Short-term and long-term risk factors in gastric cancer.

While in chronic diseases, such as diabetes, mortality rates slowly increases with age, in oncological series mortality usually changes dramatically during the follow-up, often in an unpredictable pattern. For instance, in gastric cancer mortality peaks in the first two years of follow-up and declines thereafter. Also several risk factors, such as TNM stage, largely affect mortality in the first years after surgery, while afterward their effect tends to fade. Temporal trends in mortality were compared between a gastric cancer series and a cohort of type 2 diabetic patients. For this purpose, 937 patients, undergoing curative gastrectomy with D1/D2/D3 lymphadenectomy for gastric cancer in three GIRCG (Gruppo Italiano Ricerca Cancro Gastrico = Italian Research Group for Gastric Cancer) centers, were compared with 7148 type 2 diabetic patients from the Verona Diabetes Study. In the early/advanced gastric cancer series, mortality from recurrence peaked to 200 deaths per 1000 person-years 1 year after gastrectomy and then declined, becoming lower than 40 deaths per 1000 person-years after 5 years and lower than 20 deaths after 8 years. Mortality peak occurred earlier in more advanced T and N tiers. At variance, in the Verona diabetic cohort overall mortality slowly increased during a 10-year follow-up, with ageing of the type 2 diabetic patients. Seasonal oscillations were also recorded, mortality being higher during winter than during summer. Also the most important prognostic factors presented a different temporal pattern in the two diseases: while the prognostic significance of T and N stage markedly decrease over time, differences in survival among patients treated with diet, oral hypoglycemic drugs or insulin were consistent throughout the follow-up. Time variations in prognostic significance of main risk factors, their impact on survival analysis and possible solutions were evaluated in another GIRCG series of 568 patients with advanced gastric cancer, undergoing curative gastrectomy with D2/D3 lymphadenectomy. Survival curves in the two different histotypes (intestinal and mixed/diffuse) were superimposed in the first three years of follow-up and diverged thereafter. Likewise, survival curves as a function of site (fundus vs body/antrum) started to diverge after the first year. On the contrary, survival curves differed among age classes from the very beginning, due to different post-operative mortality, which increased from 0.5% in patients aged 65-74 years to 9.9% in patients aged 75-91 years; this discrepancy later disappeared. Accordingly, the proportional hazards assumption of the Cox model was violated, as regards age, site and histology. To cope with this problem, multivariable survival analysis was performed by separately considering either the first two years of follow-up or subsequent years. Histology and site were significant predictors only after two years, while T and N, although significant both in the short-term and in the long-term, became less important in the second part of follow-up. Increasing age was associated with higher mortality in the first two years, but not thereafter. Splitting survival time when performing survival analysis allows to distinguish between short-term and long-term risk factors. Alternative statistical solutions could be to exclude post-operative mortality, to introduce in the model time-dependent covariates or to stratify on variables violating proportionality assumption.

Impact of reference category and number of traits in the cluster on risk of coronary heart disease in metabolic syndrome: prospective data from the Bruneck study.

BACKGROUND: We assessed the risk of coronary heart disease (CHD) in subjects with metabolic syndrome using different reference categories and focusing on the number of traits in the cluster. METHODS: For 15 years, we followed 840 subjects from the general population living in Bruneck, northeastern Italy, aged 40-79 years, without CHD at baseline. Metabolic syndrome was diagnosed at baseline using American Heart Association/National Heart, Lung, and Blood Institute criteria. Subjects with the syndrome were compared to subjects without, as well as to subjects without any metabolic abnormality, using Cox models adjusted for sex, age, smoking, and low-density lipoprotein-cholesterol. There were 89 incident CHD cases. RESULTS: In subjects with the metabolic syndrome, the risk of CHD was1.5-fold higher when subjects without the syndrome were the reference category. CHD risk, however, was 12.5-fold higher (95% confidence interval [CI], 1.7-92.7, P=0.014) when subjects without any metabolic abnormality composed the reference category. As compared to subjects with no abnormalities (who had a trivial number of CHD events), the risk increased from subjects with one (hazard ratio 7.6, 95% CI 1.0-56.5, P=0.047) to those with 2, 3, and 4/5 abnormalities (11.6, 1.6-84.9, P=0.016; 12.9, 1.7-96.0, P=0.013; and 10.1, 1.3-79.2, P=0.028), respectively. CONCLUSIONS: When compared to the reference category of people without any metabolic abnormality, those with the metabolic syndrome had high cardiovascular risk. However, in the Bruneck population, the risk of CHD seems to be similar in subjects having two or three to five clinical features of metabolic syndrome. Therefore, the clinical utility of identifying subjects with the syndrome using current diagnostic criteria remains uncertain and might be the focus of further specific studies.

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women.

OBJECTIVE: In hyperandrogenic women, hyperinsulinaemia amplifies 17 α-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects. DESIGN AND METHODS: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80  mU/m² × min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5  µg/h) was carried out. Serum cortisol, progesterone, 17 α-hydroxyprogesterone (17-OHP), 17 α-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion. RESULTS: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P < 0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5 α-reductase activity. CONCLUSIONS: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

Supervised walking groups to increase physical activity in type 2 diabetic patients.

OBJECTIVE: To evaluate the impact of an exercise program organized into supervised walking groups in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Fifty-nine diabetic subjects were randomized to a control group receiving standard lifestyle recommendations or an intervention group assigned to three supervised walking sessions per week and counseling. Changes in metabolic features, weight, 6-min walk test, prescription of antidiabetic medications, and overall physical activity were assessed. RESULTS: Functional capacity and overall physical activity were higher in the intervention group, whereas metabolic changes were not different between groups after 4 months. However, in subjects who attended at least 50% of scheduled walking sessions, changes in A1C and fasting glucose were greater than in control subjects. Discontinuation or reduction of antidiabetic drugs occurred in 33% of these patients versus 5% of control subjects (P<0.05). CONCLUSIONS: Supervised walking may be beneficial in diabetic subjects, but metabolic improvement requires adequate compliance.

Sustained regression of florid diabetic retinopathy in a patient with Donohue syndrome (leprechaunism).

PURPOSE: Leprechaunism is a rare congenital syndrome caused by mutations of the insulin receptor gene, transmitted in an autosomal recessive pattern. Insulin growth factor-1 (IGF-1) treatment can be a therapeutic option in this syndrome by its insulin-like effects. Nevertheless, it is of note that IGF-1 has also an angiogenic activity. METHODS: Fundus examination by ophthalmoscopy, fluorangiography, and laser treatment were performed. RESULTS: A 17-year-old girl with leprechaunism, under treatment with high doses of insulin, presented a florid diabetic retinopathy. The large neovascularization of the disk regressed after treatment with argon laser panretinal photocoagulation. Five years after treatment, the patient maintained good vision. CONCLUSIONS: This clinical case is of interest for 2 reasons: 1) the large retinal neovascularization was likely due to the high insulin dosages; 2) this is the first case in which a sustained regression of retinal neovascularization has been observed after laser treatment in leprechaunism.

Anaemia, independent of chronic kidney disease, predicts all-cause and cardiovascular mortality in type 2 diabetic patients.

OBJECTIVE: There is limited and controversial information on whether anaemia is a risk factor for cardiovascular mortality in type 2 diabetes, and whether this risk is modified by the presence of chronic kidney disease (CKD). We assessed the predictive role of lower hemoglobin concentrations on all-cause and cardiovascular mortality in a cohort of type 2 diabetic individuals. METHODS: The cohort included 1153 type 2 diabetic outpatients, who were followed for a mean period of 4.9 years. The independent association of anaemia (i.e., hemoglobin <120 g/l in women and <130 g/l in men) with all-cause and cardiovascular mortality was evaluated by Cox proportional hazards regression models and adjusted for several potential confounders, including kidney function measures. RESULTS: During follow-up, 166 (14.4%) patients died, 42.2% (n=70) of them from cardiovascular causes. In univariate analysis, anaemia was associated with increased risk of all-cause (hazard ratio HR 2.62, 95% confidence intervals 1.90-3.60, p<0.001) and cardiovascular mortality (HR 2.70, 1.67-4.37, p<0.001). After adjustment for age, sex, body mass index, smoking, hypertension, dyslipidemia, diabetes duration, hemoglobin A1c, medication use (hypoglycemic, anti-hypertensive, lipid-lowering and anti-platelet drugs) and kidney function measures, the association of anaemia with all-cause (adjusted HR 2.11, 1.32-3.35, p=0.002) and cardiovascular mortality (adjusted HR 2.23, 1.12-4.39, p=0.020) remained statistically significant. CONCLUSIONS: Anaemia is associated with increased risk of all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of the presence of CKD and other potential confounders. The advantage to treat anaemia in type 2 diabetes for reducing the risk of adverse cardiovascular outcomes remains to be demonstrated.

Body fat and insulin resistance independently predict increased serum C-reactive protein in hyperandrogenic women with polycystic ovary syndrome.

OBJECTIVE: Increased serum C-reactive protein (CRP), an independent predictor of coronary heart disease, was reported in women with polycystic ovary syndrome (PCOS). It remains unclear whether this finding is due to the association between PCOS and either insulin resistance, obesity, or androgen excess, which are all common features of this condition. The aims of this study were to assess whether increased serum CRP is a specific feature of PCOS and to investigate the mechanisms underlying this association. DESIGN AND METHODS: Serum high-sensitivity CRP (hs-CRP) was measured in 86 hyperandrogenic women (age 21.6+/-4.2 years, body mass index (BMI) 23.6+/-3.5 kg/m2), 50 with PCOS and 36 with idiopathic hyperandrogenism (HA). Thirty-five BMI-matched healthy women were also studied as controls. In these subjects, endocrine and metabolic profiles were assessed. In all hyperandrogenic subjects and 14 controls, insulin sensitivity was measured by the glucose clamp technique. Body fat was measured by bioelectrical impedance. RESULTS: Hs-CRP concentrations were higher in PCOS women (3.43+/-2.01 mg/l) than in HA subjects and healthy women (2.43+/-1.04, P<0.005; and 2.75+/-0.86 mg/l, P<0.05 respectively versus PCOS). In multiple regression analyses, increased serum hs-CRP was independently predicted by higher body fat and lower insulin sensitivity. However, in lean women, serum-free testosterone was an additional, negative, predictive variable. CONCLUSIONS: PCOS is accompanied by a low-grade chronic inflammation. Body fat appears the main determining factor of this finding, which is only partly explained by insulin resistance. At least in lean women, androgen excess per se seems to play an additional, possibly protective, role in this association.

Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients.

OBJECTIVE: There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals. RESEARCH DESIGN AND METHODS: The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders. RESULTS: During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12-1.27], P < 0.001) and cardiovascular (1.25 [1.16-1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01-1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not. CONCLUSIONS: Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.

Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

Relationship of serum gamma-glutamyltransferase to atherogenic dyslipidemia and glycemic control in type 2 diabetes.

We evaluated possible interactions between BMI and serum gamma-glutamyltransferase (GGT) concentration and their effects on the prevalence of poor glycemic control and common comorbidities of diabetes. We assessed whether the association of BMI with poor glycemic control, hypertension, atherogenic dyslipidemia (i.e., high triglycerides and/or low high-density lipoprotein (HDL) cholesterol), hypercholesterolemia, and hyperuricemia differed according to serum GGT concentration in a cohort of 3,633 type 2 diabetic individuals. The associations of BMI with different outcome measures were significant, but the associations varied remarkably by GGT concentration. As GGT concentration increased, the association of BMI with atherogenic dyslipidemia and glycemic control strengthened (P = 0.01 and 0.004 for interactions, respectively); in contrast, the association of BMI with hypertension, hypercholesterolemia, and hyperuricemia did not change substantially across GGT quartiles. For example, within the lowest GGT quartile, BMI was not associated with atherogenic dyslipidemia or poor glycemic control, whereas in the highest GGT quartile, the prevalence rates ranged from 62.3 to 74.7% for dyslipidemia and from 75.3 to 83% for poor glycemic control. The results remained unchanged after adjustment for sex, age, alcohol consumption, diabetes duration, and diabetes treatment. In conclusion, our findings show that BMI was associated with atherogenic dyslipidemia and poor glycemic control only when serum GGT activity was in its high-normal range. These findings suggest that obesity itself may not be a sufficient risk factor for atherogenic dyslipidemia or poor glycemic control in people with type 2 diabetes.

Variability of body weight, pulse pressure and glycaemia strongly predict total mortality in elderly type 2 diabetic patients. The Verona Diabetes Study.

BACKGROUND: Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long-term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients. METHODS: Fasting glycaemia, BMI and pulse pressure values were collected over a period of 3 years in 1 319 type 2 diabetic patients who were subsequently followed up for 10 years. For each patient, the means and the coefficients of variation of fasting glycaemia, BMI and pulse pressure were computed. The adverse impact of these risk factors on total mortality was assessed in patients aged < 65 years (n = 565) and in those aged > or = 65 years (n = 754), separately. RESULTS: During the 10 years of follow-up, 438 patients died. In younger diabetic patients, the means of fasting glycaemia [hazard ratio (HR) of III tertile versus I tertile = 2.11, 95% confidence interval (CI): 1.22-3.64], BMI (HR = 1.88, 1.12-3.14) and pulse pressure (HR = 2.36, 1.34-4.16) were independently associated with total mortality, while in older patients they were not. In contrast, the coefficients of variation of glycaemia (HR = 1.56, 1.17-2.08), BMI (HR = 1.34, 1.03-1.75) and pulse pressure (HR = 1.34, 1.03-1.74) independently predicted total mortality only in older patients. CONCLUSIONS: Our findings suggest that the variability of fasting glycaemia, body weight and blood pressure (BP) is independently associated with an increased risk of all-cause mortality in older type 2 diabetic patients. Future studies are required to confirm the reproducibility of our findings.

Prevalence of subclinical hypothyroidism in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Subclinical primary hypothyroidism is highly prevalent in the general population, especially in the elderly. However, the prevalence of subclinical primary hypothyroidism in persons with chronic kidney disease (CKD) not requiring chronic dialysis is not well defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Cross-sectional data from 3089 adult outpatients, who were consecutively referred by general practitioners for routine blood testing over the last two years, were analyzed. Glomerular filtration rate (GFR) was estimated by the abbreviated Modification of Diet in Renal Disease equation. Multivariable logistic regression was used to evaluate the independent association between prevalent subclinical primary hypothyroidism and estimated GFR. RESULTS: Among 3089 adult participants, 293 (9.5%) had subclinical primary hypothyroidism and 277 (9%) had an estimated GFR <60 ml/min per 1.73 m(2). The prevalence of subclinical primary hypothyroidism increased from 7% at an estimated GFR >or=90 ml/min per 1.73 m(2) to 17.9% at an estimated GFR <60 ml/min per 1.73 m(2) (P < 0.0001 for trend). Compared with participants with an estimated GFR >or=60 ml/min per 1.73 m(2), those with estimated GFR <60 ml/min per 1.73 m(2) had an increased odds of subclinical primary hypothyroidism after adjusting for age, gender, fasting plasma glucose, total cholesterol, and triglyceride concentrations. CONCLUSIONS: These findings suggest that subclinical primary hypothyroidism is a relatively common condition ( approximately 18%) among persons with CKD not requiring chronic dialysis, and it is independently associated with progressively lower estimated GFR in a large cohort of unselected outpatient adults.

Treating elderly people with diabetes and stages 3 and 4 chronic kidney disease.

Dedicated European and US clinical guidelines for type 2 diabetes in the elderly have been released, but they do not specifically address the issue of advanced chronic kidney disease (CKD) in older patients with diabetes. General clinical guidelines have been published on the treatment of patients with diabetic nephropathy (DN), but these address the issue of how to prevent progression and treat advanced DN without distinguishing between different age groups. Elderly patients with diabetes and stages 3 to 4 CKD have particular needs that differ from those of younger patients with the same conditions. This is mainly due to their frailty and shorter life expectancy. Differently tailored therapeutic strategies are needed, which may have less stringent targets; and the use of common drugs should be critically evaluated. The management agenda (metabolic control, low-protein diet, controlling BP, preventing progression of advanced DN, preventing cardiovascular outcomes) for these patients is discussed in light of the limits and perspectives of current guidelines. Intensive, simultaneous management of all items on the agenda may not be feasible for a proportion of older patients, and clinicians may have to give priority to reducing some risk factors rather than others, choosing between different therapies.

Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease.

It is unknown whether chronic kidney disease (CKD) is associated with nonalcoholic fatty liver disease among patients with type 2 diabetes. We followed 1760 outpatients with type 2 diabetes and normal or near-normal kidney function and without overt proteinuria for 6.5 yr for the occurrence of CKD (defined as overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m(2)). During follow-up, 547 participants developed incident CKD. Nonalcoholic fatty liver disease, diagnosed by liver ultrasound and exclusion of other common causes of chronic liver disease, was associated with a moderately increased risk for CKD (hazard ratio 1.69; 95% confidence interval 1.3 to 2.6; P < 0.001). Adjustments for gender, age, body mass index, waist circumference, BP, smoking, diabetes duration, glycosylated hemoglobin, lipids, baseline estimated GFR, microalbuminuria, and medications (hypoglycemic, lipid-lowering, antihypertensive, or antiplatelet drugs) did not appreciably attenuate this association (hazard ratio 1.49; 95% confidence interval 1.1 to 2.2; P < 0.01). In conclusion, our findings suggest that nonalcoholic fatty liver disease is associated with an increased incidence of CKD in individuals with type 2 diabetes, independent of numerous baseline confounding factors.

NASH predicts plasma inflammatory biomarkers independently of visceral fat in men.

We assessed the differential contribution of nonalcoholic steatohepatitis (NASH) and visceral adiposity to nontraditional cardiovascular risk biomarkers in adult men. We enrolled 45 consecutive, overweight, male patients with biopsy-proven NASH, 45 overweight male patients without ultrasound-diagnosed hepatic steatosis, and 45 healthy male volunteers. All participants were matched for age; NASH and overweight patients were also matched for BMI and visceral adiposity (as estimated by abdominal ultrasonography). Nontraditional cardiovascular risk biomarkers were measured in all participants. Plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity, and adiponectin were markedly different among the groups; the lowest values (the highest for adiponectin) were in nonobese healthy subjects, intermediate in overweight nonsteatotic patients, and the highest (the lowest for adiponectin) in those with biopsy-proven NASH. The marked differences in these cardiovascular risk biomarkers that were observed between overweight and NASH patients were only slightly weakened after adjustment for age, BMI, smoking, plasma triglycerides, and insulin resistance (IR) as assessed by homeostasis model assessment (HOMA). In multivariate regression analysis, NASH and visceral adiposity predicted cardiovascular risk biomarkers independently of potential confounders. In conclusion, our results suggest that NASH can predict a more atherogenic risk profile in a manner that is partly independent from the contribution of visceral adiposity in adult men.

Association of inflammation with anaemia in patients with chronic kidney disease not requiring chronic dialysis.

BACKGROUND: Anaemia associated with chronic kidney disease (CKD) has substantial public health importance. However, the association of haemoglobin concentrations with inflammation in the setting of decreased kidney function is not well established. METHODS: We analysed cross-sectional data from 7389 outpatient adults, who were referred by general practitioners for routine blood testing between June 2006 and June 2007. Glomerular filtration rate (eGFR) was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Multivariable linear regression analysis was used to identify factors independently associated with haemoglobin concentrations across eGFR categories as the main outcome. RESULTS: Of the 7389 participants included in the analytic cohort 2221 (30.1%) participants had eGFR >/=90 mL/min/m(2), 4310 (58.3%) 60-89 mL/min/m(2) and 858 (11.6%) <60 mL/min/m(2). There were significant, graded, increases in high sensitivity C-reactive protein (hs-CRP) and haemoglobin concentrations across eGFR categories independent of age, gender, plasma glucose and lipids (P < 0.0001 for trends). In the multivariable regression analysis, increased hs-CRP concentrations were independently associated with lower haemoglobin concentrations at different stages of eGFR (P < 0.0001 for all). Other independent predictors of lower haemoglobin were older age, female gender and lower eGFR. CONCLUSIONS: Our findings suggest that increased plasma hs-CRP concentrations are independently associated with anaemia in the setting of decreased kidney function in a large cohort of unselected adult outpatients.

Association between serum TSH, free T4 and serum liver enzyme activities in a large cohort of unselected outpatients.

OBJECTIVE: Although overt thyroid dysfunction is associated with some liver abnormalities, there is a dearth of information on liver function tests across thyroid function tests. We assessed the relationship between serum liver enzyme activity and thyroid function tests in a cohort of adult individuals. DESIGN, PATIENTS AND MEASUREMENTS: We performed a retrospective analysis on the database of the Clinical Chemistry Laboratory at the Verona University Hospital to retrieve results of serum liver enzyme activities [alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT)] and thyroid function tests (TSH and free T4), which have been performed on the whole cohort of outpatient adults consecutively referred by general practitioners for routine blood testing during the last 3 years. RESULTS: Cumulative results for serum GGT, ALT and TSH concentrations were retrieved for 10 292 (68.3% females) outpatient adults with a wide range of age and thyroid function tests. Subjects were categorized according to serum TSH concentrations as follows: < 0.1, 0.1-0.35, 0.36-4.5, 4.6-10 and >10 mU/l. Serum GGT and ALT concentrations increased steadily across the increasing TSH categories (P < 0.0001 for trends), ranging from mean values of 36 to 62 U/l for GGT and from 29 to 41 U/l for ALT, respectively. Similarly, there was a negative, graded, relationship between serum GGT and ALT concentrations and free T4 categories. The results did not change after adjusting for gender, age, lipids and fasting glucose concentrations. CONCLUSIONS: Our findings suggest that hypothyroidism and thyroid function tests, even within the reference range, are associated with slightly increased serum GGT and ALT activity concentrations.

Insulin effect on serum potassium and auto-inhibition of insulin secretion is intact in a patient with leprechaunism despite severe impairment of substrates metabolism.

BACKGROUND: The effect of insulin on glucose, protein metabolism, circulating fatty acids (FFA), potassium (K(+)) and C-peptide concentrations were investigated in a 12-year-old girl with leprechaunism. The mutations do not affect the insulin-receptor binding affinity and insulin-stimulated auto-phosphorylation of the receptor. METHODS: The subject was studied with a primed-continuous infusion of [6,6 - (2)H(2)] glucose and [1-(13)C] leucine during a basal period followed by two steps of insulin infusion (1 and 10 mU/kg/min) of 2 h each, during which plasma glucose level decreased from 131 to 115 and then to 95 mg/dL. RESULTS: Whole body glucose disposal was virtually unaffected by insulin, slightly decreasing from 21 micromol/kg/min in the basal period to 20 and to 19 micromol/kg/min during the two steps of insulin infusion, respectively. The endogenous leucine flux, an index of proteolysis, was completely insensitive to insulin, being 182, 189 and 180 micromol/kg/min, in the three periods, respectively. The FFA concentration (an indirect index of lipolysis) decreased from 1135 to 799 during step 1. During step 2 the FFA concentration rebounded to 917 micromol/L. The concentration of K(+) decreased from 4.2 to 3.2 mmol/L and an infusion of 20 mEq/h of KCl was necessary to prevent further hypokalemia (final value 3.3 mmol/l). The C-peptide concentration declined from 1.85 to 0.97 and then to 0.29 pmol/mL. CONCLUSIONS: The dissociation of control exerted by insulin on K+ uptake and on beta-cell secretion may rely on a differential expression and folding of the mutated receptors in the different insulin target tissues.