Cholestatic Itch Management.

Cholestatic itch is a feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, the inherited form of cholestasis, and intrahepatic cholestasis of pregnancy. Although undervalued by physicians, cholestatic itch can be a source of great discomfort to the patient and significantly affects quality of life. Many pruritogens such as bile salts, opioids, serotonin, and histamine have been implicated in the pathogenesis of cholestatic itch, but no causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may be key elements in its pathogenesis. Treatment options for patients with cholestatic itch include the anion exchange resin cholestyramine, bile acid ursodeoxycholic acid, PXR agonist rifampicin, opioid antagonist naltrexone, and the serotonin inhibitor sertraline. These drugs can be used as a stepwise therapeutic approach. The body of evidence for many of these options, however, is not very robust. Patients who do not respond to medical therapy can be candidates for interventional measures, such as albumin dialysis, plasmapheresis, or nasobiliary drainage, or certain experimental approaches such as UVB phototherapy. Research over the past decade has elucidated many of the receptors and neuropeptides involved in itch sensation and transmission; it is hoped that in the future this will lead to the development of novel antipruritic medication for cholestatic itch.

Role of Cholestyramine in Refractory Hyperthyroidism: A Case Report and Literature Review.

BACKGROUND: Hyperthyroidism is a common disease that usually responds to the conventional therapy of anti-thyroidal medications (methimazole or PTU) and beta-blocker. Refractory hyperthyroidism is a rare condition in which hyperthyroidism fails to respond to the above therapy. Cholestyramine has been shown to decrease thyroid hormone level when added to the ongoing anti-thyroidal medications. CASE REPORT: A 52-year-old woman with past medical history of enlarging goiter presented with obstructive symptoms of worsening shortness of breath and snoring. Admission thyroid function test showed mild hyperthyroidism (suppressed TSH, slightly high FT4, and high normal FT3) that worsened after she received a CT scan with contrast and failed to respond to a 3-week course of high-dose dexamethasone, high-dose carbimazole, and up-titrated propranolol. Five days after cholestyramine was added, her FT4 decreased by 30% and normalized after 12 days. The patient underwent total thyroidectomy as definitive treatment for the hyperthyroidism and for the obstructive symptoms. CONCLUSIONS: Cholestyramine is an effective additional treatment for hyperthyroidism and may be an effective treatment for refractory iodine-induced hyperthyroidism. The possibility of self-remission (natural course) is less likely given the dramatic and rapid response to cholestyramine.

Systematic review: the management of chronic diarrhoea due to bile acid malabsorption.

BACKGROUND: Bile acid malabsorption (BAM) is a common, yet under-recognised, cause of chronic diarrhoea, with limited guidance available on the appropriate management of patients with BAM. AIM: To summarise the evidence supporting different treatments available for patients with bile acid malabsorption, noting their impact on clinical outcomes, tolerability and associated side effects. METHODS: A literature search was conducted through PubMed, the Cochrane Database of Systematic Reviews and Scopus. Relevant articles studied patients who had been diagnosed with BAM and were clinically assessed before and after therapy. RESULTS: A total of 30 relevant publications (1241 adult patients) were identified, which investigated the clinical response to drugs, including colestyramine, colestipol, colesevelam, aluminium hydroxide and obeticholic acid. The most commonly used diagnostic test of bile acid malabsorption was the SeHCAT test (24 studies). Colestyramine treatment was by far the most studied of these agents, and was successful in 70% of 801 patients (range: 63-100%). CONCLUSIONS: Colestyramine and colestipol are generally effective treatments of gastrointestinal symptoms from BAM, but may be poorly tolerated and reduce the bioavailability of co-administered agents. Alternative therapies (including colesevelam and aluminium hydroxide) as well as dietary intervention may also have a role, and the promising results of the first proof-of-concept study of obeticholic acid suggest that its novel approach may have an exciting future in the treatment of this condition. Future trials should employ accurate diagnostic testing and be conducted over longer periods so that the long-term benefits and tolerability of these different approaches can be evaluated.

Cholestatic liver injury associated with dietary supplements: a report of five cases in active duty service members.

The use of dietary supplements (DS) is common in the active duty population, often without physician knowledge or approval. DS have been associated with drug-induced liver injury, with rare cases resulting in liver failure or death. We report five cases of transient drug-induced liver injury temporally associated with the use of a total of six DS in active duty service members. All patients presented with elevated serum bilirubin and liver-associated enzymes: three patients had a cholestatic liver enzyme pattern, one had a hepatocellular pattern, and one had a mixed pattern. In all cases, percutaneous needle core biopsies of the liver were obtained and demonstrated a cholestatic pattern of injury with variable periportal fibrosis. Causality was considered highly probable for three cases, probable for one case, and possible for one case. Hepatotoxicity has been previously associated with four of the supplements in our cases. For the two remaining supplements, C4 Extreme and Animal Stak, we are unaware of any previous reports of hepatotoxicity. Health care professionals, in particular military physicians, should be aware of the potential risk of these supplements and be prepared to discuss these risks with their patients.

Advances in pathogenesis and treatment of pruritus.

The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritus.

The challenge of cholestatic pruritus.

Pruritus can be the dominant symptom of cholestatic liver disease but is difficult to treat since unraveling its pathophysiology is a great challenge. Serum autotaxin activity correlates with pruritus intensity, but its causal relationship, expression pattern and exact mode of action during cholestasis remain to be established. The anion exchange resin cholestyramine, the PXR agonist rifampicin, the opioid antagonist naltrexone and the serotonine reuptake inhibitor sertraline are recommended by evidence-based guidelines as stepwise therapeutic approaches to treat itch in cholestasis. Rifampicin, the most effective antipruritic agent in cholestatic itch, has been shown to reduce autotaxin transcription in vitro. Experimental approaches include UVB phototherapy, extracorporeal albumin dialysis, nasobiliary drainage and in desperate cases even liver transplantation. Relevant clinical observations along with the different metabolic, neurologic and endocrine targets of available therapies in cholestatic pruritus are reviewed here.

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.

Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients?

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.

Cholesterol, cholesterol-lowering agents/statins, and urologic disease: Part III--A rapid review of FDA-approved cholesterol-lowering agents.

There are a variety of agents, dosages, and mechanisms involved in reducing cholesterol. Statins are the most well-known class and three of the six currently available agents have now lost patent protection. Thus, large reductions in price are expected in 2006-2007 across the entire class. The other classes of cholesterol-lowering agents include targeted triglyceride reducers and high-density lipoprotein boosters; two other classes include primarily cholesterol absorption inhibitors. A recent addition to the cholesterol-lowering prescriptions include prescription omega-3 products, which are highly concentrated, have excellent quality control, and are used to reduce abnormally high levels of triglycerides. All of these agents can be used in some restricted combination, or individually to significantly impact the various forms of lipids in the bloodstream. The bottom line is that practitioners have a large diversity of medications available for cholesterol lowering, and this is enormously exciting at a time when these agents have such profound effects in a variety of disciplines.

Rationale for combination therapy with statin drugs in the treatment of dyslipidemia.

Although statin therapy is a mainstay of lipid treatment, complementary effects of other cholesterol-lowering therapies modify the lipid panel and other aspects of coronary disease risk. These other therapies lower low-density lipoprotein cholesterol and triglycerides and/or raise high-density lipoprotein cholesterol, improve diabetic control, and modify other cardiovascular risks. Historically, combination therapy has been reserved for the small minority of patients with severe dyslipidemia, due to perceived risk. More recently, however, it has been recognized that the potential complications of this combination are far outweighed by the clinical benefits that are possible.

[Drug clinics. How I treat various metabolic diseases treated by a drug intervention that targets the intestine]. / Pharma clinics. Comment je traite.... Certaines maladies métaboliques grâce à une intervention pharmacologique ciblée sur l'intestin.

Besides the classical dietary regimen, it is possible to use specific pharmacological approaches, targeted at the intestine, in order to treat some metabolic disorders. Three approaches will be described: anionic resins for treating hypercholesterolaemia, alpha-glucosidase inhibitors for treating diabetes mellitus and reactive hypoglycaemia, and intestinal lipase inhibitors for treating obesity. All these drugs are based on original concepts, but their clinical use is often limited by the occurrence of digestive side-effects. The latter may generally be reduced by progressive and individual titration of the dosage of each drug and/or by following an appropriate diet.

Protective effects of cholestyramine in rats fed a low-fiber diet containing toxic doses of sodium cyclamate or amaranth.

Immature male rats were fed a purified, low-fiber diet containing massive doses of sodium cyclamate or amaranth (FD and C Red No. 2). Sodium cyclamate when incorporated at a 5% level in the purified, low-fiber diet resulted in toxic manifestations which were counteracted by the concurrent administration of the anion exchange resin cholestyramine at a 2 1/2% level in the diet. Other anion exchange resins were also active in this regard. Cholestyramine at a 2 1/2% level of supplementation was also active in counteracting the toxic effects induced by amaranth when the latter was incorporated at a 5% level in the purified, low-fiber diet.

[Double blind test with a protective ointment (Ivosin) on the hands of cement workers]. / Doppelblindversuch mit einer Schutzsalbe (Ivosin) an den Händen von Zementarbeitern

56 builder's labourers manipulating lime cement applied a protective cream on their hands and 57 used a placebo in a double blind test of two months' duration. The labourers, the doctors who surveyed the condition of their hands, and the statistician who analyzed the results knew only that one cream had a blue label, and the other a green one. Before and after the test, the presence or the absence of certain symptoms on the hands were objectively examined, while the subjective opinion of the labourers was registered at the end of the test. As usual in tests of that kind, the great majority of the labourers (more than 75%) were satisfied, 62% of them acknowledged an improvement. That percentage justified a comparative double-blind study that revealed a much higher quota (86% of the test persons) of satisfaction among the labourers treated with Ivosin than in the placebo group (66%). That difference was statistically significant. On the other hand, no objective difference could be revealed between the two groups. It was impossible to discover among the symptoms studied, any objective cause of that subjective difference.