Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study.

UNLABELLED: Given that little is known about the prevalence of, and factors associated with, liver fibrosis in the general population, we aimed to investigate this in a large, well-characterized cohort by means of transient elastography (TE). This study was part of the Rotterdam Study, a population-based study among individuals ≥45 years. All participants underwent abdominal ultrasound and TE. Liver stiffness measurement (LSM) ≥8.0 kilopascals (kPa) was used as a cutoff suggesting clinically relevant fibrosis. Of 3,041 participants (age, 66.0 ± 7.6 years) with reliable LSM, 169 (5.6%) participants had LSM ≥8.0 kPa. Age (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.72-3.36; P < 0.001), alanine aminotransferase (ALT; OR, 1.24; 95% CI: 1.12-1.38; P < 0.001), smoking (OR, 1.77; 95% CI: 1.16-2.70; P = 0.008), spleen size (OR, 1.23; 95% CI: 1.09-1.40; P = 0.001), hepatitis B surface antigen, or anti-hepatitis C virus positivity (OR, 5.38; 95% CI: 1.60-18.0; P = 0.006), and combined presence of diabetes mellitus (DM) and steatosis (OR, 5.20; 95% CI: 3.01-8.98; P < 0.001 for combined presence) were associated with LSM ≥8.0 kPa in multivariable analyses. The adjusted predicted probability of LSM ≥8.0 kPa increased per age decade, with probabilities ranging from 1.4% (0.9-3.6) in participants ages 50-60 years to 9.9% (6.8-14.5) in participants >80 years. Participants with both DM and steatosis had the highest probabilities of LSM ≥8.0 kPa (overall probability: 17.2% [12.5-23.4]; this probability did not increase with age [P = 0.8]). CONCLUSION: In this large population-based study of older adults, LSM ≥8.0 kPa, suggestive of clinically relevant fibrosis, was present in 5.6% and was strongly associated with steatosis and DM. In the context of an aging population and an increased prevalence of DM and obesity, this study illustrates that liver fibrosis may become a more prominent public health issue in the near future.

Increased Prevalence of Advanced Liver Fibrosis in Patients with Psoriasis: A Cross-sectional Analysis from the Rotterdam Study.

Prevalence of non-alcoholic fatty liver disease is increased in patients with psoriasis. However, it is not known how liver fibrosis correlates with psoriasis. This study investigated the association between psoriasis and liver fibrosis compared with participants without psoriasis within the population-based Rotterdam Study. All participants were screened for liver fibrosis using transient elastography. Liver stiffness > 9.5 kPa suggested advanced liver fibrosis. Psoriasis was identified using a validated algorithm. A total of 1,535 participants were included (mean age ± standard deviation 70.5 ± 7.9 years; 50.8% female; median body mass index 26.4 kg/m2 (interquartile range 24.2-28.9)) of whom 74 (4.7%) had psoriasis. Prevalence of advanced liver fibrosis was 8.1% in psoriasis patients compared with 3.6% in the reference group (p = 0.05). The risk of advanced liver fibrosis in psoriasis patients remained comparable after adjustment for demographics, lifestyle characteristics and laboratory findings (odds ratio 2.57 (95% confidence interval 1.00-6.63). This study suggests that elderly people with psoriasis are twice as likely to have advanced liver fibrosis irrespective of common risk factors.

Statin therapy is associated with a reduced risk of non-alcoholic fatty liver in overweight individuals.

BACKGROUND: Non-alcoholic fatty liver or hepatic steatosis is considered the hepatic manifestation of the metabolic syndrome. Statins are often used by patients with metabolic syndrome, but their effect in steatosis is not well established. AIMS: To study the association between statins and the presence of steatosis. METHODS: In the population-based Rotterdam Study, 2578 subjects underwent liver ultrasonography and had prescription data available. In a cross-sectional design, we investigated the effect of current, past, and duration of statin use. Logistic regression analyses were adjusted for age, sex, and other known risk factors. RESULTS: The prevalence of steatosis was 35.3%. We identified 631 current and 359 past statin users. In multivariable analyses, current statin use >2 years was associated with a significantly lower steatosis prevalence [OR 0.43, 95% CI 0.19-0.96]. Stratification by mean body mass index showed that this association was stronger in patients with body mass index ≥ 27.5 [OR 0.30, 95% CI 0.11-0.81 for current use >2 years], while in patients with body mass index <27.5 the association was non-significant. CONCLUSION: Within the Rotterdam study, in patients with body mass index ≥ 27.5 current use of statins for >2 years was associated with a lower prevalence of steatosis.

Serum liver enzymes are associated with all-cause mortality in an elderly population.

BACKGROUND & AIMS: Little is known about the association of serum liver enzymes with long-term outcome in the elderly. We sought to clarify the association of serum gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with all-cause and cause-specific mortality in an elderly population. METHODS: This study was embedded in the Rotterdam Study, a large population-based cohort of persons aged 55 years or older. Cox-regression analyses were performed to examine the association of baseline serum GGT, ALP, and aminotransferase levels with mortality, adjusted for age, sex, education, smoking status, alcohol intake, hypertension, diabetes mellitus, body mass index and total cholesterol levels. Liver enzyme levels were categorized according to sample percentiles; levels <25th percentile were taken as a reference. RESULTS: During a follow-up of up to 19.5 years, 2997 of 5186(57.8%) participants died: 672 participants died of causes related to cardiovascular diseases (CVD) and 703 participants died of cancer. All serum liver enzymes were associated with all-cause mortality (all P < 0.001). Moreover, GGT was associated with increased CVD mortality (P < 0.001), and ALP and AST with increased cancer-related mortality (P = 0.03 and P = 0.005 respectively). Participants with GGT and ALP in the top 5% had the highest risk for all-cause mortality (HR1.55; 95%CI 1.30-1.85 and HR1.49; 95%CI 1.25-1.78 respectively). AST and ALT <25th percentile were also associated with a higher risk of all-cause mortality. CONCLUSIONS: All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated.

Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: Results from a population-based study.

BACKGROUND: Recent case-control studies observed an increased prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with psoriasis, which is relevant in selecting optimal psoriasis treatment. OBJECTIVE: We sought to compare the prevalence of NAFLD in people with psoriasis and those without psoriasis. METHODS: This large prospective population-based cohort study (part of the Rotterdam Study) enrolled elderly participants (>55 years). NAFLD was diagnosed as fatty liver on ultrasonography in the absence of other liver diseases. Participants with psoriasis were identified using a validated algorithm. Multivariable logistic regression model was used to assess whether psoriasis was associated with NAFLD after adjusting for demographic, lifestyle characteristics, and laboratory findings. RESULTS: In total, 2292 participants were included (mean age 76.2 ± 6.0 years; 58.7% female; mean body mass index 27.4 ± 4.2kg/m(2)) of whom 118 (5.1%) had psoriasis. The prevalence of NAFLD was 46.2% in patients with psoriasis compared with 33.3% for the reference group without psoriasis (P = .005). Psoriasis was significantly associated with NAFLD; after adjustment for alcohol consumption, pack-years and smoking status, presence of metabolic syndrome, and alanine aminotransferase, psoriasis remained a significant predictor of NAFLD (adjusted odds ratio 1.7, 95% confidence interval 1.1-2.6). LIMITATIONS: This was a cross-sectional study. CONCLUSION: Elderly participants with psoriasis are 70% more likely to have NAFLD than those without psoriasis independent of common NAFLD risk factors.

External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study.

BACKGROUND & AIMS: We aimed to validate the fatty liver index (FLI), an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase. We calculated its ability to identify fatty liver disease from any cause or nonalcoholic fatty liver disease (NAFLD) in a large population of white elderly persons. METHODS: We collected ultrasonography and FLI data from participants of the Rotterdam Study from February 2009 to February 2012; 2652 subjects (mean age, 76.3 ± 6.0 years) were interviewed and received a clinical examination that included abdominal ultrasound, analysis of blood samples during fasting, and anthropometric assessment. The ability of the FLI to detect (nonalcoholic) fatty liver was assessed by using area under the receiver operator characteristic (AUROC) curve analysis. RESULTS: FLI score was associated with NAFLD in multivariable analysis (odds ratio, 1.05; 95% confidence interval [CI], 1.04-1.05; P < .001). FLI identified patients with NAFLD with an AUROC curve of 0.813 (95% CI, 0.797-0.830) and those with fatty liver from any cause with an AUROC curve of 0.807 (95% CI, 0.792-0.823). CONCLUSIONS: The FLI (an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase) accurately identifies NAFLD, confirmed via ultrasonography, in a large, white, elderly population.

Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) appears to increase with age. However, limited data are available concerning the prevalence of NAFLD in the elderly. Our aim was to determine the prevalence and risk factors of NAFLD in an elderly population. METHODS: This study was based on participants in the population-based Rotterdam Study. Each participant was interviewed and had a clinical examination at the research center, including a fasting blood collection, liver ultrasonography, and anthropometric assessment. Ordinal and logistic regression analysis was used to assess associations between covariables and (severity of) NAFLD. RESULTS: Data from 2811 participants (mean age 76.4 ± 6.0 years) were analyzed. The prevalence of NAFLD was 35.1%. The prevalence of NAFLD decreased with advancing age (p<0.001). In logistic regression analysis, age (OR 0.97; 95% CI 0.95-0.99; p<0.001), total physical activity level (OR 0.98, 95% CI 0.96-0.99; p=0.005), pack years of smoking (OR 1.01, 95% CI 1.00-1.01; p=0.02), waist circumference >88 cm for women and > 102 cm for men (OR 4.89; CI 4.00-5.96; p<0.001), fasting glucose ≥ 100 mg/dl or drug treatment for elevated blood glucose (OR 2.11, 95% CI 1.72-2.59; p<0.001), blood pressure ≥ 130/85 mmHg or drug treatment for elevated blood pressure (OR 1.80, 95% CI 1.08-3.01; p=0.03), and triglycerides ≥ 150 mg/dl or treatment with serum lipid reducing agents (OR 1.56, 95% CI 1.28-1.91; p<0.001) were associated with NAFLD. CONCLUSIONS: NAFLD is common in the elderly, although the prevalence decreases with advancing age. Further studies are warranted exploring potential factors contributing to this apparent positive selection effect in the elderly.

Growth hormone, dehydroepiandrosterone and adiponectin levels in non-alcoholic steatohepatitis: an endocrine signature for advanced fibrosis in obese patients.

BACKGROUND AND AIMS: Liver-related clinical consequences of non-alcoholic fatty liver disease (NAFLD) are seen only in the minority of patients with advanced fibrosis. The aim of our study was to generate insight into a potential endocrine basis of steatohepatitis with advanced fibrosis in NAFLD. METHODS: Biopsy and blood samples were prospectively collected from patients with medically complicated obesity. Patients were categorized, according to liver histology, into: (i) normal, (ii) simple steatosis (SS), (iii) non-alcoholic steatohepatitis (NASH) with fibrosis stage (FS) 0-1 and (iv) NASH with FS ≥ 2. A broad panel of potential biomarkers included DHEA-S, growth hormone (GH), homeostasis model assessment-insulin resistance (HOMA-IR), leptin, resistin, adiponectin and cytokeratin 18 (CK-18) fragments. RESULTS: We studied 160 patients (mean BMI 46.8 ± 8.2 kg/m(2) ). Liver biopsies demonstrated normal histology in 10%, SS in 45%, NASH with FS 0-1 in 37.5% and NASH with FS ≥ 2 in 7.5%. C-reactive protein, IL-6, GH, CK-18, adiponectin, HOMA-IR and quantitative insulin sensitivity check index (QUICKI) were significantly associated with NASH in univariate analysis, but overall predictivity of these parameters was low (AUC ROC = 0.62-0.68). In contrast, all patients with NASH with FS ≥ 2 had insulin resistance, as measured by QUICKI, and GH levels <0.45 ng/ml and all but one patient with NASH FS 2-3 had low DHEA levels (<123 µg/dl). CONCLUSIONS: Low serum levels of GH and DHEA are very common in patients with NASH with more advanced fibrosis. Other biomarkers, including CK-18 fragment levels, have predictivity characteristics that would be of low clinical utility for distinguishing patients with normal histology or SS from those with NASH. These findings demonstrate an endocrine profile associated with advanced fibrosis.

The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis.

The germline JAK2 46/1 haplotype has been associated with the development of JAK2(V617F)-positive as well as JAK2(V617F)-negative myeloproliferative neoplasms (MPNs). In this study we examined the role of the 46/1 haplotype in the etiology and clinical presentation of patients with splanchnic vein thrombosis (SVT), in which MPNs are the most prominent underlying etiological factor. The single-nucleotide polymorphism rs12343867, which tags 46/1, was genotyped in 199 SVT patients. The 46/1 haplotype was overrepresented in JAK2(V617F)-positive SVT patients compared with controls (P < .01). Prevalence of the 46/1 haplotype in JAK2(V617F)-negative SVT patients did not differ from prevalence in the controls. However, JAK2(V617F)-negative SVT patients with a proven MPN also exhibited an increased frequency of the 46/1 haplotype (P = .06). Interestingly, 46/1 was associated with increased erythropoiesis in JAK2(V617F)-negative SVT patients. We conclude that the 46/1 haplotype is associated with the development of JAK2(V617F)-positive SVT. In addition, our findings in JAK2(V617F)-negative SVT patients indicate an important role for the 46/1 haplotype in the etiology and diagnosis of SVT-related MPNs, independent of JAK2(V617F), that requires further exploration.

Fatty liver and liver transplantation.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are common complications of overnutrition and obesity. In the setting of worsening epidemics of obesity in developed and developing countries, the global prevalence and impact of NAFLD seems likely to increase. The large number of patients at risk will translate into major challenges for the liver transplant community, affecting donors and recipients. The comorbidities and hepatic effects of obesity and NAFLD present important new challenges in the management of donors and recipients. This article addresses some of these challenges.