Diagnosis and Management of Microscopic Colitis.

Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea, especially in older persons. Associated symptoms, including abdominal pain and arthralgias, are common. The diagnosis is based upon characteristic histological findings in the presence of diarrhea. The two types of MC, collagenous and lymphocytic colitis, share similar clinical features, with the main difference being the presence or absence of a thickened subepithelial collagen band. There are several treatment options for patients with MC, although only budesonide has been well studied in multiple controlled clinical trials. This review will describe the clinical features, epidemiology, pathophysiology, diagnostic criteria, and treatment of patients with MC.

Bile acid sequestrants: more than simple resins.

PURPOSE OF REVIEW: Bile acid sequestrants (BAS) have been used for more than 50 years in the treatment of hypercholesterolemia. The last decade, bile acids are emerging as integrated regulators of metabolism via induction of various signal transduction pathways. Consequently, BAS treatment may exert unexpected side-effects. We discuss a selection of recently published studies that evaluated BAS in several metabolic diseases. RECENT FINDINGS: Recently, an increasing body of evidence has shown that BAS in addition to ameliorating hypercholesterolemia are also effective in improving glycemic control in patients with type 2 diabetes, although the mechanism is not completely understood. Furthermore, some reports suggested using these compounds to modulate energy expenditure. Many of these effects have been related to the local effects of BAS in the intestine by directly binding bile acids in the intestine or indirectly by interfering with signaling processes. SUMMARY: A substantial effort is being made by researchers to fully define the mechanism by which BAS improve glycemic control in type 2 diabetic patients. A new challenge will be to confirm in clinical trials the recent discoveries coming from animal experiments suggesting a role for bile acids in energy metabolism.

New insights into bile acid malabsorption.

Bile acid malabsorption occurs when there is impaired absorption of bile acids in the terminal ileum, so interrupting the normal enterohepatic circulation. The excess bile acids in the colon cause diarrhea, and treatment with bile acid sequestrants is beneficial. The condition can be diagnosed with difficulty by measuring fecal bile acids, or more easily by retention of selenohomocholyltaurine (SeHCAT), where this is available. Chronic diarrhea caused by primary bile acid diarrhea appears to be common, but is under-recognized where SeHCAT testing is not performed. Measuring excessive bile acid synthesis with 7α-hydroxy-4-cholesten-3-one may be an alternative means of diagnosis. It appears that there is no absorption defect in primary bile acid diarrhea but, instead, an overproduction of bile acids. Fibroblast growth factor 19 (FGF19) inhibits hepatic bile acid synthesis. Defective production of FGF19 from the ileum may be the cause of primary bile acid diarrhea.

Conservative treatment of patients with faecal soiling.

PURPOSE: A prospective evaluation of fifty patients with faecal soiling but normal sphincter function treated by a conservative treatment algorithm. PATIENTS AND METHODS: Between January 2010 and January 2011, 50 consecutive patients of two different clinical centres, with faecal soiling and normal anorectal function as assessed by endoanal ultrasound, MRI and anal manometry, were eligible for the purpose of this study. All patients started the therapy by psyllium (PS) and a fibre-rich diet daily after 2 months followed by rectal irrigation (RI) in case of incomplete response and after 4 months by 4 g colestyramine (CO), respectively. The patients completed the Vaizey incontinence score and a 2-week diary card. All tests were performed repeated after 2, 4 and 8 months, respectively. RESULTS: The study group consisted of 41 men and 9 women and a mean age of 38 years (21-70). The soiling complaints resolved completely in 37 (79%) patients. After treatment with PS, RI and CO, 12 (24%) patients, 24 (73%) patients and 1 (79%) patient, respectively, resolved completely of faecal soiling. Average weekly soiling frequency, the amount of patients wearing pads daily and the Vaizey incontinence score diminished significantly after treatment with psyllium and after treatment with rectal irrigation (P < 0.001). CONCLUSION: Conservative treatment focussed on complete evacuation or clearing the anorectal canal is effective in the treatment of patients with faecal soiling.

[Optimal lipid treatment: possibilities and current limitations]. / Möglichkeiten und Grenzen der modernen Lipidtherapie.

Prevention is a major contributor to the decline in cardiovascular morbidity and mortality. Cardiovascular diseases still are the leading cause of death (42%) in Germany and indicate unmet preventive needs. Limitations of healthy lifestyle, the basis of many recommendations, include insufficient compliance and efficacy in individual cases. In their latest metaanalysis the Cholesterol Treatment Trialists' Collaborators showed updated estimates of treatment effects of statins including more or less intensive regimens.The average reduction in major vascular events was 21% per 1.0 mmol/l reduction in LDL cholesterol. Appropriateness of receiving lipid modulating treatment in the population will be discussed in the light of controversial recommendations in treatment strategies. Residual risk in statin treated patients may be ameliorated by options beyond LDL-lowering. Suggestions for clinical practice are provided on the background of clinical relevant characteristics of current lipid lowering drugs and future developments are outlined.

[Pruritus associated with cholestasis]. / Prurito asociado a colestasis.

Pruritus is commonly associated with cholestatic disorders and shows wide interindividual variability. The presence of skin lesions due to scratching and the application of a visual analogue scale are useful for clinical evaluation. Although the pathophysiology of this entity is not well understood, advances have recently been made in understanding of the pruritoceptive neural pathway, which shares certain similarities with the nociceptive pathway, although there are other distinguishing characteristics such as the action of a specific neurotransmitter, GPR, on the first synapsis at the posterior horn of the spinal cord. Amongst the modulator systems of the pruritoceptive pathway is the action of the endogenous opioids. An increase of these opioids in cholestatic situations is the most widely accepted hypothesis for pruritus in these patients. Some treatments have proven efficacy in randomized clinical trials in patients with cholestatic disorders, such as anion exchange resins, rifampicin, opioid antagonists and ursodeoxycholic acid; the latter is especially useful in intrahepatic cholestasis of pregnancy.

Recent advances in the understanding of bile acid malabsorption.

INTRODUCTION: Bile acid malabsorption (BAM) is a syndrome of chronic watery diarrhoea with excess faecal bile acids. Disruption of the enterohepatic circulation of bile acids following surgical resection is a common cause of BAM. The condition is easily diagnosed by the selenium homocholic acid taurine (SeHCAT) test and responds to bile acid sequestrants. Idiopathic BAM (IBAM, primary bile acid diarrhoea) is the condition where no definitive cause for low SeHCAT retention can be identified. SOURCES OF DATA: Review of PubMed and major journals. AREAS OF AGREEMENT: Evidence is accumulating that BAM is more prevalent than first thought. Management of chronic diarrhoea involves excluding secondary causes. Treatment of the condition is with bile acid binders. AREAS OF CONTROVERSY: SeHCAT testing is not widely performed, limiting awareness of how common this condition can be. The underlying mechanism for IBAM has been unclear. GROWING POINTS: Increasing awareness of the condition is important. Alternative mechanisms of IBAM have been suggested which involve an increased bile acid pool size and reduced negative feedback regulation of bile acid synthesis by FGF19. New sequestrants are available. AREAS TIMELY FOR DEVELOPING RESEARCH: Further research into the precise mechanism of IBAM is needed. Improvements in the recognition of the condition and optimization of treatment are required.

Successful treatment of leflunomide-induced acute pneumonitis with cholestyramine wash-out therapy.

Drug-induced acute pneumonitis is a rare but potentially fatal adverse drug reaction. A high index of suspicion is needed for early diagnosis as it mimics community acquired pneumonia and interstitial lung disease that can occur in rheumatoid arthritis. We report a 32-year-old Chinese lady who suffered from leflunomide-induced pneumonitis and improved dramatically after receiving cholestyramine wash-out therapy. This case illustrates the need for clinical alertness to this potentially fatal complication. When in doubt, discontinuation of leflunomide and empirical wash-out therapy should be administered without delay.

LDL-cholesterol: The lower the better. / Colesterol LDL, cuanto más bajo mejor.

The reduction of low density lipoprotein-cholesterol (LDL-chol) has been associated with a decrease in cardiovascular morbidity and mortality. It has been demonstrated that there is no value of LDL-chol below which there ceases to be a preventive benefit with its reduction, and neither has it been observed that there is a higher incidence of secondary effects associated with lower concentrations of LDL-chol. Although there is a wide range of lipid-lowering drugs available, a high percentage of patients do not achieve the desired LDL-chol levels. The high-potency statins reduce the LDL-chol by 15-30%, and can double the percentage of patients that reach their desired level. This combination has shown to be safe and effective in the primary and secondary prevention of cardiovascular disease. Another option is the combination of statins with exchange resins, although this requires a more complex management. The inhibition of PCSK9 protein with monoclonal antibodies reduces the LDL-chol by more than 60%, and is effective in the prevention of cardiovascular disease. However, due to its cost, its use is restricted to patients with ischaemia or familial hypercholesterolaemia that do not achieve the desired levels with conventional drugs. The evidence base as regards the benefit and safety of achieving the desired levels of LDL-chol is very wide and is still increasing. In the next few years, it may be necessary to adjust the intensity of the hypercholesterolaemia treatment to the level of vascular risk of the patients, and to the level of reduction necessary to achieve the therapeutic targets. This will result in a more effective cardiovascular prevention and in a better quality of life, particularly in the large group of patients at higher vascular risk.

Cholestyramine decreases apparent total tract macronutrient digestibility and alters fecal characteristics and metabolites of healthy adult dogs.

Absorption of dietary lipids in the small intestine is dependent on the emulsification by bile acids (BA) and the formation of chylomicrons. Cholestyramine is a common drug used in humans-and potentially dogs-to treat BA malabsorption associated with chronic diarrhea. It is known to bind BA to form insoluble complexes, preventing their reabsorption and possibly proper emulsification and absorption of dietary fats. The objective of this study was to evaluate the effects of cholestyramine on 1) macronutrient apparent total tract digestibility (ATTD), and 2) fecal characteristics and metabolites of healthy adult dogs. We hypothesized that cholestyramine would decrease ATTD of fat and organic matter (OM), increase fecal dry matter (DM) content, and increase fecal output. Twelve healthy beagles (3.2 ± 0.8 yr; 10.4 ± 0.9 kg) were used in a randomized crossover design. All procedures were approved by the University of Illinois Institutional Animal Care and Use Committee before the study. The study included a baseline period and two 14-d experimental periods separated by a 14-d washout. All dogs were fed the same experimental diet, formulated to meet all nutrient needs recommended by AAFCO, throughout the study. Dogs were randomized into 2 groups [diet only (control) or diet + 11.4 g/d cholestyramine (8 g/d active ingredient)] in Period 1 and received the other treatment in Period 2. During the washout, all dogs were fed the diet only. Dogs were fed once daily (0800 h) to maintain BW. Total fecal output was collected during the last 4 d of each period for ATTD analysis. On day 14 of each of period, fresh fecal and blood samples were collected for metabolite analysis. Dogs fed cholestyramine had lower (P < 0.001) ATTD of DM, OM, energy, crude protein, and fat and lower (P < 0.01) fecal scores (firmer stools) than controls. Dogs fed cholestyramine had greater (P < 0.01) as-is and dry fecal output than controls. Dogs fed cholestyramine had lower (P < 0.05) fecal ammonia and phenol concentrations, but greater (P < 0.05) fecal indole, acetate, butyrate, and total short-chain fatty acid concentrations than controls. Fecal DM% and pH were greater (P < 0.01) in dogs fed cholestyramine. Our results indicate that cholestyramine, when given with a meal, is safe and well tolerated but significantly decreases nutrient digestibility and alters fecal characteristics. Future studies are required to explore the effects of cholestyramine on dogs with gastrointestinal disease.

Beyond cholesterol lowering: pleiotropic effects of bile acid binding resins against cardiovascular disease risk factors in patients with metabolic syndrome.

Prospective epidemiologic studies have shown that dyslipidemia and hyperglycemia are major risk factors for atherosclerotic cardiovascular diseases. Undesirable metabolic conditions are observed to coexist in patients with metabolic syndrome, which is an important risk factor for cardiovascular disease. To prevent cardiovascular disease, a pleiotropic agent is needed to improve the metabolic disorder in patients with metabolic syndrome. Bile acid binding resins increase the fecal excretion of bile acids. The decrease in bile acids returned to the liver leads to an up-regulation of hepatic low-density lipoprotein (LDL) receptor activity, which decreases LDL cholesterol (LDL-C) in the circulation and increases high-density lipoprotein cholesterol. On the other hand, bile acids can also regulate the transcription of genes involved in LDL-C synthesis and cholesterol homeostasis via nuclear hormone receptors. Consequently, these receptors may represent novel therapeutic targets for dyslipidemia and provide insight into the role of the bile acid pathway in other metabolic processes. This review focuses on the recent findings on bile acid binding resins and cardiovascular disease risk factors. Moreover, known and proposed mechanisms of how bile acid binding resins may improve glucose and energy metabolism are discussed; these effects may help to explain the mechanisms by which bile acid binding resins may reduce cardiovascular disease.

Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase.

BACKGROUND: Hypercholesterolemia enhances platelet aggregability. Statins have beneficial effects on cardiovascular events. The purpose of this study is to investigate whether statins inhibit platelet aggregation and, if so, the mechanisms. METHODS AND RESULTS: Twelve patients with hypercholesterolemia were prospectively randomized in a crossover design to receive either fluvastatin (20 mg/d) or colestimide (3000 mg/d) for 12 weeks. The subjects were switched to the opposite arm for additional 12 weeks. Before and after first and second treatments, experiments were performed. Eleven age-matched volunteers with normal lipid profiles served as controls. ADP-induced platelet aggregation, platelet-derive nitric oxide (PDNO) release, intraplatelet levels of GSH and GSSG, and intraplatelet nitrotyrosine production during platelet aggregation were measured. Fluvastatin and colestimide equally lowered total and low density lipoprotein cholesterol levels in hypercholesterolemia. Platelet aggregation was greater in hypercholesterolemia than in normocholesterolemia before treatment and was altered by fluvastatin. PDNO release, intraplatelet glutathione level, and GSH/GSSG ratio were lower in hypercholesterolemia than in normocholesterolemia before treatment and were increased by fluvastatin. Intraplatelet nitrotyrosine formation was greater in hypercholesterolemia than in normocholesterolemia, and decreased by fluvastatin. Colestimide did not have such effects. In vitro application of fluvastatin dose-dependently inhibited platelet aggregation. Furthermore, in vitro application of fluvastatin dose-dependently inhibited platelet nitrotyrosine expressions and the inhibitory effects by fluvastatin were reversed by preincubation with geranylgeranylpyrophosphate. CONCLUSIONS: Fluvastatin altered platelet aggregability in hypercholesterolemic patients in a cholesterol-lowering independent manner, which was partly mediated by the improvement of intraplatelet redox imbalance.

Understanding and Treating Pruritus in Primary Biliary Cholangitis.

Pruritus is a common symptom with primary biliary cholangitis. Research has focused on refining understanding of the neurohumoral pathways involved in transduction of pruritus from peripheral cutaneous receptors to the central nervous system, and identifying modulating drugs. Current treatments have variable efficacy and safety. Because of the deleterious effects on quality of life or debilitation, many patients necessitate individualized therapeutic approaches; clinicians may need to consider invasive treatment options. This article highlights various therapeutic interventions, from general measures to invasive strategies, and novel agents under investigation, providing clinicians with the management tricks of the trade.

Management of Chronic Hepatic Itch.

Hepatic itch remains among the most agonizing symptoms for affected patients and a major clinical challenge for physicians. Pruritus may occur in almost all liver diseases, particularly those with cholestatic features. Hepatic itch arises irrespective of the severity of the underlying liver disease or extent of cholestasis. Antihistamines are ineffective in hepatic itch. Therapeutic recommendations consist of a guideline-based stepwise approach, starting with the anion exchange resin cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors are promising future treatment options. Experimental and invasive procedures should be reserved for refractory pruritus.

Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure.

Sevelamer, or more precisely 'sevelamer hydrochloride', is a weakly basic anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of patients with end-stage renal failure, usually those on long-term haemodialysis. The rationale for this therapy was that sevelamer would sequester phosphate within the gastrointestinal tract, so preventing its absorption and enhancing its faecal excretion. Over the succeeding years, large numbers of patients have been treated with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure. However, it is only one of many anion-exchange resins that could be used for this purpose, some of which are currently available for clinical use and are much less costly than sevelamer. Theoretical considerations suggest that some of these other resins might be at least as efficient as sevelamer in sequestering phosphate in the gastrointestinal tract. Neither sevelamer, nor any of these other agents, has been submitted to a proper metabolic balance study to measure the amount of phosphate sequestered by the resin in the bowel, and without this information it is impossible to judge which is the ideal resin for this purpose.

[Therapy of dyslipidemia in post-infarction: state of the art]. / Terapia delle dislipidemie nel post-infarto: stato dell'arte.

Between the risks factors involved in the atherogenesis LDL-cholesterol is determinant because highly associated to cardiovascular events. The primary target for the prevention of coronary diseases is a reduction of LDL-cholesterol because that reduces the cardiovascular mortality and the total mortality. The NCEP ATP III 2004 guide-lines propose as therapeutic target for the high-risk patients the reduction of plasma levels of LDL-cholesterol under 100 mg/dl and according to new trials under 70 mg/dl. The dyslipidaemia treatments are based on two approaches, i.e., the therapeutic lifestyle change and the pharmacological therapy. The available drugs are statins, fibrates, anion exchange resins, nicotinic acid. In the acute coronary syndrome patients is desirable to start immediately a therapy with statins since the hospital phase and direct the treatment to aggressive therapy. Unfortunately, the statin doses used in the most secondary prevention trials allow to get LDL-cholesterol under 100 mg/dl in the only half high-risk patients. The innovative therapeutic approach to hypercholesterolemia today is based on a double inhibition of cholesterol synthesis and absorption combining a statin with ezetimibe.

[Physiopathology and management of cholestatic pruritus in children]. / Physiopathologie et prise en charge thérapeutique du prurit cholestatique de l'enfant.

Pruritus is a disabling symptom accompanying chronic cholestasis. In some cases, refractory pruritus may require invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway and several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adult patients, there is no consensus in children, given the difficulty in conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of therapy that should always be associated with local cutaneous care and with nonspecific treatment of cholestasis including ursodeoxycholic acid therapy. Pruritus should be assessed as objectively as possible between each therapeutic step. Rifampicin, an enzyme inducer, is the specific first-line treatment of cholestatic pruritus. The second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease, the experience of the center and the will of the child and his family. It could be inhibitors of serotonin reuptake (sertraline) or an opioid antagonist (naloxone). Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases.