Quality of Life in Cushing's disease: A long term issue?

The purpose of this review is to describe how quality of life (QoL) is impaired in patients with hypercortisolism due to Cushing's syndrome of any aetiology, including pituitary-dependent Cushing's disease. It is worse in active disease, but improvement after successful therapy is often incomplete, due to persistent physical and psychological co-morbidities, even years after endocrine “cure”. Physical symptoms like extreme fatigability, central obesity with limb atrophy, hypertension, fractures, and different skin abnormalities severely impair the affected patients’ everyday life. Psychological and cognitive problems like bad memory, difficulties to concentrate and emotional distress, often associated with anxiety and depression, make it difficult for many patients to overcome the aftermath of treated Cushing's syndrome. Recent studies have shown diffuse structural abnormalities in the central nervous system during active hypercortisolism, thought to be related to the wide distribution of glucocorticoid receptors throughout the brain. Even though they improve after treatment, normalization is often not complete. Shortening the exposure to active Cushing's syndrome by reducing the often long delay to diagnosis and promptly receiving effective treatment is highly desirable, together with preparing the patient for the difficult periods, especially after surgery. In this way they are prepared for the impairments they perceive in every day life, and live with the hope of later improvement, which can be therapeutic in many instances.     

Aspecific ileitis: Crohn’s disease or not Crohn’s disease? A prospective study

Purpose

It is not clear whether aspecific ileitis may represent an early manifestation or a milder variant of Crohn’s disease or not. The aim of this study was to evaluate the clinical outcomes of aspecific ileitis.

Methods

Subjects with at least one of the following signs at retrograde ileoscopy: erythema, nodularity, aftae, erosions, and ulcers were considered. They should not have had defined gastrointestinal disease, biochemical signs of inflammation, use of drugs, celiac disease, and intestinal infectious disease.

Results

We enrolled 51 subjects (22 men), mean age (± SD) at colonoscopy of 41.1 ± 13.1 years. Indications to colonoscopy were overt or occult intestinal bleeding (18), diarrhoea (15), systemic signs (10), IBS-like symptoms (5), other (3). Ileal lesions were ulcers (9), erosions (26), aftae (10), nodularity (3), and erythema (3). At histological evaluation aspecific findings were observed. Forty-four out of 51 (86.3%) subjects underwent further investigations of small bowel. Second colonoscopy was performed in 31 (60.8%) persisting symptomatic subjects: ileitis was confirmed in 14 (46.6%). Ten out of 51 (19.6%) were eventually diagnosed as affected by Crohn’s disease.

Conclusions

A substantial proportion of subjects with endoscopic and histological findings of aspecific ileitis is eventually diagnosed as affected by Crohn’s disease. In these subjects, a strict follow-up is strongly recommended.

     

Timing of surgery in Crohn＇s disease： A key issue in the management

The timing of the decision for operation in Crohn＇s disease is based on an evaluation of the several factors such as the failure of medical treatment, complications due to the Crohn＇s disease or to the farmacological therapy, development of dysplasia or cancer and growth retardation. A complete evaluation of these factors should result in operation timed to the patient＇s best advantage, achieving maximal relief of symptoms with improvement of quality of life. Given the complexity and heterogeneity of the disease and the different options for treatment, is difficult to systematize when the optimal moment for the surgery is arrived. A very important factor in the management of Crohn＇s disease is the multidisciplinary approach and the patient preference should be a significant factor in determining the choice of therapy. The surgery should be considered such another option in the sequential treatment of Crohn＇s disease. We have analyzed the factors that are involved in the decision taking of the surgical treatment regarding to the experience and the published literature. When did the medical therapy fail？ when is the appropriate moment to operate on the patient？ Or which complications of Crohn＇s disease need a surgery？ These are some of the questions we will try to answer.     

Increased haemoglobin A2 percentage in HIV infection: disease or treatment?

An elevated haemoglobin A2 percentage has been reported in HIV-infected patients, possibly attributable to therapy. In cross-sectional and cohort studies we have established that A2 is often elevated in untreated patients; a further rise during treatment is attributable specifically to zidovudine. The haemoglobin A2 may be high enough to lead to a misdiagnosis of beta thalassemia trait if there is a lack of awareness of this unexpected effect of HIV infection and its treatment.     

L-arginine in cardiovascular disease: dream or reality?

L-arginine is the substrate for endothelial nitric oxide synthase (eNOS), and the precursor for the synthesis of nitric oxide (NO). This amino acid exerts a number of actions in the cardiovascular system, mainly through the production of NO. However, it also has a number of NO-independent properties, such as the ability to regulate blood and intracellular pH and the effect on the depolarization of endothelial cell membranes. It also has antihypertensive and antioxidant properties, it influences blood viscosity and the coagulation/fibrinolysis system, and it affects the metabolism of glucose, lipids and proteins. L-arginine influences a number of atherosclerosis risk factors such as hypercholesterolemia, hypertension and smoking, improving endothelial function in these patients. However, it does not affect endothelial function in patients with diabetes mellitus. The role of L-arginine in coronary artery disease is still controversial, but it seems that oral or parenteral administration of this amino acid restores endothelial function in the brachial artery and improves coronary microcirculation. The role of L-arginine in heart failure is currently under investigation, and the first results are rather hopeful. In conclusion, L-arginine seems to provide a hopeful prospect for the treatment of cardiovascular diseases. However, more data derived from large-scale prospective studies evaluating the effects of long-term treatment with L-arginine are needed.     

Surgery for Crohn’s disease in the era of biologicals: A reduced need or delayed verdict?

Crohn’s disease(CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract.Ultimately,up to 70% of all patients will need surgery,despite optimized medical therapy.Moreover,about half of the patients will need redo-surgery because of disease recurrence.The introduction of anti-tumor necrosis factor(TNF) drugs(Infliximab in 1998) revolutionized the treatment of CD.Different randomized trials assessed the efficacy of anti-TNF treatment not only to induce,but also to maintain,steroid-free remission.Furthermore,these agents can rapidly lead to mucosal healing.This aspect is important,as it is a major predictor for long-term disease control.Subgroup analyses of responding patients seemed to suggest a reduction in the need for surgery at median-term follow up(1-3 years).However if one looks at population surveys,one does not observe any decline in the need for surgery since the introduction of Infliximab in 1998.The short follow-up term and the exclusion of patients with imminent surgical need in the randomized trials could bias the results.Only 60% of patients respond to induction of anti-TNF therapy,moreover,some patients will actually develop resistance to biologicals.Many patients are diagnosed when stenosing disease has already occurred,obviating the need for biological therapy.In a further attempt to change the actual course of the disease,top down strategies have been progressively implemented.Whether this will indeed obviate surgery for a substantial group of patients remains unclear.For the time being,surgery will still play a pivotal role in the treatment of CD.     

Early-onset colorectal cancer: A sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.     

Statin therapy in renal disease: Harmful or protective?

Chronic kidney disease (CKD) creates one of the highest-risk atherosclerotic states that can occur in human beings. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has gained widespread acceptance in the general population for the purposes of lowering low-density lipoprotein cholesterol (LDL-C) and reducing the future risks of myocardial infarction, stroke, and cardiac death. In patients with CKD, these benefits are believed to be enjoyed to the same or greater degrees. Reductions in LDL-C with statins may be associated with a reduced progression of CKD. Importantly, recent studies suggest statins are associated with a reduction in rates of acute renal failure after cardiopulmonary bypass surgery and exposure to iodinated contrast. In patients with end-stage renal disease (ESRD), recent data suggest that the annual rate of coronary artery calcification can be attenuated or reduced with LDL-C reduction. However, two large trials demonstrating LDL-C reduction with statins and with these drugs have failed to demonstrate a reduction in cardiovascular events in ESRD. Thus, the potential benefits of statins and LDL-C reduction in CKD have to be considered in light of evidence suggesting a reduced benefit if any, in patients with ESRD. In addition, studies suggest that there are higher adverse drug effects with statins in CKD.     

Bilirubin in coronary artery disease: Cytotoxic or protective?

Bilirubin has traditionally been considered a cytotoxic waste product.However,recent studies have shown bilirubin to have anti-oxidant,anti-inflammatory,vasodilatory,anti-apoptotic and anti-proliferative functions.These properties potentially confer bilirubin a new role of protection especially in coronary artery disease(CAD),which is a low grade inflammatory process exacerbated by oxidative stress.In fact,recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD.In this article,we review the current literature exploring the association between levels of bilirubin and risk of CAD.We conclude that current evidence is inconclusive regarding the protective effect of bilirubin on CAD.A causal relationship between low serum bilirubin level and increased risk of CAD is not currently established.     

Aspirin in peripheral arterial disease: breakthrough or pitfall?

BACKGROUND: This paper introduces a proof-of-concept trial in progress, supposedly providing new important information on anti-platelet drugs used in patients with peripheral arterial disease (PAD). The Arteriogenesis Competence Network (Art.Net.) of the Universities of Basel, Berlin, and Freiburg could show in animal models that Aspirin (ASA), in contrast to Clopidogrel, inhibits the formation of an appropriate collateral network (arteriogenesis). This trial is supposed to reproduce the animal data in man. MATERIALS AND METHODS: In a prospective, double-blind, parallel-group, bi-national (D, CH), multicentre trial, 250 patients will be randomised to either 100 mg ASA or 75 mg Clopidogrel once daily. Patients will then enter a three months structured rehabilitation programme with daily physical training supposed to induce arteriogenesis. The claudication distances will be tested as the primary endpoint at baseline, 6 weeks, and at 3 months. Also, the 24h physical activity profile of all patients will be electronically documented. CONCLUSIONS: This trial will provide information on potential disadvantages when using ASA in PAD patients. If data emerging from animal pharmacology can be reproduced in man, the present standard scheme of anti-aggregant treatment in PAD patients has to be reconsidered.     

Statin therapy in renal disease: Harmful or protective?

Chronic kidney disease (CKD) creates one of the highest-risk atherosclerotic states that can occur in human beings. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has gained widespread acceptance in the general population for the purposes of lowering low-density lipoprotein cholesterol (LDL-C) and reducing the future risks of myocardial infarction, stroke, and cardiac death. In patients with CKD, these benefits are believed to be enjoyed to the same or greater degrees. Reductions in LDL-C with statins may be associated with a reduced progression of CKD. Importantly, recent studies suggest statins are associated with a reduction in rates of acute renal failure after cardiopulmonary bypass surgery and exposure to iodinated contrast. In patients with end-stage renal disease (ESRD), recent data suggest that the annual rate of coronary artery calcification can be attenuated or reduced with LDL-C reduction. However, two large trials demonstrating LDL-C reduction with statins and with these drugs have failed to demonstrate a reduction in cardiovascular events in ESRD. Thus, the potential benefits of statins and LDL-C reduction in CKD have to be considered in light of evidence suggesting a reduced benefit, if any, in patients with ESRD. In addition, studies suggest that there are higher adverse drug effects with statins in CKD.     

Obesity in chronic kidney disease: good or bad?

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in chronic kidney disease (CKD) patients. As traditional risk factors cannot alone explain the high prevalence and incidence of CVD in this high-risk population, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as important non-traditional risk factors. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has recently been shown that fat tissue secretes a number of adipokines - including leptin, adiponectin and retinol-binding protein, as well as cytokines such as resistin, visfatin, tumor necrosis factor and interleukin-6. Adipokine serum levels are furthermore markedly elevated in CKD, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and putatively CVD. As fat tissue is also a storage depot for energy, much needed in the catabolic milieu of uremia, further research is still needed to elucidate the likely complex interactions between these signaling networks, vascular health and outcome in this high-risk population.