Burden of gallstone disease in the United States population: Prepandemic rates and trends.

BACKGROUND: Gallstone disease is one of the most common digestive disorders in the United States and leads to significant morbidity, mortality, and health care utilization. AIM: To expand on earlier findings and investigate prepandemic rates and trends in the gallstone disease burden in the United States using national survey and claims databases. METHODS: The National Ambulatory Medical Care Survey, National Inpatient Sample, Nationwide Emergency Department Sample, Nationwide Ambulatory Surgery Sample, Vital Statistics of the United States, Optum Clinformatics® Data Mart, and Centers for Medicare and Medicaid Services Medicare 5% Sample and Medicaid files were used to estimate claims-based prevalence, medical care including cholecystectomy, and mortality with a primary or other gallstone diagnosis. Rates were age-adjusted (for national databases) and shown per 100000 population. RESULTS: Gallstone disease prevalence (claims-based, 2019) was 0.70% among commercial insurance enrollees, 1.03% among Medicaid beneficiaries, and 2.09% among Medicare beneficiaries and rose over the previous decade. Recently, in the United States population, gallstone disease contributed to approximately 2.2 million ambulatory care visits, 1.2 million emergency department visits, 625000 hospital discharges, and 2000 deaths annually. Women had higher medical care rates with a gallstone disease diagnosis, but mortality rates were higher among men. Hispanics had higher ambulatory care visit and hospital discharge rates compared with Whites, but not mortality rates. Blacks had lower ambulatory care visit and mortality rates, but similar hospital discharge rates compared with whites. During the study period, ambulatory care and emergency department visit rates with a gallstone disease diagnosis rose, while hospital discharge and mortality rates declined. Among commercial insurance enrollees, rates were higher compared with national data for ambulatory care visits and hospitalizations, but lower for emergency department visits. Cholecystectomies performed in the United States included 605000 ambulatory laparoscopic, 280000 inpatient laparoscopic, and 49000 inpatient open procedures annually. Among commercial insurance enrollees, rates were higher compared with national data for laparoscopic procedures. CONCLUSION: The gallstone disease burden in the United States is substantial and increasing, particularly among women, Hispanics, and older adults with laparoscopic cholecystectomy as the mainstay treatment. Current practice patterns should be monitored for better health care access.

Longitudinal Study of Comorbidities and Clinical Outcomes in Persons with Gallstone Disease Using Electronic Health Records.

BACKGROUND: Gallstone disease (GSD) is common and leads to significant morbidity, mortality, and health care utilization in the USA. We examined comorbidities and clinical outcomes among persons with GSD using electronic health records (EHR). METHODS: In this retrospective study of 1,381,004 adults, GSD was defined by ICD-9 code 574 or ICD-10 code K80 using Optum® longitudinal EHR from January 2007 to March 2021. We obtained diagnosis, procedure, prescription, and vital sign records and evaluated associations between demographics, comorbidities, and medications with cholecystectomy, digestive cancers, and mortality. RESULTS: Among persons with GSD, 30% had a cholecystectomy and were more likely to be women, White, and younger, and less likely to have comorbidities, except for obesity, gastroesophageal reflux disease (GERD), abdominal pain, hyperlipidemia, and pancreatitis. Among persons with GSD, 2.2% had a non-colorectal digestive cancer diagnosis during follow-up and risk was 40% lower among persons with a cholecystectomy. Non-colorectal digestive cancer predictors included older age, male sex, non-White race-ethnicity, lower BMI, other cancers, diabetes, chronic liver disease, pancreatitis, GERD, and abdominal pain. Among persons with GSD, mortality was 15.1% compared with 9.7% for the whole EHR sample. Persons with a cholecystectomy had 40% lower mortality risk and mortality predictors included older age, male sex, Black race, lower BMI, and most comorbidities. CONCLUSIONS: In this EHR analysis of persons with GSD, 30% had a cholecystectomy. Mortality was higher compared with the whole EHR sample. Persons with cholecystectomy were less likely to have non-colorectal digestive cancer or to die.

The Burden of Digestive Diseases in the United States Population.

Background and rationale: Digestive diseases are common and lead to significant morbidity, mortality, and health care utilization. We used national survey and claims databases to expand on earlier findings and investigate current trends in the digestive disease burden in the United States. Methods: The National Ambulatory Medical Care Survey, Nationwide Emergency Department Sample, National Inpatient Sample, Vital Statistics of the U.S., Surveillance, Epidemiology, and End Results Program, Optum Clinformatics® Data Mart, and Centers for Medicare and Medicaid Services Medicare 5% Sample databases were used to estimate medical care, mortality, cancer incidence, and claims-based prevalence with a digestive disease diagnosis. Rates were age-adjusted (for national databases) and shown per 100,000 population. Results: For all digestive diseases, prevalence (claims-based, all-listed diagnoses) was 30.5% among commercial insurance enrollees (2020) and 53.1% among Medicare beneficiaries (2019). In the U.S. population, digestive diseases contributed to approximately 126 million ambulatory care visits (2015), 41 million emergency department visits (2018), 16 million hospital discharges (2018), and 472,000 deaths (2019) annually. Prevalence, medical care, and mortality rates with a digestive disease diagnosis were higher among children and younger adults (except for emergency department visits) and then increased with age. Women had higher prevalence and medical care rates with a digestive disease diagnosis, but mortality rates were higher among men. Prevalence and medical care rates with a digestive disease diagnosis were higher among Blacks, followed by Whites, then Hispanics, and lowest among Asians. Mortality rates were higher among Blacks compared with Whites and lower among Hispanics compared with non-Hispanics. Between 2004 and the most recent year, ambulatory care visit rates with a digestive disease diagnosis increased by 4%, hospital discharge rates decreased by 3%, and mortality rates decreased by 7%. Among commercial insurance enrollees, rates were higher compared with national data for ambulatory care visits and hospital discharges, but lower for emergency department visits. The medical care use and mortality burdens varied among individual digestive diseases. Conclusion: The digestive disease burden in the United States is substantial, particularly among Blacks and older adults.

Increasing gallstone disease prevalence and associations with gallbladder and biliary tract mortality in the US.

BACKGROUND AND AIMS: We examined gallbladder and biliary tract mortality predictors in the US National Health and Nutrition Examination Survey (NHANES), 1988-1994, with 31 years of linked mortality data, and gallstone disease prevalence trends and associations in NHANES 2017-March 2020 prepandemic data. APPROACH AND RESULTS: In NHANES 1988-1994, 18,794 participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2019. In NHANES 2017-March 2020, gallstone disease history was ascertained from 9232 adults. During NHANES 1988-2019 follow-up (median, 23.3 y), 8580 deaths occurred from all causes and 72 deaths with gallbladder or biliary tract disease. In multivariable-adjusted analysis, older age, male sex, prediabetes or diabetes, and physical inactivity were associated with gallbladder and biliary tract mortality, and non-Hispanic Black and Mexican American race-ethnicity were inversely associated. Between 1988-1994 and 2017-March 2020, gallstone disease prevalence increased from 7.4% to 13.9% and gallbladder surgery from 6.0% to 11.6%. In 2017-March 2020 in multivariable-adjusted analysis, female sex, diabetes, liver disease, proton pump inhibitors, abdominal pain, increased age, BMI, and liver stiffness were associated with gallstone disease, and non-Hispanic Black and non-Hispanic Asian race and alcohol were inversely associated. CONCLUSIONS: In the US population, gallstone disease prevalence doubled over 3 decades, possibly because of the worsening of metabolic risk factors and growth of laparoscopic cholecystectomy. Gallbladder and biliary tract mortality and gallstone disease associations included factors such as prediabetes or diabetes, liver stiffness and proton pump inhibitors.

Prepandemic Prevalence Estimates of Fatty Liver Disease and Fibrosis Defined by Liver Elastography in the United States.

BACKGROUND AND AIMS: Fatty liver disease is a growing public health burden. We estimated prepandemic fatty liver disease prevalence determined by transient elastography-assessed hepatic steatosis and fibrosis, and examined associations with lifestyle and other factors in a United States population sample. METHODS: Liver stiffness and controlled attenuation parameter (CAP) were assessed on 7923 non-Hispanic white, non-Hispanic black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey (NHANES) 2017-March 2020 prepandemic data. RESULTS: The prevalence of fatty liver disease (CAP > 300 dB/m) was 28.8% and of fibrosis (liver stiffness > 8 kPa) was 10.4%. Only 7.2% of participants with fatty liver disease and 10.9% with fibrosis reported being told by a health care provider that they had liver disease. In addition to known risk factors such as metabolic factors and ALT, persons with fatty liver disease were less likely to meet physical activity guidelines, more likely to be sedentary for ≥ 12 h a day, and reported a less healthy diet. Persons with fibrosis were less likely to have a college degree and reported a less healthy diet. CONCLUSIONS: In the U.S. population, most persons with fatty liver disease are unaware of their condition. Physical activity and dietary modifications might reduce the fatty liver disease burden. There is an urgent need for fatty liver disease management in high-risk individuals using transient elastography or other noninvasive methods to intervene in disease progression.

Transient Elastography Measures of Hepatic Steatosis and Fibrosis Are Associated With Body Composition Among US Adolescents.

OBJECTIVES: Obesity-related fatty liver disease impacts long-term adolescent liver health. We examined transient elastography assessed hepatic steatosis and fibrosis distributions and relationships with body composition and lifestyle factors in a United States national adolescent population sample. METHODS: Liver stiffness and controlled attenuation parameter (CAP) were assessed on 1080 non-Hispanic white, non-Hispanic black, non-Hispanic Asian, and Hispanic boys and girls aged 12-19 years in the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Participants underwent anthropometry and dual-energy x-ray absorptiometry (DXA). RESULTS: Compared with girls, boys had higher mean CAP (223.7 dB/m vs 215.3 dB/m) and liver stiffness (5.1 kPa vs 4.9 kPa). CAP and liver stiffness increased markedly with body mass index (BMI). In multivariable-adjusted analysis, CAP in the upper quartile was associated with Hispanic and non-Hispanic Asian ethnicity and increased BMI, waist-to-hip ratio, systolic blood pressure, and sedentary time, and decreased physical activity and Healthy Eating Index-2015 score. In multivariable-adjusted analysis, liver stiffness in the upper quartile was associated with male sex, non-Hispanic black ethnicity, and increased BMI, alanine aminotransferase, CAP, and serum cotinine. DXA total percent fat and trunk fat percent were positively related to CAP ( P < 0.001 for each), but not to liver stiffness with multivariable adjustment. Results were similar with CAP and liver stiffness as continuous characteristics. CONCLUSIONS: In US adolescents, increased anthropometric and DXA body composition measures and lifestyle factors were associated with higher CAP and liver stiffness. Transient elastography and similar noninvasive markers may be utilized for early detection of liver disease in high-risk pediatric populations.

Nutrient intake differs among persons with celiac disease and gluten-related disorders in the United States.

Persons with celiac disease (CD) may develop nutritional deficiencies, while individuals following a gluten-free diet (GFD) may lack essential nutrients. We examined nutrient intake from diet and supplements among persons with CD and GFD in the cross-sectional National Health and Nutrition Examination Survey, 2009-2014. Among 15,610 participants 20 years and older, we identified CD based on positive serology for immunoglobulin A against tissue transglutaminase, health care provider diagnosis, and adherence to a GFD. People without CD avoiding gluten (PWAG) adhered to a GFD without a diagnosis of CD. Two 24-h recalls assessed nutrient intake from diet and supplements. Compared to participants without CD or PWAG, persons with diagnosed CD had lower intake of total energy, carbohydrates, fat, and saturated and monounsaturated fatty acids. In contrast, persons with undiagnosed CD and positive serology had higher intake of those nutrients, sugar, and protein. Total carbohydrate and sugar intake was lower among PWAG. Persons with diagnosed CD had higher vitamin A and E intake, while those with undiagnosed CD had increased intake of calcium, phosphorus, magnesium, iron, zinc, copper, sodium, potassium, vitamin A, alpha-carotene, folic acid, and choline. Higher micronutrient intake with undiagnosed CD was observed more at high latitudes. PWAG had higher beta-carotene and lutein/zeaxanthin and lower folic acid intake. In the U.S. population over a 6-year period, total energy and macronutrient intake was decreased among persons with diagnosed CD, while intake of total energy, macronutrients, and multiple micronutrients was increased among persons with undiagnosed CD. Nutriomics studies of multiple analytes measured simultaneously across affected persons and populations are needed to inform screening for malabsorption and treatment strategies.

Transient Elastography-Assessed Hepatic Steatosis and Fibrosis Are Associated With Body Composition in the United States.

BACKGROUND & AIMS: We examined transient elastography assessed hepatic steatosis and fibrosis distributions and relationships with body composition in a representative United States population sample. METHODS: Liver stiffness and controlled attenuation parameter (CAP) were assessed on 4870 non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Participants underwent anthropometry and dual-energy x-ray absorptiometry (DXA). RESULTS: Compared to women, men had higher mean CAP (274.2 dB/m vs 254.4 dB/m) and liver stiffness (6.4 kPa vs 5.5 kPa). CAP and liver stiffness increased through middle age and markedly with BMI. In multivariate-adjusted analysis, CAP in the upper quartile was associated with increased age, BMI, waist-to-hip ratio, diabetes, hypertension, alanine aminotransferase (ALT) and C-reactive protein and decreased HDL cholesterol. After adjustment, non-Hispanic Blacks had lower CAP and non-Hispanic Asians had higher CAP. In multivariate-adjusted analysis, liver stiffness in the upper quartile was associated with male sex, increased age, BMI, diabetes, hepatitis C virus positivity, ALT and CAP. Lower stiffness among Non-Hispanic Asians was not significant after adjustment for BMI. DXA trunk and extremity fat mass were positively related to both CAP and liver stiffness with multivariate adjustment (P < .001 for each). Results were similar with CAP and liver stiffness as continuous characteristics. CONCLUSIONS: In the United States population, increased anthropometric and DXA body composition measures were associated with higher CAP and liver stiffness. Racial-ethnic differences observed merit further research to elucidate the burden of obesity and liver health disparities.

The national institutes of health's approach to address research gaps in pancreatitis, diabetes and early detection of pancreatic cancer.

PURPOSE OF REVIEW: Diseases of the pancreas are a broad spectrum of conditions resulting from metabolic, inflammatory, and neoplastic processes (pancreatitis, pancreatogenic diabetes, and pancreatic cancers). Pancreatic diseases cause significant morbidity, mortality, and cost. RECENT FINDINGS: Research progress in diseases of the exocrine pancreas (chronic pancreatitis [CP], pancreatogenic diabetes mellitus, and pancreatic cancer) has been hampered by the disorders' heterogeneity, the limitations of previous small cross-sectional studies, the inability to safely obtain pancreatic tissue for study, and the lack of structured epidemiology tools, genetic testing, and biomarker development. SUMMARY: Given the increasing incidence and prevalence of CP and its complications, high mortality rate, and associated healthcare cost, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the Consortium for the study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) to identify research gaps and foster multidisciplinary collaborations to better diagnose, characterize and manage CP and its sequelae and to understand the diabetes/pancreatic cancer association.The studies undertaken by the CPDPC are described in other articles in this journal's issue.

Patatin-Like Phospholipase Domain-Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population.

BACKGROUND AND AIMS: Fatty liver causes premature death worldwide and requires long-term health care. We examined relationships of liver disease markers, including patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M, with mortality in the U.S. National Health and Nutrition Examination Survey, 1988-1994, with 27 years of linked mortality data. APPROACH AND RESULTS: We studied 13,298 viral hepatitis negative adults who fasted at least 4 hours using the nonalcoholic fatty liver disease (NAFLD) liver fat score and NAFLD fibrosis score. PNPLA3 I148M was genotyped in a subgroup of participants from 1991 to 1994 (n = 5,640). Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2015. During follow-up (median, 23.2 years), cumulative mortality was 33.2% overall and 1.1% with liver disease, including primary liver cancer. Increased liver disease mortality was associated with PNPLA3 I148M (hazard ratio [HR], 2.9; 95% confidence interval [CI], 0.9-9.8) and 148M genotypes (HR, 18.2; 95% CI, 3.5-93.8), an intermediate (HR, 3.8; 95% CI, 1.3-10.7) or high (HR, 12.6; 95% CI, 4.3-36.3) NAFLD liver fat score, and a high NAFLD fibrosis score (HR, 12.2; 95% CI, 1.9-80.6) adjusted for risk factors. Survival curves suggest that increased mortality risk with two 148M alleles was greatest beginning in the second decade of follow-up. Overall, but not cardiovascular disease, mortality was associated with the PNPLA3 148M allele, and both mortality outcomes were associated with higher fat and fibrosis scores. CONCLUSIONS: In the U.S. population, PNPLA3 I148M and higher NAFLD liver fat and fibrosis scores were associated with increased liver disease mortality. Genetic variant PNPLA3 I148M may complement other liver disease markers for NAFLD surveillance.

Autoimmune and Allergic Disorders are More Common in People With Celiac Disease or on a Gluten-free Diet in the United States.

GOALS: We analyzed demographics, lifestyle patterns, and clinical characteristics of people with celiac disease (CD) and people without CD avoiding gluten (PWAG) to better understand associations with medical conditions and consumer behavior. BACKGROUND: Clinical significance of CD and gluten avoidance in the general population is incompletely understood. Recently, a high incidence of CD in adolescents with susceptibility genotypes, similar to other autoimmune or allergic disorders, and regional differences in consumer practices of gluten avoidance were reported. METHODS: Among 22,277 participants in the National Health and Nutrition Examination Survey 2009-2014, we identified persons with CD by testing CD serology or by both a health care provider diagnosis and adherence to a gluten-free diet. Similarly, PWAG were defined as adherent to a gluten-free diet without a CD diagnosis. Consumer behavior and characteristics of both groups, CD and PWAG were compared with those without these conditions, using survey-weighted generalized logistic regression. RESULTS: Participants with CD considered nutrition very important when grocery shopping and tended to have more constipation and thyroid disease. PWAG tended to spend more money on groceries, purchase organic foods, and check food labels more frequently during grocery shopping. They also reported having more food allergies, asthma, and thyroid disease. CONCLUSIONS: Our study confirms that CD and PWAG share comorbidities of autoimmune nature. PWAG had more autoimmune/allergy-related disorders that may be associated with non-celiac gluten sensitivity a self-justifiable reason to be on the diet.

Liver fat scores predict liver disease mortality in the United States population.

BACKGROUND: Fatty liver is a significant global public health burden, contributing to premature death. AIM: To examine whether liver fat scores were associated with increased overall and disease-specific mortality in a United States (US) population-based survey with up to 27 years of linked mortality data. METHODS: We studied 9200 fasted viral hepatitis-negative adults in the third National Health and Nutrition Examination Survey, 1988-1994. Liver fat was predicted using the US fatty liver index (US FLI), fatty liver index (FLI), non-alcoholic fatty liver disease liver fat score (NAFLD LFS), and hepatic steatosis index (HSI). Participants were passively followed up for mortality, identified by death certificate underlying or contributing causes, by linkage to National Death Index records through 2015. Mortality hazard ratios (HR) were calculated using Cox proportional hazards regression to adjust for mortality risk factors. RESULTS: During follow-up (median, 23.3 years), cumulative mortality was 31.4% overall and 1.1% with liver disease, including primary liver cancer. Elevated liver disease mortality was associated with a high US FLI (HR, 5.7; 95% confidence interval (CI), 1.3-24.5), and intermediate (HR, 3.1; 95% CI, 1.1-9.1) or high (HR, 11.4; 95% CI, 2.9-44.4) NAFLD LFS, but not with a higher FLI or HSI. Overall and cardiovascular disease mortality was unassociated with higher liver fat scores. CONCLUSIONS: In the US population, a higher US FLI and NAFLD LFS were associated with increased liver disease mortality, but not with other mortality outcomes. Liver fat scores may be useful for metabolic health surveillance and long-term liver disease risk stratification and may complement fibrosis markers for tracking.

Liver fibrosis scores predict liver disease mortality in the United States population.

Fatty liver disease is common in the United States and worldwide due to changing lifestyles and can progress to fibrosis and cirrhosis contributing to premature death. We examined whether liver fibrosis scores were associated with increased overall and disease-specific mortality in a United States population-based prospective survey with up to 23 years of linked-mortality data. Data were analyzed from 14,841 viral hepatitis-negative adult participants in the third National Health and Nutrition Examination Survey, 1988-1994. Liver fibrosis was predicted using the aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and Forns score. Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to National Death Index records through 2011. Hazard ratios (HR) for mortality were calculated using Cox proportional hazards regression to adjust for mortality risk factors. During follow-up, cumulative mortality was 28.0% from all causes and 0.82% with liver disease, including primary liver cancer. Elevated liver disease mortality was found with an intermediate to high APRI (HR, 9.44; 95% confidence interval [CI], 5.02-17.73), intermediate (HR, 3.15; 95% CI, 1.33-7.44) or high (HR, 25.14; 95% CI, 8.38-75.40) FIB-4 score, high NFS (HR, 6.52; 95% CI, 2.30-18.50), and intermediate (HR, 3.58; 95% CI, 1.78-7.18) or high (HR, 63.13; 95% CI, 22.16-179.78) Forns score. Overall mortality was also greater with higher fibrosis scores. CONCLUSION: In the United States population, higher liver fibrosis scores were associated with increased liver disease and overall mortality. Liver health management with common clinical measures of fibrosis risk stratification merits further investigation. (Hepatology 2017;66:84-95).

Lower Prevalence of Celiac Disease and Gluten-Related Disorders in Persons Living in Southern vs Northern Latitudes of the United States.

BACKGROUND & AIMS: The association between prevalence of celiac disease and geographic region is incompletely understood, but the occurrence of several autoimmune disorders has been found to vary along a North-South gradient. We examined geographic, demographic, and clinical factors associated with prevalence of celiac disease and gluten-free diet in the United States. METHODS: In a population-based study, we analyzed data on gluten-related conditions from the National Health and Nutrition Examination Survey, from 2009 through 2014, on 22,277 participants 6 years and older. We identified persons with celiac disease based on results of serum tests for IgA against tissue transglutaminase and endomysium or on both a health care provider diagnosis and adherence to a gluten-free diet. Gluten avoidance without celiac disease was defined as adherence to a gluten-free diet without a diagnosis of celiac disease. We compared mean serum levels of biochemical and nutritional markers based on status of gluten-related conditions. RESULTS: We found 0.7% of participants to have celiac disease and 1.1% of participants to avoid gluten without celiac disease. Celiac disease was more common among individuals who lived at latitudes of 35°-39° North (odds ratio, 3.2; 95% confidence interval, 1.4-7.1) or at latitudes of 40° North or more (odds ratio, 5.4; 95% CI, 2.6-11.3) than individuals who lived at latitudes below 35° North, independent of race or ethnicity, socioeconomic status, and body mass index. Gluten avoidance without celiac disease was more common among individuals who lived at latitudes of 40° North or more, independent of demographic factors and body mass index. Participants with undiagnosed celiac disease (identified by positive results from serologic tests) had lower mean levels of vitamin B-12 and folate (data collected from 2009 through 2012) than persons without celiac disease. Participants with a health care provider diagnosis of celiac disease had a lower mean level of hemoglobin than persons without celiac disease. Mean levels of albumin, calcium, iron, ferritin, cholesterol, vitamin B-6, and vitamin D (data collected from 2009 through 2010) did not differ between participants with gluten-related conditions and those without. CONCLUSIONS: In the US population, a higher proportion of persons living at latitudes of 35° North or greater have celiac disease or avoid gluten than persons living south of this latitude, independent of race or ethnicity, socioeconomic status, or body mass index. Mean levels of vitamin B-12 and folate are lower in individuals with undiagnosed celiac disease, and levels of hemoglobin are lower in participants with a diagnosis of celiac disease, compared with individuals without celiac disease.

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

Less Hidden Celiac Disease But Increased Gluten Avoidance Without a Diagnosis in the United States: Findings From the National Health and Nutrition Examination Surveys From 2009 to 2014.

OBJECTIVE: To investigate the trends in the prevalence of diagnosed celiac disease (CD), undiagnosed CD, and people without celiac disease avoiding gluten (PWAG) in the civilian noninstitutionalized US population from 2009 to 2014. PATIENTS AND METHODS: We studied the occurrence of CD and PWAG in the 2009 to 2014 National Health and Nutrition Examination Surveys. The serum of all participants aged 6 years or older from the National Health and Nutrition Examination Surveys from 2009 to 2014 was tested for CD serology at Mayo Clinic. Participants were interviewed for a diagnosis of CD and the use of a gluten-free diet (GFD). The design effects of the survey and sample weights were incorporated in all statistical analyses. RESULTS: In the US general population, the prevalence of CD did not change significantly from 0.7% (95% CI, 0.6%-0.8%) in 2009 to 2010 to 0.8% (95% CI, 0.4%-1.2%) in 2011 to 2012 to 0.7% (95% CI, 0.3%-1.0%) in 2013 to 2014. However, the prevalence of undiagnosed CD decreased from 0.6% in 2009 to 2010 to 0.3% in 2013 to 2014. In contrast, the prevalence of PWAG increased significantly from 0.5% (95% CI, 0.2%-0.9%) in 2009 to 2010 to 1.0% (95% CI, 0.6%-1.4%) in 2011 to 2012 to 1.7% (95% CI, 1.1%-2.4%) in 2013 to 2014 (P=.005 for trend). CONCLUSION: Although the overall prevalence of CD remained stable from 2009 to 2014, the proportion of individuals with CD that is hidden considerably decreased. Moreover, the proportion of individuals without CD but following a GFD increased markedly from 2009 to 2014. Long-term health consequences of a GFD warrant further investigation.

Association between metabolic syndrome and liver histology among NAFLD patients without diabetes.

BACKGROUND: Metabolic syndrome (MetS) and obesity are associated with non-alcoholic fatty liver disease (NAFLD). The aim of this observational study was to examine the relationship of MetS and a diagnosis of non-alcoholic steatohepatitis (NASH) in patients without diabetes in the NASH Clinical Research Network (CRN). METHODS: Clinical, demographic, histological, laboratory and anthropometric data were collected on 356 adult patients without diabetes with NAFLD. Obesity was defined as body mass index ≥30.0. MetS was determined using the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATPIII) 2001 criteria to include 3 or more of the following: increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, hypertension and elevated fasting blood glucose. RESULTS: Most patients were obese (71%) and had MetS (67%). Obesity was more prevalent among patients with MetS (80% vs 52%; p≤0.001). Markers of insulin resistance such as homoeostasis model assessment of insulin resistance (6.5 vs 4.9, p≤0.001) were higher among those with MetS compared with those without MetS. Histologically, patients without MetS had higher hepatocellular (p=0.04) and reticuloendothelial system iron (p=0.04). Patients with MetS were more likely to have severe hepatic steatosis (p=0.04) and chronic portal inflammation (p=0.01). On multiple logistic regression analysis, patients with definite NASH were almost 2.5 times more likely to have MetS than those without definite NASH (OR=2.41, p=0.01). CONCLUSIONS: MetS is common in patients without diabetes with NAFLD and is associated with greater insulin resistance, hepatic steatosis and portal inflammation. While patients without MetS have greater iron overload, patients with MetS may have an increased propensity to have NASH. Therefore, presence of MetS in patients without diabetes with NAFLD may serve as a potential criterion for liver biopsy. TRIAL REGISTRATION NUMBER: NCT00063622; Pre-results.

A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease.

UNLABELLED: Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self-reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of <40 years) and time from menopause (age at study enrollment - age at menopause, years) with fibrosis severity (stage 0-4) were assessed using multiple ordinal logistic regression models with and without adjusting for clinical confounders. Among the participants (age at menopause 43.7 ± 8.6 years), women with premature menopause (29.3%) were younger at enrollment (P < 0.001) and used hormone replacement therapy more often (P < 0.003). After adjusting for age at enrollment, race, waist circumference standardized by body mass index, current smoking, current alcohol use, hypertension, diabetes/impaired fasting glucose, homeostatic model assessment of insulin resistance, and hormone replacement therapy, premature menopause was associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio = 1.9, 95% confidence interval 1.3-2.7, P = 0.001), while time from menopause was directly associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio for 5-year unit = 1.2, 95% confidence interval 1.1-1.3, P = 0.002). CONCLUSION: Duration of estrogen deficiency in postmenopausal state confers fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. (Hepatology 2016;64:85-91).

Noninvasive fatty liver markers predict liver disease mortality in the U.S. population.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) contributes to premature death along with obesity, diabetes, and cardiovascular disease (CVD). We examined whether hepatic steatosis (HS) on ultrasound and liver enzyme activities were associated with increased liver disease mortality in the U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, with up to 23 years of linked-mortality data. Survey-linked National Death Index records were analyzed among 14,527 adult participants who were negative for viral hepatitis B and C and iron overload. HS on ultrasound was categorized as normal, mild, moderate, or severe. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) elevation was defined as the highest sex-specific decile. Cumulative mortality was 36.2% from all causes, including 16.3% from CVD, 10.8% from cancer, 5.4% from diabetes, and 1.1% from liver disease. Severe HS was associated with increased liver disease mortality in both age-adjusted (hazard ratio [HR]: 3.92; 95% confidence interval [CI]: 1.49-10.27; P for trend: 0.011) and multivariate-adjusted analyses (HR, 2.68; 95% CI: 1.02-7.03; P for trend: 0.072). HS was not independently associated with mortality from all causes, CVD, cancer, or diabetes. Higher liver disease mortality was found with elevated ALT (HR, 4.08; 95% CI: 1.99-8.33), AST (HR, 4.33; 95% CI: 2.18-8.59), and GGT (HR, 7.91; 95% CI: 3.06-20.46). GGT elevation was associated with increased overall mortality (HR, 1.45; 95% CI: 1.21-1.74). Liver enzymes were otherwise unrelated to overall or cause-specific mortality. CONCLUSIONS: In the U.S. population, severe hepatic steatosis on ultrasound and liver enzyme elevation were associated with increased liver disease mortality, but were not independently associated with mortality from all causes (except for GGT), CVD, cancer, or diabetes.