of new-onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not appear to differ when predisposed siblings were used as the reference controls. Our findings, if substantiated by longer-term prospective studies in humans or mechanistic preclinical investigations, suggest the need to further emphasise antibiotic stewardship to prevent the rise in dysbiosis-related chronic diseases, including IBD.

Funding: National Institutes of Health. Crohn's and Colitis Foundation.
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http://dx.doi.org/10.1016/S2468-1253(20)30267-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034612PMC
November 2020

Epoxygenase-Derived Epoxyeicosatrienoic Acid Mediators Are Associated With Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Fibrosis.

Gastroenterology 2020 12 5;159(6):2232-2234.e4. Epub 2020 Aug 5.

Harvard Medical School, Boston, Massachusetts; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725909PMC
December 2020

Association of Hepatic Steatosis With Major Adverse Cardiovascular Events, Independent of Coronary Artery Disease.

Clin Gastroenterol Hepatol 2021 07 21;19(7):1480-1488.e14. Epub 2020 Jul 21.

Cardiovascular Imaging Research Center, Massachusetts General Hospital, Boston, Massachusetts; Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon.

Background & Aims: Hepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).

Methods: We conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.

Results: Among the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.

Conclusions: Hepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.
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http://dx.doi.org/10.1016/j.cgh.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855524PMC
July 2021

Association between Aspirin and Hepatocellular Carcinoma. Reply.

N Engl J Med 2020 06;382(25):2481-2482

Karolinska Institutet, Stockholm, Sweden

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http://dx.doi.org/10.1056/NEJMc2009497DOI Listing
June 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

Br J Cancer 2020 07 7;123(2):316-324. Epub 2020 May 7.

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).

Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.

Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
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http://dx.doi.org/10.1038/s41416-020-0835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374167PMC
July 2020

Physical Activity and Risk of Hepatocellular Carcinoma Among U.S. Men and Women.

Cancer Prev Res (Phila) 2020 08 20;13(8):707-714. Epub 2020 Apr 20.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Mounting evidence indicates a potential beneficial effect of vigorous-intensity physical activity on hepatocellular carcinoma (HCC). However, the association between moderate-intensity physical activity, such as brisk walking, and the risk of HCC remains largely unknown. Two prospective cohorts of 77,535 women from the Nurses' Health Study and 44,540 men from the Health Professionals Follow-up Study were included. Weekly time spent on physical activities were updated biennially. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HR) and 95% confidence intervals (95% CI). After an average 23-year follow-up, we identified 138 incident HCC cases. A higher amount of total physical activity was not significantly associated with a reduced risk of HCC (top tertile vs. bottom tertile; HR = 0.78; 95% CI, 0.51-1.18; = 0.33). For the same comparison, there was an inverse association between moderate-intensity activity and HCC risk (HR = 0.60; 95% CI, 0.38-0.94; = 0.04), whereas no statistically significant association with vigorous-intensity activity (HR = 0.88; 95% CI, 0.56-1.37; = 0.74). Engaging in brisk walking was significantly associated with a lower risk of HCC (over 1 hour/week vs. non-brisk walking; HR = 0.50; 95% CI, 0.31-0.78; = 0.006). The association between brisk walking and HCC risk was generally present across all subgroups, including age, body mass index, type 2 diabetes mellitus, smoking status, aspirin use, and alcohol consumption (all ≥ 0.05). In conclusion, moderate-intensity activity, especially brisk walking, was associated with reduced risk of HCC among U.S. men and women. If confirmed, brisk walking might serve a feasible way for HCC prevention.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415536PMC
August 2020

Brief Report: Relationship Between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease in Persons With HIV.

J Acquir Immune Defic Syndr 2020 08;84(4):400-404

Department of Medicine, Liver Center, Massachusetts General Hospital, Boston, MA.

Background: Nonalcoholic fatty liver disease (NAFLD) and HIV are independently associated with cardiovascular disease (CVD). However, the factors associated with NAFLD in persons living with HIV (PWH) and whether CVD is more frequent in PWH with NAFLD are currently unknown.

Methods: From the Partners HealthCare Research Patient Data Registry, we identified PWH with and without NAFLD between 2010 and 2017. NAFLD was defined using validated histological or radiographic criteria. CVD was defined by an ICD-9 diagnosis of coronary artery disease, myocardial infarction, coronary revascularization, peripheral vascular disease, heart failure, transient ischemic attack, or stroke and was confirmed by clinician review. Multivariable logistic regression was performed to examine the relationship between NAFLD and CVD.

Results: Compared with PWH without NAFLD (n = 135), PWH with NAFLD (n = 97) had higher body mass index and more frequently had hypertension, obstructive sleep apnea, diabetes mellitus, dyslipidemia, coronary artery disease, and CVD (P < 0.01 for all). PWH with NAFLD were also more likely to have CD4 T-cell counts (CD4) <200 cells/mm. In multivariable models, the presence of NAFLD was significantly associated with CVD (adjusted odds ratio 3.08, 95% confidence interval: 1.37 to 6.94) and CD4 <200 cells/mm (adjusted odds ratio 4.49, 95% confidence interval: 1.74 to 11.55).

Conclusion: In PWH, CVD was independently associated with prevalent NAFLD after controlling for traditional CVD risk factors. NAFLD was also associated with CD4 <200 cells/mm, suggesting that immune dysfunction may be related to NAFLD. Both CVD and low CD4 count as risk factors for NAFLD require prospective evaluation.
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http://dx.doi.org/10.1097/QAI.0000000000002359DOI Listing
August 2020

Plant-Based and Animal-Based Low-Carbohydrate Diets and Risk of Hepatocellular Carcinoma Among US Men and Women.

Hepatology 2021 01;73(1):175-185

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background And Aims: Little is known about the role of low-carbohydrate diets (LCDs) in the development of hepatocellular carcinoma (HCC). We prospectively evaluated the associations between plant-based and animal-based LCDs and risk of HCC in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).

Approach And Results: Dietary intake was assessed every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). HRs are shown for a 1-standard deviation (SD) increment with variables modeled as continuous. During 3,664,769 person-years of follow-up, there were 156 incident HCC cases. Although there were no associations between overall or animal-based LCD score and risk of HCC, plant-based LCD score was inversely associated with HCC risk (HR, 0.83; 95% CI, 0.70-0.98; P  = 0.03). Carbohydrate intake, especially from refined grains (HR, 1.18; 95% CI, 1.00-1.39; P  = 0.04), was positively, while plant fat (HR, 0.78; 95% CI, 0.65-0.95; P  = 0.01) was inversely associated with HCC risk. Substituting 5% of energy from plant fat and protein for carbohydrate (HR, 0.74; 95% CI, 0.58-0.93; P  = 0.01) or refined grains (HR, 0.70; 95% CI, 0.55-0.90; P  = 0.006) was associated with lower HCC risk. In conclusion, a plant-based LCD and dietary restriction of carbohydrate from refined grains were associated with a lower risk of HCC. Substituting plant fat and protein for carbohydrate, particularly refined grains, may decrease HCC incidence.

Conclusions: Our findings support a potential benefit in emphasizing plant sources of fat and protein in the diet for HCC primary prevention; additional studies that carefully consider hepatitis B and C virus infections and chronic liver diseases are needed to confirm our findings.
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http://dx.doi.org/10.1002/hep.31251DOI Listing
January 2021
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