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-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.

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.

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.

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.

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.

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.

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).

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.

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.

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).

Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Therapeutic options are limited for patients with non-alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin-angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension. METHODS: Cross-sectional study where clinical information including demographics, anthropometry, medical history, concomitant medication use, biochemical and histological features were ascertained in 290 hypertensive patients with biopsy proven NAFLD followed at two hepatology outpatient clinics. Stage of hepatic fibrosis was compared in patients with and without RAS blocker use. Other risk factors for fibrosis were evaluated from the electronic medical records and patient follow-up. RESULTS: Baseline characteristics of hypertensive patients treated with and without RAS blockers were similar except for less ballooning (1.02 vs. 1.31, P = 0.001) and lower fibrosis stage (1.63 vs. 2.16, P = 0.002) in patients on RAS blockers On multivariate analysis, advancing age (OR: 1.04; 95%CI: 1.01-1.06, P = 0.012) and presence of diabetes (OR: 2.55; 95%CI: 1.28-5.09, P = 0.008) had an independent positive association, while use of RAS blockers (OR: 0.37; 95%CI: 0.21-0.65, P = 0.001) and statins (OR: 0.52; 95%CI: 0.29-0.93, P = 0.029) had a negative association with advanced fibrosis. CONCLUSION: Hypertensive patients with NAFLD on baseline RAS blockers had less advanced hepatic fibrosis suggesting a beneficial effect of RAS blockers in NAFLD.

Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease among US children, may be associated with cardiovascular disease (CVD) risk. The present study sought to determine the prevalence of dyslipidemia in children with NAFLD and assess dyslipidemia by liver histology and histologic changes. METHODS: Individuals in the Treatment of NAFLD in Children (TONIC) trial were included (N = 173). In the TONIC trial, children with NAFLD were randomized to vitamin E, metformin, or placebo for 96 weeks. Nonalcoholic steatohepatitis (NASH) improved in 56 children. Change in lipid levels from baseline and 96 weeks was compared between patients with and without histologic improvement and with and without NASH. RESULTS: Dyslipidemia was frequent, with low high-density lipoprotein (HDL) (< 40 mg/dL) in 61.8%, hypertriglyceridemia (≥ 130 mg/dL) in 50.3%, hypercholesterolemia (≥ 200 mg/dL) in 23.7%, elevated low-density lipoprotein (LDL) (≥ 130 mg/dL) in 21.5%, elevated non-HDL cholesterol (non-HDL-C) (≥ 145 mg/dL) in 35.2%, and triglycerides/HDL > 3.0 in 57.2% of patients. Histologic improvement was associated with significant decreases in cholesterol (-11.4 mg/dL vs -1.9 mg/dL, P = 0.04), LDL (-11.2 mg/dL vs -2.1 mg/dL, P = 0.04), and non-HDL-C (-8.8 mg/dL vs 0.5 mg/dL, P = 0.03) compared with those without improvement. Children with NASH resolution had significant decreases in cholesterol (-10.0 mg/dL vs -0.9 mg/dL, P = 0.02) and non-HDL-C (-7.3 mg/dL vs 1.1 mg/dL, P = 0.01) compared with those without NASH resolution. There was no improvement in triglycerides, HDL level, or triglycerides/HDL ratio in either group. CONCLUSIONS: Dyslipidemia is frequent in children with NAFLD. NASH resolution and histologic improvement are associated with improvements in some forms of dyslipidemia.

Age impacts ability of aspartate-alanine aminotransferase ratio to predict advanced fibrosis in nonalcoholic Fatty liver disease.

BACKGROUND AND AIM: While histological differences have been reported between pediatric and adult nonalcoholic fatty liver disease (NAFLD), potential age-related changes in serum transaminases and liver histology remain largely unexplored. Our study sought to investigate the clinical and histological characteristics of NAFLD across age. METHODS: This was a prospective cross-sectional study of 502 biopsy-proven NAFLD patients. Clinical data were evaluated and compared among different age groups; group A (ages 18-44), B (ages 45-64), and C (≥ ages 65). RESULTS: 34.9, 56.0, and 9.1 % of the cohort were distributed among group A, B, and C, respectively. While the prevalence of nonalcoholic steatohepatitis (NASH) was comparable across age groups, the prevalence of advanced fibrosis increased with age (p = 0.000). Although the mean ALT progressively decreased with age; 87, 64, 56 U/L in group A, B, and C, respectively (p = 0.000), there was no difference in mean AST (p = 0.939) across age. The AST:ALT ratio (AAR) progressively increased from 0.7, 0.9, and 1.1 in group A, B, and C, respectively (p = 0.000). In group C, an AAR ≥ 1 was found in 74 and 40 % of patients with and without advanced fibrosis. CONCLUSION: With advancing age, ALT levels progressively declined while AST levels remained stable, leading to a higher AAR. Although higher AAR is often used as a surrogate measure of advanced fibrosis, advancing age can also contribute to increased AAR. In fact, an AAR ≥ 1 was found in significant number of elderly patients without advanced fibrosis. Consequently, an increased AAR may be a function of decreasing ALT with age in addition to progressive fibrosis.

Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels.

OBJECTIVE: To investigate the histological spectrum of nonalcoholic fatty liver disease (NAFLD) in children with normal, mildly elevated (26-50 U/L boys, 23-44 U/L girls), or elevated (>50 U/L in boys, >44 U/L in girls) serum alanine aminotransferase (ALT) levels. STUDY DESIGN: The Nonalcoholic Steatohepatitis Clinical Research Network enrolls children aged 5-18 years with NAFLD. We analyzed baseline clinical and histological data from 91 children with suspected NAFLD and normal or mildly elevated ALT and liver biopsy analysis within 180 days of ALT measurement, and compared them with data from 392 children with elevated ALT. RESULTS: Seventeen of the 91 children with suspected NAFLD (19%) had a normal ALT level, and 74 (81%) had a mildly elevated ALT level. Overall, 45% of the biopsy specimens analyzed had steatosis ≥33%, 22% had grade ≥2 lobular inflammation, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had "suspicious/borderline" steatohepatitis, 8% had definite nonalcoholic steatohepatitis, 34% had an NAFLD activity score ≥4, and 46% had fibrosis (38% mild/moderate and 8% bridging/cirrhosis). Marked steatosis (50% vs 24%) and fibrosis (54% vs 12%) were significantly more common in the patients with mildly elevated ALT compared with those with normal ALT, with no difference in ballooning, inflammation, or NAFLD activity score ≥4 between the 2 groups. Fibrosis stage 3/4 was seen in none of the children with normal ALT, in 9% of those with mildly elevated ALT, and in 15% of those with elevated ALT. CONCLUSION: Liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis in children with mildly elevated ALT. Thus, measurement of ALT may underestimate liver injury in NAFLD. The use of appropriate ALT cutoff levels can help identify children at risk for more severe disease.

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.

Ethnicity and nonalcoholic fatty liver disease.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States; however, few data are available about racial and ethnic variation. We investigated relationships between ethnicity, NAFLD severity, metabolic derangements, and sociodemographic characteristics in a well-characterized cohort of adults with biopsy-proven NAFLD. Data were analyzed from 1,026 adults (≥18 years) in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) from 2004 to 2008, for whom liver histology data were available within 6 months of enrollment. Associations between ethnicity (i.e., Latino versus non-Latino white) and NAFLD severity (i.e., NASH versus non-NASH histology and mild versus advanced fibrosis) were explored with multiple logistic regression analysis. We also investigated effect modification of ethnicity on metabolic derangements for NAFLD severity. Within the NASH CRN, 77% (N = 785) were non-Latino white and 12% (N = 118) were Latino. Sixty-one percent (N = 628) had NASH histology and 28% (N = 291) had advanced fibrosis. Latinos with NASH were younger, performed less physical activity, and had higher carbohydrate intake, compared to non-Latino whites with NASH. Gender, diabetes, hypertension, hypertriglyceridemia, aspartate aminotransferase (AST), platelets, and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with NASH. Age, gender, AST, alanine aminotransferase, alkaline phosphatase, platelets, total cholesterol, hypertension, and HOMA-IR, but not ethnicity, were significantly associated with advanced fibrosis. The effect of HOMA-IR on the risk of NASH was modified by ethnicity: HOMA-IR was not a significant risk factor for NASH among Latinos (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.85-1.02), but was significant among non-Latino whites (OR, 1.06; 95% CI: 1.01-1.11). CONCLUSION: Metabolic risk factors and sociodemographic characteristics associated with NASH differ by ethnicity. Additional insights into NASH pathogenesis may come from further studies focused on understanding ethnic differences in this disease.

Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study.

UNLABELLED: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.