Eline H. van den Berg

Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort

Background & aims Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date. Methods Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729), a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI)≥60. Exclusion criteria were age <18 years, immigrants, missing data to assess FLI and metabolic syndrome, excessive alcohol use, previous-diagnosed hepatitis or cirrhosis and non-fasting blood sampling. Results Out of 37,496 included participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a FLI≥60. Individuals with a FLI≥60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P<0.0001). Participants with a FLI≥60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%), metabolic syndrome (54.2% vs. 6.2%), impaired renal function (20.1% vs. 8.7%) and cardiovascular disease (4.6% vs. 1.6%) (all P<0.0001). Multivariable logistic analysis showed that smoking, hemoglobin, leucocytes, c-reactive protein, platelets, alanine aminotransferase, alkaline phosphatase, albumin, impaired renal function (OR 1.27, 95%CI 1.15–1.41), metabolic syndrome (OR 11.89, 95%CI 11.03–12.82) and its individual components hyperglycemia (OR 2.53, 95%CI 2.34–2.72), hypertension (OR 1.89, 95%CI 1.77–2.01) and reduced high-density lipoprotein cholesterol (OR 3.44, 95%CI 3.22–3.68) were independently associated with suspected non-alcoholic fatty liver disease (all P<0.0001). Conclusion Twenty-two percent (22.0%) of the population in the North of the Netherlands is suspected to suffer from non-alcoholic fatty liver disease, coinciding with a significant increased risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease and impaired renal function.

Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: The Lifelines Cohort Study

OBJECTIVE Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects. METHODS The study was conducted in the Lifelines Cohort Study, a population-based cohort study of participants living in the North of the Netherlands. Only euthyroid subjects (thyroid-stimulating hormone (TSH) 0.5-4.0mU/L, free thyroxine (FT4) 11-19.5pmol/L and free triiodothyronine (FT3) 4.4-6.7pmol/L) older than 18years were included. Exclusion criteria were participants with excessive alcohol use, known hepatitis or cirrhosis, liver functions ≥ three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid or glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI≥60 was categorized as NAFLD. A P<0.01 was considered significant. RESULTS FLI≥60 was found in 4274 (21.1%) of 20,289 individuals (62.1% male, median age 46years) with increased prevalence of MetS (P<0.0001). In age- and sex-adjusted analysis FLI≥60 was independently associated with a higher FT3 (OR 1.34, 95% CI 1.29-1.39, per SD increment, P<0.0001) and a lower FT4 (OR 0.73, 95% CI 0.70-0.75, P<0.0001) but not by TSH. The strongest association was found for the FT3/FT4 ratio (OR 1.44, 95% CI 1.39-1.49, P<0.0001). These associations remained similar after additional adjustment for the presence of MetS. In subjects with enlarged waist circumference, TSH and FT4 were lower while FT3 was higher, resulting in an increased FT3/FT4 ratio (P<0.0001). CONCLUSIONS Euthyroid subjects with suspected NAFLD are characterized by higher FT3, lower FT4 and higher FT3/FT4 ratio, probably consequent to central obesity.

Low normal thyroid function attenuates serum alanine aminotransferase elevations in the context of metabolic syndrome and insulin resistance in white people

OBJECTIVES Thyroid hormones play a key role in hepatic lipid metabolism. Although hypothyroidism is associated with increased prevalence of non-alcoholic fatty liver disease (NAFLD), the relationship of NAFLD with low normal thyroid function is unclear. We tested the association of serum alanine transferase (ALT), as a surrogate of NAFLD, with variations in thyroid function within the normal range. DESIGN AND METHODS Thyroid stimulating hormone (TSH), free T4, ALT, insulin resistance (homeostasis model assessment (HOMA-IR)) and adiponectin were measured in 82 non-diabetic white subjects with TSH and free thyroxine (free T4) levels within the reference range. Nineteen participants were classified with metabolic syndrome (MetS). RESULTS ALT was higher in MetS subjects (p<0.05), coinciding increased HOMA-IR (p<0.001). TSH and free T4 levels were not different in subjects with and without MetS. In all subjects combined, ALT was correlated positively with HOMA-IR and inversely with adiponectin (both p<0.001). Remarkably, ALT was correlated inversely with TSH in subjects with MetS (r=-0.642, p=0.003), but not in subjects without MetS (r=-0.132, p=0.30). Accordingly, in age- and sex-adjusted multivariable linear regression analysis the relationship of ALT with TSH was modified by the presence of MetS (interaction: β=-0.244, p=0.026), and likewise by HOMA-IR (interaction: β=-0.203, p=0.037). TSH also interacted with adiponectin on ALT (interaction: β=0.204, p=0.037). CONCLUSIONS Low normal thyroid function may attenuate ALT elevations in the context of MetS and insulin resistance. It is conceivable that effect modification of low normal thyroid function on adiponectin-mediated pathways may be involved.

High prevalence of apolipoprotein B dyslipoproteinemias in non-alcoholic fatty liver disease : The lifelines cohort study

OBJECTIVE Cardiovascular disease (CVD) is a major adverse consequence of non-alcoholic fatty liver disease (NAFLD). The association of NAFLD with various apolipoprotein B (apoB) dyslipoproteinemias is unclear. We determined the prevalence of specific apoB dyslipoproteinemias in subjects with suspected NAFLD. METHODS This study was conducted among 22,865 fasting adults living in the northern part of the Netherlands (Lifelines Cohort Study). Six apoB dyslipoproteinemias were defined using an algorithm derived from apoB, total cholesterol and triglycerides. NAFLD was defined as Fatty Liver Index (FLI) ≥60. Advanced hepatic fibrosis was defined as NAFLD fibrosis score (NFS) ≥0.676. RESULTS 4790 participants (20.9%) had an FLI≥60. NAFLD subjects were older, more likely to be men, more obese and more often had diabetes and metabolic syndrome (P<0.001 for each). Among NAFLD subjects, any apoB dyslipoproteinemia was present in 61.5% vs. 16.5% in subjects without NAFLD (P<0.001). Elevated chylomicrons were not observed in NAFLD. In univariate analysis, NAFLD was associated with a higher prevalence of each apoB dyslipoproteinemia vs. subjects with an FLI<60 (P<0.001), except for low density lipoprotein (LDL) dyslipoproteinemia. Additionally, each apoB dyslipoproteinemia was independently associated with NAFLD in age- and sex-adjusted logistic regression analysis, including the apoB dyslipoproteinemias together (P<0.001). The prevalence of apoB dyslipoproteinemias was not altered in subjects with NFS ≥0.676. CONCLUSIONS NAFLD rather than advanced hepatic fibrosis is independently associated with increased prevalence of chylomicrons+very low-density lipoproteins (VLDL) remnants, VLDL, LDL and VLDL+LDL dyslipoproteinemias. ApoB dyslipoproteinemias may contribute to increased CVD risk associated with NAFLD.

Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity

BACKGROUND Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis. AIM Investigate short-term complications in patients transplanted for NASH cirrhosis. METHODS Single center retrospective cohort study including patients >18years who underwent LT between 2009-2015. Exclusion criteria were LT for acute liver failure and non-cirrhotic disease. Post-operative complications and severity within 90-days were classified using the Clavien-Dindo classification of surgical complications and comprehensive complication index (CCI). P<0.05 was significant. RESULTS Out of 169 eligible patients, 34 patients (20.1%) were transplanted for NASH cirrhosis. These patients were significantly older (59.2 vs. 54.8 years, P=0.01), more obese (61.8% vs. 8.1%, P<0.01), had more diabetes mellitus (73.5% vs. 20%, P<0.01), metabolic syndrome (83.3% vs. 37.8%, P<0.01) and cardiovascular disease (29.4% vs. 11.1%, P<0.01). More grade 1 complications (OR 1.64, 95%CI 1.03-2.63, P=0.04) and more grade 2 urogenital infections (OR 3.4, 95%CI 1.1-10.6, P=0.03) were found. Major complications, CCI, 90-day mortality and graft survival were similar. CONCLUSION Despite significantly increased comorbidities in patients transplanted for NASH cirrhosis, major morbidity, mortality and graft survival after 90days were comparable to patients transplanted for other indications.

Radiological Position and Clinical Outcome of Preoperative Self-Expanding Metal Stents for Obstructing Colonic Cancer: A Single-Centre Cohort Study.

Background: Preoperative placement of self-expanding metal stents is used in patients with obstructing colon carcinoma to prevent an emergency operation. The perceived benefits remain the subject of discussion. The data-evaluating function and complications of stents in relation to radiological position are limited. Methods: Patients receiving a preoperative stent between 2003 and 2013 were retrospectively analysed in this single-centre study. We analysed radiological deployment, eccentricity and angulation of the stent directly after placement. Endpoints were clinical success (resolution of ileus), complications needing non-elective surgery (blow-out, perforation, persistent ileus, dislocation) and other complications (bleeding, infiltrate). Associations were corrected for other potential influences. Results: Eighty-two patients were included. In 22 patients (26.8%), the stent was placed proximal to the splenic flexure. Clinical success was present in 85.4%. Twenty-two patients (26.8%) had a complication of which 16 (19.5%) underwent urgent surgery for insufficient functioning of the stent; there were two blow-outs (2.4%). A more symmetrically placed stent was associated with clinical success (p = 0.042), with large overlap between groups. However, no association was found with non-elective surgery or complications. Also, angulation and deployment were unassociated with these outcomes. Conclusions: We could not establish an association between symmetry, angulation or deployment of self-expandable colonic stents with clinical success and complications.

Plasma lecithin:cholesterol acyltransferase and phospholipid transfer protein activity independently associate with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition which contributes to atherogenic apolipoprotein B dyslipoproteinemias. Lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) are both synthesized by the liver and are important in lipid metabolism. Here, we interrogated the impact of NAFLD on plasma LCAT and PLTP activities.

Cholesterol efflux capacity is impaired in subjects with an elevated Fatty Liver Index, a proxy of non-alcoholic fatty liver disease

BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) parallels the obesity epidemic and associates with components of the metabolic syndrome (MetS). Cholesterol efflux capacity (CEC) represents a key metric of high density lipoprotein (HDL) function which may predict atherosclerotic cardiovascular disease (CVD). Here we assessed the relationship of CEC with NAFLD. METHODS CEC was determined from THP-1 macrophage foam cells towards apolipoprotein B-depleted plasma among 639 subjects (454 men; 36 subjects with type 2 diabetes mellitus (T2D); 226 with MetS), participating in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. RESULTS 372 participants had a FLI ≥60, which coincided with an increased prevalence of T2D and MetS (p = 0.009 and p < 0.001), as well as with central obesity, higher systolic blood pressure, glucose, total cholesterol, triglycerides and high sensitivity C-reactive protein (hsCRP), and decreased HDL cholesterol (p < 0.001 for each). In multivariable linear regression analyses, CEC was inversely associated with an elevated FLI, when taking account of clinical covariates (fully adjusted model: β = -0.091, p = 0.043), and alternatively when taking account of systolic blood pressure, waist/hip ratio, glucose, HDL cholesterol, triglycerides and hsCRP (fully adjusted model: β = -0.103, p = 0.034). CONCLUSIONS Impaired CEC is associated with NAFLD, as inferred from a FLI≥60, even when taking account of lower HDL cholesterol and enhanced low-grade chronic inflammation. Reduced CEC could contribute to accelerated CVD in NAFLD patients.

Outcomes of Self-Expanding Metal Stents in Malignant Colonic Obstruction are Independent of Location or Length of the Stenosis : Results of a Retrospective, Single-Center Series

Aim: To evaluate the length and location of stenosis in the colon as predictors of technical and clinical outcomes of stent placement in patients presenting with obstructive colorectal cancer. Methods: A prospective single-center cohort study of patients treated with a colonic stent for malignant obstruction, regardless of stenosis length or location. Stenosis length was assessed globally on the appropriate CT slice as well as by 3D CT reconstruction. We analyzed whether outcomes were different in patients with a right sided-tumor and/or a stenosis >4 cm long. Results: One hundred forty-one patients were evaluated, 63 with a stenosis >4 cm, 48 with a stenosis proximal to the splenic flexure. Technical failure (n = 9) was mainly caused because of looping or due to the difficulty in engaging the stenosis precluding analysis of the relation between the stenosis length and technical success. Both measurement methods showed good agreement. Clinical outcomes were not associated with stenosis length or location. Conclusion: Clinical outcomes of stenting did not differ between groups regardless of stenosis length or location. Measuring stenosis length more precisely using 3D CT reconstructions is not of help.