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The Cochrane Database of Systematic... Jul 2017Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review.
OBJECTIVES
To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia.
SEARCH METHODS
Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline.Date of most recent search: 20 February 2017.
SELECTION CRITERIA
Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed studies for inclusion and extracted data.
MAIN RESULTS
We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (moderate quality evidence). Serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations, did not differ between treated and placebo groups at any time point (low quality evidence). The risks of myopathy (low quality evidence) and clinical adverse events (moderate quality evidence) were very low and also similar in both groups. In one study simvastatin was shown to improve flow-mediated dilatation of the brachial artery (low quality evidence), and in another study treatment with pravastatin for two years induced a significant regression in carotid intima media thickness (low quality evidence).
AUTHORS' CONCLUSIONS
Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. No significant safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.
Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Brachial Artery; Carotid Intima-Media Thickness; Child; Child, Preschool; Cholesterol, LDL; Creatine Kinase; Female; Heterozygote; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Male; Puberty; Randomized Controlled Trials as Topic; Vasodilation
PubMed: 28685504
DOI: 10.1002/14651858.CD006401.pub4 -
Gels (Basel, Switzerland) Jun 2023Bile acid sequestrants (BASs) are non-systemic therapeutic agents used for the management of hypercholesterolemia. They are generally safe and not associated with... (Review)
Review
Bile acid sequestrants (BASs) are non-systemic therapeutic agents used for the management of hypercholesterolemia. They are generally safe and not associated with serious systemic adverse effects. Usually, BASs are cationic polymeric gels that have the ability to bind bile salts in the small intestine and eliminate them by excretion of the non-absorbable polymer-bile salt complex. This review gives a general presentation of bile acids and the characteristics and mechanisms of action of BASs. The chemical structures and methods of synthesis are shown for commercial BASs of first- (cholestyramine, colextran, and colestipol) and second-generation (colesevelam and colestilan) and potential BASs. The latter are based on either synthetic polymers such as poly((meth)acrylates/acrylamides), poly(alkylamines), poly(allylamines) and vinyl benzyl amino polymers or biopolymers, such as cellulose, dextran, pullulan, methylan, and poly(cyclodextrins). A separate section is dedicated to molecular imprinting polymers (MIPs) because of their great selectivity and affinity for the template molecules used in the imprinting technique. Focus is given to the understanding of the relationships between the chemical structure of these cross-linked polymers and their potential to bind bile salts. The synthetic pathways used in obtaining BASs and their in vitro and in vivo hypolipidemic activities are also introduced.
PubMed: 37367171
DOI: 10.3390/gels9060500 -
Gut and Liver May 2015Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or... (Review)
Review
Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn's disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as (75)selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Topics: Anticholesteremic Agents; Bile Acids and Salts; Crohn Disease; Diarrhea; Feces; Fibroblast Growth Factors; Gastrointestinal Microbiome; Humans; Irritable Bowel Syndrome
PubMed: 25918262
DOI: 10.5009/gnl14397 -
The American Journal of Gastroenterology Oct 2020Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue... (Review)
Review
Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.
Topics: Benzothiazoles; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestenones; Cholestyramine Resin; Chronic Disease; Colesevelam Hydrochloride; Colestipol; Diarrhea; Diet, Fat-Restricted; Feces; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Isoxazoles; Liver; Malabsorption Syndromes; Receptors, Cytoplasmic and Nuclear; Sequestering Agents; Taurocholic Acid
PubMed: 32558690
DOI: 10.14309/ajg.0000000000000696 -
Alimentary Pharmacology & Therapeutics May 2014Bile acid malabsorption (BAM) is a common, yet under-recognised, cause of chronic diarrhoea, with limited guidance available on the appropriate management of patients... (Review)
Review
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.
Topics: Adult; Anion Exchange Resins; Bile Acids and Salts; Chronic Disease; Diarrhea; Gastrointestinal Diseases; Humans; Steatorrhea; Taurocholic Acid
PubMed: 24602022
DOI: 10.1111/apt.12684