Intrahepatic Cholestasis:Diagnosis and Management

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Probiotics: which and when?

There is a natural feeling between our intestinal flora and the gut. These microorganisms, living in the various tracts of human intestine, may affect the host homeostasis. Some of these bacteria can perhaps be a source of infection and sepsis when the bowel barrier is physically or functionally breached. The term 'probiotic' dates from the beginning of the last century and in the last years a market for probiotics worldwide, estimated to be worth billions of pounds, has developed. Although there is persuasive advertising for probiotics and there have been methodological advances in the study of the intestinal microbiota, much remains unproven, e.g. how probiotics work, which strains are effective, what can be expected to be achieved, and what dosage is required for effectiveness. This review of the literature is an evidence-based guide through the developing microbial universe affecting our life.     

Bisphosphonates and atherosclerosis: why?

The increasing knowledge on bone calcification processes has revealed some similarities with vascular tissue, where calcifications of arteries and cardiac valves contribute to several cardiovascular problems, such as heart failure, systolic hypertension, and myocardial and peripheral ischemic disease. Bisphosphonates have been used extensively for over two decades for the treatment of diseases associated with excessive bone resorption, i.e., osteoporosis, osteolytic bone metastasis, hypercalcemia and Paget's disease, by blocking osteoclastic function. Etidronate, pamidronate and clodronate has been shown to inhibit the development of experimental atherosclerosis, and proposed mechanisms for this action include inhibition of arterial calcification and lipid accumulation, degradation of atherogenic LDL-cholesterol and reduced foam cell formation. Bisphosphonates inhibit various enzymes involved in cholesterol biosynthesis and suppress macrophages in atheromatous lesions. The possibility of pharmacological agents that effectively treat both osteoporosis and atherosclerosis is attractive, however, current evidence is not conclusive and further research is necessary to confirm these actions in the clinical setting.     

Late Drug-eluting Stent Thrombosis and Erythropoietin: Cause and Effect?

A case of late thrombosis of a sirolimus-eluting stent, 16 months after implantation, is described. Two weeks prior to presentation with stent thrombosis the patient had a 50% dose increase of longterm erythropoietin. The prothrombotic effect of erythropoietin may have precipitated the thrombotic event.     

Diabetes and stroke: Part one—Risk factors and pathophysiology

Diabetes is a major risk factor for stroke and is associated with an increase in overall stroke mortality. The metabolic syndrome associated with insulin resistance is also a significant risk factor for stroke. The etiology of stroke in diabetics is frequently microvascular disease from fibrinoid necrosis, which causes small subcortical infarcts designated as lacunar strokes. Diabetics also have an increased incidence of large vessel intracranial vascular disease. Although strict control of blood sugar has not been shown to reduce the overall incidence of stroke in diabetics, careful management of other associated risk factors, particularly hypercholesterolemia and hypertension, are imperative for the prevention of stroke in diabetic patients.     

Thyroid hormone and cerebellum development: direct and indirect effects?

Thyroid hormone (T3) exerts an important influence on neurodevelopment, which can be analysed by using the postnatal development of rodent cerebellum as a model. T3 acts on all types of neuronal and glial cells, which express at least the TRα1 nuclear receptor, and, for some of them, the TRβ1 isoform. However, as T3 also activates the secretion of neurotrophins, it can also affect cellular differentiation in an indirect manner. Ongoing experiments, based on mouse genetics and genome wide analysis of gene expression, provide a promising way to study the basic mechanisms of neurodevelopment. This review describes new mouse genetics models and recent advance in this field.     

Glycation and insulin resistance: novel mechanisms and unique targets?

Multiple biochemical, metabolic, and signal transduction pathways contribute to insulin resistance. In this review, we present evidence that the posttranslational process of protein glycation may play a role in insulin resistance. The posttranslational modifications, the advanced glycation end products (AGEs), are formed and accumulated by endogenous and exogenous mechanisms. AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of tumor necrosis factor-α direct modification of the insulin molecule, thereby leading to its impaired action, generation of oxidative stress, and impairment of mitochondrial function, as examples. AGEs may stimulate signal transduction via engagement of cellular receptors, such as receptor for AGEs. AGE-receptor for AGE interaction perpetuates AGE formation and cellular stress via induction of inflammation, oxidative stress, and reduction in the expression and activity of the enzyme glyoxalase I that detoxifies the AGE precursor, methylglyoxal. Once set in motion, glycation-promoting mechanisms may stimulate ongoing AGE production and target tissue stresses that reduce insulin responsiveness. Strategies to limit AGE accumulation and action may contribute to the prevention of insulin resistance and its consequences.     

Glycoxidation and Diabetic Complications: Modern Lessons and a Warning?

Reviews in Endocrine and Metabolic Disorders -     

Contrast-Induced Nephropathy and Long-Term Adverse Events: Cause and Effect?

Background and objectives: The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs.Design, setting, participants, & measurements: We obtained long-term (≥1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a χ² test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions.Results: The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs.Conclusions: The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.Contrast-induced nephropathy (CIN), a form of acute kidney injury (AKI), has received increasing attention in the past few years as a result of new knowledge regarding its pathogenesis, the proliferation of innovative approaches to its prevention, and recognition that CIN is associated with long-term adverse events (AEs) (1–5). The increased incidence of AEs after CIN is derived primarily from retrospective analyses of large databases (2,4,5) or observational studies (3) of patients who have undergone coronary angiography and/or percutaneous coronary intervention. A cause-and-effect relationship cannot be determined from such data. Patients with an increased burden of cardiovascular risk factors before contrast medium exposure may be more likely to develop CIN and independent of the occurrence of CIN have more long-term AEs. Alternatively, the occurrence of CIN may in some as-yet-undefined manner alter the future likelihood of AEs (i.e., CIN is on a pathophysiologic pathway that leads to AEs).Randomized, prospective trial designs provide an opportunity to explore causal relationships. If CIN is causally related to long-term AEs, then a strategy that prevents CIN should reduce long-term AEs, as long as the strategy itself does not alter any other risk factors for those AEs. In a randomized trial of two different treatments, the assumption is that the baseline risk factors for long-term AEs will be equally distributed between the two treatments being tested. Differences in the incidence of CIN between treatments, if paralleled by differences in long-term AEs, would suggest that CIN is on a pathophysiologic pathway that leads to those AEs.The Cardiac Angiography in Renally Impaired Patients (CARE) Study was a large, multicenter, prospective, double-blind, randomized clinical trial of patients who had moderate to severe chronic kidney disease and were undergoing cardiac angiography (6). The primary end point was the incidence of CIN. Patients were randomly assigned to two different treatments represented by two different contrast media: The low-osmolar, nonionic monomer iopamidol (Isovue; Bracco Diagnostics Inc., Princeton, NJ) and the iso-osmolar, nonionic dimer iodixanol (Visipaque; GE Healthcare, Princeton, NJ). Neither contrast medium has any known effect on the baseline risk factors that might contribute to long-term AEs. In this report, follow-up data were collected on 294 of the original participants of the CARE trial approximately 12 mo after entry into the trial. To explore whether a causal link exists between CIN and long-term AEs, we studied the differences in the incidence of CIN and long-term AEs between the two treatments (contrast media). Since the results of the CARE study were published, new definitions of AKI and thus CIN have been suggested (7). These new definitions increase the incidence of CIN and thus enhance the statistical power to detect associations with long-term outcomes.     

Liver transplantation for intrahepatic and perihilar cholangiocarcinoma: Current and future

Cholangiocarcinomas are categorized as intrahepatic cholangio- carcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and dis- tal cholangiocarcinoma (dCCA) [1] . iCCA and pCCA are the second most common primary hepatobiliary malignant neoplasms [ 1 , 2 ]. Most patients with iCCA and pCCA have asymptomatic clinical course, highly aggressive nature and dismal prognosis [3] . Com- plete surgical resection offers the best possibility of long-term sur- vival but only a minority of patients are amenable to R0 resec- tion [4] . Tumor involvement of segmental bilateral intrahepatic bile duct, inadequate remnant liver volume or hepatic functional reserve due to underlying chronic liver disease, are key factors limiting the resectability of iCCA and pCCA. Liver transplantation (LT) provides an option for patients with unresectable iCCA and pCCA [4] .