Liver fibrosis by FibroScan® independently of established cardiovascular risk parameters associates with macrovascular and microvascular complications in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM.

Prospective evaluation of metabolic syndrome and its features in a single-center series of hematopoietic stem cell transplantation recipients.

Available studies on metabolic syndrome (MS) after hematopoietic stem cell transplantation (HSCT) are retrospective with heterogeneous inclusion criteria, and little is known about the early post-transplant phase. In our prospective study, clinical and laboratory data were collected in 100 HSCT recipients, 48 allogeneic and 52 autologous, at baseline, at + 30, + 100 and + 360 days. At baseline, MS was observed in 24 patients, significantly associated with insulin resistance and leptin on multivariate analysis. At + 30, the diagnosis of MS was confirmed in 43 patients, significantly related to insulin resistance and allogeneic transplants. If the whole series was considered, patients with MS had significantly higher mortality from any cause. The baseline presence of any MS feature was a predictor of + 30 MS. Isolated occurrences of MS features were related to hyperleptinemia and hyperinsulinemia, except in the case of low HDL cholesterol, linked to adiponectin and resistin. Our data confirm that patients undergoing HSCT have a high prevalence of MS, with hyperleptinemia playing a major role. The early peak of new MS cases is primarily attributable to insulin resistance, notably but not exclusively immunosuppression-induced; the subsequent long-term increase in MS cases may be an effect of persistent adipokine imbalance.

Progressively invalidating orthostatic hypotension: A common symptom for a challenging diagnosis.

We discuss here an uncommon condition of neurogenic hypotension in the context of immunoglobulin light chain (amyloid light-chain) amyloidosis. The most serious feature was autonomic nervous system impairment, mainly characterized by severe refractory orthostatic hypotension, which became progressively invalidating, forcing the patient to bed. Moreover, since the systemic involvement of the disease, the patient presented also diarrhea, dysphagia, asthenia, peripheral edema because of gastrointestinal, and kidney dysfunction. Eventually, the massive myocardial depression and infiltration led to a fatal outcome.

Evolution of liver fibrosis in diabetic patients with NAFLD in a follow-up study: Hepatoprotective effects of sodium-glucose co-transporter-2 inhibitors.

BACKGROUND AND AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are at high risk of hepatic fibrosis. To prospectively evaluate changes in fibrosis in diabetic patients with NAFLD, predisposing factors and sodium glucose cotransporter 2 inhibitors (SGLT2i) influence. METHODS: 237 T2DM outpatients (mean age 67 ± 9 years, 54% male) were enrolled and re-evaluated after 52 ± 10 months. At baseline and follow-up NAFLD and liver fibrosis (LSM) were detected by ultrasonography and Fibroscan®. RESULTS: During follow-up an increase in LSM (6.0 ± 2.8 vs 5.8 ± 2.7 kPa, p = 0.02) and in the prescription of SGLT2i (20% vs 6%, p<0.001) was registered, despite stability of diabetic control. LSM worsened in 133(56%) subjects, 92 (39%) with worsening >10% from baseline. Patients with worsening versus non worsening of LSM had higher prevalence of increase in BMI during follow-up (45% vs 32%, p = 0.06) and lower SGLT2i prescription (15% vs 27%, p = 0.034). In multivariate analysis use of SGLT2-inhibitors at follow-up reduced the risk of LSM worsening (HR 0.34, 95% CI 0.13-0.88), even when considered>10% from baseline. CONCLUSIONS: A high prevalence of fibrosis progression was observed in diabetic subjects with NAFLD over a nearly 5-years follow up and SGLT2-inhibitors seem to reduce the risk of worsening of liver stiffness.

Central hyperthermia, brain hyperthermia and low hypothalamus temperature.

UNLABELLED: INTRODUCTION, PATIENTS AND METHODS: We measured brain temperature in a case of central hyperthermia. RESULTS: Brain temperature was increased except for hypothalamus that was colder. CONCLUSION: We suppose that central hyperthermia is driven by cold hypothalamus.

Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major.

With the optimization of transfusional and chelation regimens, beta-thalassemia has changed from a pediatric disease with poor life expectancy into a chronic disease. Bone demineralization is an important cause of morbidity in older patients; the etiology is multifactorial and partially unknown. We examined, cross-sectionally, 111 adult patients with beta-thalassemia major (66 females and 45 males, 32.6 ± 6 years) who were regularly transfused, sufficiently chelated and replaced for endocrine defects. Bone demineralization was detected in 92.7% of patients with different severity according to gender and site: osteopenia was the prominent finding at the femur, osteoporosis at the lumbar spine (p < 0.001), more evident in males. The femoral site was more influenced by biochemical and clinical factors; despite adequate replacement, the femoral T-score was lower in the hypogonadic group than in the eugonadic group (p = 0.047). A significant correlation was found between the bone mass and body mass index (BMI), alkaline phosphatase (ALP), and pre-transfusional Hb levels. The multivariate analysis indicated as significant regressors ALP, BMI and hypoparathyroidism (T-score, p = 0.005, 0.035, and 0.002; Z-score, 0.002, 0.009, and 0.003, respectively) at the femoral site; whereas, only ALP at the lumbar spine (p = 0.008 and 0.045 for T-and Z-scores, respectively). The statistical significance was reached more frequently by the T-score, while the Z-score seemed to be a less sensitive parameter. Despite best care facilities, bone demineralization in thalassemic patients remains a challenge. Further exploration of the relationships between bone loss and endocrine, biochemical and hematologic parameters is warranted to find effective measures to reduce the risk of fracture in this disease.

NAFLD fibrosis score (NFS) can be used in outpatient services to identify chronic vascular complications besides advanced liver fibrosis in type 2 diabetes.

We demonstrate in 351 diabetic patients with steatosis that NAFLD fibrosis score (NFS), a rapid and affordable score to diagnose hepatic fibrosis, identifies patients at higher risk of advanced fibrosis and vascular diabetic complications (especially peripheral neuropathy), pointing NFS as a first-line vascular and hepatic screening in diabetic patients.

Subclinical cerebrovascular disease in NAFLD without overt risk factors for atherosclerosis.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease is recognized not only as part of the metabolic syndrome but also as an independent predictor of cardiovascular disease. METHODS: In this study, NMR spectroscopy method, together with perfusion techniques, was used to detect subclinical brain vascular damage in subjects with NAFLD without overt atherosclerosis risk factors (i.e. hypertension, diabetes, hypercholesterolemia, obesity). RESULTS: The results suggest that subjects with histologically proven NAFLD have a reduced cerebral perfusion (CBFr) confined to limited brain areas, i.e., left semioval center and posterior cingulate cortex. No statistically significant differences in CBFr values were found, dividing the NAFLD cohort into subgroups, considering NAS score, presence/absence of NASH/fibrosis, and degree of steatosis. CONCLUSIONS: Our data suggest that NAFLD per se may be involved in cerebral atherosclerotic disease. It will be interesting to draw longitudinal studies to determine whether these changes could evolve in more serious cerebral injury.

Extrapulmonary tuberculosis: an unusual presentation in an immunocompetent patient.

A 50-year-old Brazilian woman was admitted to our department because of pelvic pain irradiated to the lower left limb, ipsilateral ankle swelling and progressive weight loss. Doppler ultrasound demonstrated deep venous femoropopliteal thrombosis, while a thorax-abdomen CT scan showed multiple solid hypodense pulmonary lesions, a large hypodense lesion in the iliopsoas muscles bilaterally and a complex cystoid lesion at the hepatic hilum. These findings were better characterised as active inflammatory colliquated lymph nodes by positron emission tomography and echo-guided percutaneous fine-needle aspiration of the left iliopsoas abscessual lesion finally allowed the diagnosis of tubercular infection with positive cultures for Mycobacterium tuberculosis complex.

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.

Bone disease in adult patients with ß-thalassaemia major: a case-control study.

Despite the extraordinary improvements carried out in diagnostic and therapeutic management of thalassaemia major over the past few decades, bone demineralization is still a common finding, even in optimally treated patients. The relationships between bone density and several clinical characteristics or hematological markers have been described, and many factors contributing to demineralization have been identified; among them endocrine complications seem to play an important role. Nevertheless, the complex etiological mechanisms of this heterogeneous osteopathy still remains incompletely clarified. While previous studies focused on the characteristics of thalassaemic patients affected from bone demineralization, we conducted a case-control study focused on thalassaemic patients free from bone disease, aimed to detect the distinctive characteristics and any possible protective feature. Among a large cohort of 150 adult patients with ß-thalassaemia major, we enrolled 20 patients with normal bone mineralization and 20 patients with osteoporosis matched for gender, BMI, age at first transfusion, serum ferritin and pre-transfusional hemoglobin (Hb) levels. The differences in demographic, clinical and endocrinological profiles were investigated, correcting for physical and hematological features known as confounding variables. The comparison of the two groups for biochemical parameters and endocrine function showed a protective role of normal gonadic function and IGF-1 levels against osteoporosis, and a similar influence of hypoparathyroidism. Treatment-corrected hypothyroidism and diabetes seemed not to affect bone mineralization. In conclusion, from a different perspective our results corroborate the role of endocrinopathies in thalassaemic osteopathy, and once again underline the crucial importance of an early and multi-disciplinary intervention in preventing bone complications in thalassaemic patients.

Metabolic syndrome in patients with hematological diseases.

The term metabolic syndrome (MS) defines a clustering of cardiovascular risk factors, formerly known as syndrome X. There is some debate about the diagnostic criteria; but the most widely accepted framework is that defined by the National Cholesterol Education Program Adult Treatment Panel III, which requires the simultaneous occurrence of at least three of abdominal obesity, arterial hypertension, hyperglycemia, hypertrigliceridemia and low high-density lipoprotein cholesterol (HDL-C). The prevalence of MS increases with age and varies depending on genetic factors. An abnormally high prevalence has been observed in patients with heterogeneous conditions, such as solid organ transplant recipients, AIDS patients and long-term cancer survivors. As some of the pathogenetic factors possibly involved include cyclosporine A, corticosteroids and cancer chemoradiotherapy, it is possible that MS may also be a complication in hematological patients. Some of the characteristics of MS have been reported with a certain frequency in thalassemia patients, and are mainly attributed to iron overload. Impaired hemostasis is a feature of MS rather than a factor predisposing to its development. In oncohematology, an abnormally high prevalence of MS features has been observed in survivors of pediatric acute lymphoblastic leukemia. In addition to corticosteroid- and cancer therapy-related hypogonadism, hypothyroidism and defective growth hormone incretion are other factors related to the development of MS. Moreover, the highest frequency of MS is observed in hematopoietic stem cell transplantation (HSCT) recipients. Pediatric patients and allogeneic HSCT recipients have been the subject of foremost investigations; but adult patients and autologous HSCT recipients have also been studied more recently. A wide range of factors may contribute to the development of MS in HSCT recipients. Unfortunately, the real entity of the problem is far from clear because of the retrospective design of the studies, the limited size of their populations and their heterogeneous selection criteria, thus making it difficult to determine whether MS is a transient and possibly reversible phenomenon or a true late effect of the procedure.

Unusual presentation in a case of primary hyperparathyroidism.

This report describes a case of classic severe primary hyperparathyroidism (PH) with clinical presentation that is very infrequent nowadays, which was osteitis fibrosa cystica. As bone scintigraphy demonstrated multiple areas of increasing uptake associated with hypercalcemia, a thorough investigation was conducted to exclude the neoplasms which most frequently are responsible for bone secondarisms. A fludeoxyglucose (FDG) positron emission tomography/CT demonstrated diffuse and multiple foci of increased FDG uptake and a focal uptake at the left thyroid region. Parathyroid function was studied, revealing unexpectedly high parathyroid hormone (PTH) levels. Further tests confirmed the diagnosis of PH and localized a parathyroid adenoma in the lower left side.

Neuropsychological functions and metabolic aspects in subclinical hypothyroidism: the effects of L-thyroxine.

Thyroid hypofunction is a slowly progressing graded phenomenon [Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43(1):55-68]; subclinical forms (SCH) often represent a laboratory diagnosis in apparently asymptomatic patients. In the absence of adequate parameters for thyroid hormone action in tissues, the level of TSH increase corresponding to negative effects remains unsettled. We studied a wide range of physiological processes in a strictly selected population of 38 female patients (56.4+/-12.6 years) with minor forms of SCH (TSH 6.6+/-1.8 mIU/L), after exclusion of neurological, psychiatric and somatic disorders or confounding conditions. The investigations, performed at admission and after 6 months of l-thyroxine (LT4) treatment, included metabolic evaluation, health status perception and an extensive battery of neuropsychological tests and psychological rating scales. Lipid metabolism improved after LT4 (total cholesterol: 231.9+/-49.6 mg/dl pre- vs 221.0+/-40.0 mg/dl post-treatment; LDL cholesterol: 183.1+/-62.9 vs 162.7+/-53.7 mg/dl; apolipoprotein A1: 183.5+/-64.5 vs 160.9+/-50.3 mg/dl; p<0.05 for all comparisons), while glucose metabolism was unchanged. Health status perception was favourably influenced by the treatment (total SF-36 score 97.8+/-18.4 pre- vs 108.5+/-14.8 post-, p<0.0001); in a matched control group with euthyroid goiter, tested to examine the effects of medical care in the absence of treatment, no significant differences were found in the SF-36 scores at admission and after 6 months (109.3+/-15.1 vs 109+/-14.2, p=0.9). Attention performance improved after LT4; HRSD and HRSA scores did not significantly change, but negative correlations were found between FT3 levels and affective scores at admission, and between the post-treatment changes of affective scores and of FT3. In our study subtle disturbances of health status perception, attention and lipid metabolism associated to SCH of mildest degrees were reverted by LT4 replacement, reinforcing reports of unfavourable consequences of marginal thyroid disease.

Is affluence a risk factor for bronchial asthma and type 1 diabetes?

In the last decades, an increase in bronchial asthma and type 1 diabetes occurrence has been observed in affluent countries, and a positive association between the two disorders has been demonstrated at the population level. This association could be explained by common risk factors predisposing to both disorders. Altered environmental and lifestyle conditions, possibly related to socio-economic status, might account for the rising trend of the two disorders. To test this hypothesis, we calculated the correlation between the occurrence of type 1 diabetes and asthma, the gross national product (GNP) and the infant mortality rate, in several European and extra-European countries. GNP was positively correlated with the incidence of type 1 diabetes and with symptoms of asthma in European (r(sp): 0.53 and 0.69; p = 0.001 and p < 0.0001, respectively) and extra-European countries (r(sp): 0.44 and 0.46; p = 0.04 for both diseases). Infant mortality rate was inversely correlated with GNP and with the occurrences of the two diseases in Europe (r(sp): -0.66, p < 0.0001 for type 1 diabetes; r(sp):- 0.51, p = 0.01 for asthma). In extra-European countries, a significant relationship was found between infant mortality and asthma (r(sp): -0.46; p = 0.03); a trend towards a negative correlation between infant mortality and type 1 diabetes was also found, although no statistical significance was reached (r(sp): -0.21; p = 0.31). This analysis indicates that type 1 diabetes and asthma are positively associated with the GNP at the population level. Similarly, countries with low infant mortality rates tend to have a higher incidence of these immune-mediated diseases. Although GNP reflects many societal and lifestyle differences, it is notable that a high socio-economic status implies a reduced or delayed exposure to infectious agents. The reduced pressure of infectious agents on the immune system throughout life might contribute to increase the susceptibility to bronchial asthma and type 1 diabetes.