Serum paraoxonase-1 activity is inversely related to free thyroxine in euthyroid subjects: The PREVEND Cohort Study.

BACKGROUND: Low-normal thyroid function within the euthyroid range has been suggested to enhance atherosclerosis susceptibility. Paraoxonase-1 (PON-1) may protect against atherosclerotic cardiovascular disease development by attenuating oxidative stress. We evaluated relationships of PON-1 with thyroid stimulating hormone (TSH), free T4 , free T3 , lipids and apolipoprotein (apo)A-I in euthyroid subjects, and assessed whether such relationships are modified in the context of the metabolic syndrome (MetS). MATERIALS AND METHODS: Serum PON-1 activity (arylesterase activity), TSH, free T4 , free T3 , lipids and apoA-I was measured in 2206 euthyroid subjects (aged 28-75 years; 1138 men (age 49 ± 13 years) and 1068 women (age 46 ± 12 years), recruited from the general population (PREVEND cohort). RESULTS: In age- and sex-adjusted analysis, PON-1 activity (divided into tertiles) was positively related to TSH (ß = -0.045, P = .036) and inversely to free T4 (ß = -0.042, P = .050) but not to free T3 (ß = -0.027, P = .20). PON-1 activity was positively related to total cholesterol, non-HDL cholesterol and triglycerides, as well as to HDL cholesterol and apoA-I (P < .01 to <.001). The inverse relationship of PON-1 activity with free T4 remained present after adjustment for lipids and other potential confounders (ß = -0.066, P = .002), but the positive relationship with TSH lost significance (ß = 0.034, P = .11). The inverse relationship of PON-1 activity with free T4 was not different in subjects with vs without MetS (P = .94), nor modified by the presence of its individual components (P ≥ .22 for each). CONCLUSIONS: Serum PON-1 activity is inversely associated with free T4 in euthyroid subjects, suggesting that low-normal thyroid function may affect PON-1 regulation.

Increased leptin/adiponectin ratio relates to low-normal thyroid function in metabolic syndrome.

BACKGROUND: Low-normal thyroid function within the euthyroid range may contribute to increased atherosclerosis susceptibility. The leptin/adiponectin (L/A) ratio is associated with cardiovascular disease and reflects adipose tissue dysfunction. Relationships of the L/A ratio with low-normal thyroid function are unknown. METHODS: Relationships of thyroid stimulating hormone (TSH) and free thyroxine (free T4) with leptin, adiponectin and the L/A ratio in euthyroid subjects were documented in 67 fasting subjects with metabolic syndrome (Mets) and 86 euthyroid subjects without MetS (TSH and free T4 levels within the institutional reference range). RESULTS: Neither plasma leptin nor adiponectin was significantly correlated with TSH or free T4 in subjects with and without MetS. In the whole group, high sensitivity C-reactive protein (hs-CRP) was positively correlated with the L/A ratio (r = 0.485, P < 0.001). Notably, the L/A ratio was positively correlated with TSH in subjects with MetS (r = 0.252, P = 0.040) but not in subjects without MetS (r = -0.068, P = 0.54; interaction term, P = 0.027). In MetS subjects, the L/A ratio remained positively related with TSH after adjustment for age, sex, diabetes status, hs-CRP and the use of antihypertensive and glucose lowering medication (ß = 0.283, P = 0.018), as well as after adjustment for individual MetS components (ß = 0.294, P = 0.020). CONCLUSIONS: In the context of MetS, a higher TSH within the euthyroid range confers an increased L/A ratio, a proposed marker of atherosclerosis susceptibility and adipocyte dysfunction.

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.

Pre-ß-HDL formation relates to high-normal free thyroxine in type 2 diabetes mellitus.

OBJECTIVES: Low-normal thyroid function within the euthyroid range may influence plasma lipoprotein levels. Associations between variation in thyroid function and pre-ß-high density lipoproteins (pre-ß-HDL), i.e. lipid-poor or lipid free HDL particles that act as initial acceptor of cell-derived cholesterol, are unknown. We determined relationships of plasma pre-ß-HDL with thyroid function in euthyroid subjects with and without type 2 diabetes mellitus (T2DM). DESIGN AND SUBJECTS: TSH, free T4, plasma (apo)lipoproteins, pre-ß-HDL, pre-ß-HDL formation (pre-ß-HDL generation during incubation with lecithin:cholesterol acyltransferase being inhibited) and phospholipid transfer protein (PLTP) activity were measured in fasting plasma from 72 T2DM and 82 non-diabetic subjects. RESULTS: TSH was similar and free T4 was slightly higher (P < 0.05) in T2DM vs. non-diabetic subjects. HDL cholesterol and apoA-I were lower, whereas pre-ß-HDL (expressed as % of apoA-I), triglycerides and PLTP activity were higher in T2DM (P < 0.05 to P < 0.001). In T2DM, pre-ß-HDL formation (in apoA-I concentration and in % of apoA-I) was positively related to free T4, PLTP activity, total cholesterol and triglycerides (P < 0.05 for each). Multivariable linear regression analyses, adjusted for age, sex, PLTP activity, total cholesterol and triglycerides, demonstrated that pre-ß-HDL formation was positively related to free T4 (in apoA-I concentration: ß = 0.278, P = 0.014; in % of apoA-I: ß = 0.343, P = 0.003) in T2DM, but not in non-diabetic subjects (both P > 0.30; interaction terms: both P < 0.05). CONCLUSIONS: Variations in thyroid function within the euthyroid range may influence the metabolism of pre-ß-HDL in T2DM.

Low-normal thyroid function and novel cardiometabolic biomarkers.

The concept is emerging that low-normal thyroid function, i.e., either higher thyroid-stimulating hormone or lower free thyroxine levels within the euthyroid reference range, could contribute to the development of atherosclerotic cardiovascular disease. It is possible that adverse effects of low-normal thyroid function on cardiovascular outcome may be particularly relevant for specific populations, such as younger people and subjects with high cardiovascular risk. Low-normal thyroid function probably relates to modest increases in plasma total cholesterol, low density lipoprotein cholesterol, triglycerides and insulin resistance, but effects on high density lipoprotein (HDL) cholesterol and non-alcoholic fatty liver disease are inconsistent. Low-normal thyroid function may enhance plasma cholesteryl ester transfer, and contribute to an impaired ability of HDL to inhibit oxidative modification of LDL, reflecting pro-atherogenic alterations in lipoprotein metabolism and HDL function, respectively. Low-normal thyroid function also confers lower levels of bilirubin, a strong natural anti-oxidant. Remarkably, all these effects of low-normal thyroid functional status appear to be more outspoken in the context of chronic hyperglycemia and/or insulin resistance. Collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures.

Low-normal thyroid function and the pathogenesis of common cardio-metabolic disorders.

BACKGROUND: Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and PubMed up to November 2014. RESULTS: Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far. CONCLUSIONS: Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far.

[Paraneoplastic pemphigus in a patient with non-Hodgkin lymphoma]. / Paraneoplastische pemfigus bij een patiënt met een non-hodgkinlymfoom.

A 53-year-old man with non-Hodgkin lymphoma developed red, flaky skin, which was initially suggestive of a drug reaction. He also had pneumonia, for which he was admitted for antibiotic treatment. During admission the skin picture changed and blisters and erosions appeared on his body. Skin biopsy and immunological examination led to the diagnosis of paraneoplastic pemphigus (PNP). The patient died five months after the diagnosis of PNP due to PNP pneumonia. PNP is a rare and often aggressive bullous disease with an autoimmune pathogenesis, associated with underlying lymphoproliferative disease. It is characterised by a polymorphous skin rash, painful mucosal erosions, sometimes with respiratory complications due to bronchiolitis obliterans. Diagnosis is based on clinical, histological and immunological findings. The prognosis is unfavourable; death occurs in 90 percent of patients. This case illustrates the importance of histology, immunofluorescence microscopy, and immunoserology in misunderstood skin disorders in patients with lymphoproliferative disease.