Cholesterol Monohydrate Crystals Research Articles

Biliary sludge syndrome induced by cephalosporins in children: clinical and diagnostic markers, management

Biliary sludge can occur when taking medicines (oral contraceptives, cephalosporins, octreotide, furosemide, clofibrate, morphine, calcium preparations, etc.). In particular, 30–40 % of ceftriaxone, which is widely used in pediatric inpatient practice, is excreted with bile, 5–15 % of all side effects of the drug are due to biliary sludge. The mechanism of ceftriaxone-associated biliary sludge is due to the fact that ceftriaxone competes with bilirubin for albumin, which induces an increase in unconjugated bilirubin in the blood. The drug enters the bile in the form of a divalent anion, binds to calcium in ceftriaxone-calcium complexes with inclusions of cholesterol monohydrate crystals and bilirubinate granules. In patients taking cephalosporins, when complaints from the gastrointestinal tract appear, ultrasound screening is mandatory. Children with a family history of gallstone disease and risk factors should undergo ultrasound screening on the 10th day and 1 month after treatment with cephalosporins, even in the absence of complaints. The administration of ursodeoxycholic acid leads to a significant regression of clinical symptoms of biliary sludge and objective ultrasound signs in 2/3 of children after 2 months.

Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations.

About 20% of adults worldwide have gallstones which are solid conglomerates in the biliary tree made of cholesterol monohydrate crystals, mucin, calcium bilirubinate, and protein aggregates. About 20% of gallstone patients will definitively develop gallstone disease, a condition which consists of gallstone-related symptoms and/or complications requiring medical therapy, endoscopic procedures, and/or cholecystectomy. Gallstones represent one of the most prevalent digestive disorders in Western countries and patients with gallstone disease are one of the largest categories admitted to European hospitals. About 80% of gallstones in Western countries are made of cholesterol due to disturbed cholesterol homeostasis which involves the liver, the gallbladder and the intestine on a genetic background. The incidence of cholesterol gallstones is dramatically increasing in parallel with the global epidemic of insulin resistance, type 2 diabetes, expansion of visceral adiposity, obesity, and metabolic syndrome. In this context, gallstones can be largely considered a metabolic dysfunction-associated gallstone disease, a condition prone to specific and systemic preventive measures. In this review we discuss the key pathogenic and clinical aspects of gallstones, as the main clinical consequences of metabolic dysfunction-associated disease.

Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation.

The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical-chemical state of bile predisposing to supersaturation with cholesterol. Changes in biliary phospholipid concentrations influence cholesterol crystallization by yielding both liquid crystalline and "anhydrous" crystalline metastable intermediates, evolving into classical parallelogram-shaped cholesterol monohydrate crystals in supersaturated bile. As a result, five distinct crystallization pathways, A-E, have been defined, mainly based on the prime habits of liquid and solid crystals in the physiological or pathophysiological cholesterol saturation of gallbladder and hepatic bile. This review concisely summarizes the chemical structures and physical-chemical properties of biliary phospholipids and their physiological functions in bile formation and cholesterol solubility in bile, as well as comprehensively discusses the latest advances in the role of biliary phospholipids in cholesterol crystallization and growth in gallstone formation, largely based on the findings from clinical and animal studies and in vitro experiments. The insights gleaned from uncovering the cholelithogenic mechanisms are expected to form a fundamental framework for investigating the hitherto elusive events in the earliest stage of cholesterol nucleation and crystallization. This may help to identify better measures for early diagnosis and prevention in susceptible subjects and effective treatment of patients with gallstones.

Mechanistic Aspects of the Evolution of 3D Cholesterol Crystallites in a Supported Lipid Membrane via a Quartz Crystal Microbalance with Dissipation Monitoring.

The irreversible formation of cholesterol monohydrate crystals within biological membranes is the leading cause of various diseases, including atherosclerosis. Understanding the process of cholesterol crystallization is fundamentally important and could also lead to the development of improved therapeutic strategies. This has driven several studies investigating the effect of the environmental parameters on the induction of cholesterol crystallite growth and the structure of the cholesterol crystallites, while the kinetics and mechanistic aspects of the crystallite formation process within lipid membranes remain poorly understood. Herein, we fabricated cholesterol crystallites within a supported lipid bilayer (SLB) by adsorbing a cholesterol-rich bicellar mixture onto a glass and silica surface and investigated the real-time kinetics of cholesterol crystallite nucleation and growth using epifluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) monitoring. Microscopic imaging showed the evolution of the morphology of cholesterol crystallites from nanorod- and plate-shaped habits during the initial stage to mostly large, micron-sized three-dimensional (3D) plate-shaped crystallites in the end, which was likened to Ostwald ripening. QCM-D kinetics revealed unique signal responses during the later stage of the growth process, characterized by simultaneous positive frequency shifts, nonmonotonous energy dissipation shifts, and significant overtone dependence. Based on the optically observed changes in crystallite morphology, we discussed the physical background of these unique QCM-D signal responses and the mechanistic aspects of Ostwald ripening in this system. Together, our findings revealed mechanistic details of the cholesterol crystallite growth kinetics, which may be useful in biointerfacial sensing and bioanalytical applications.

The Effect of the Phospholipid Bilayer Environment on Cholesterol Crystal Polymorphism.

Cholesterol crystallization from mixtures of unesterified cholesterol with phospholipids and cholesterol esters is believed to be a key event in atherosclerosis progression. Not much is understood, however, about the influence of the lipid environment on cholesterol crystallization. Here we study cholesterol monohydrate crystal formation from mixed bilayers with palmitoyl-oleoyl-phosphatidylcholine (POPC), dipalmitoyl-phosphatidylcholine (DPPC) and sphingomyelin. We show that disordered phospholipids and sphingomyelin stabilize the formation of crystal plates of the triclinic cholesterol monohydrate polymorph, whereas saturated glycerolipids stabilize helical and tubular crystals of the metastable monoclinic polymorph. We followed the subsequent transformation of these helical crystals into the stable triclinic plates. Discovering the relations between membrane lipid composition and cholesterol crystal polymorphism may provide important clues to the understanding of cholesterol crystal formation in atherosclerosis.

The physical presence of gallstone modulates ex vivo cholesterol crystallization pathways of human bile.

BackgroundCholesterol crystallization is an essential step toward gallstone formation. Although model bile studies showed that competition occurs between the gallstone surface and the surrounding aqueous phase for cholesterol molecules available for crystallization, this has not been investigated in human bile.MethodsFresh gallbladder bile was obtained during laparoscopic cholecystectomy from 13 patients with cholesterol (n = 10) or pigment (n = 3) stones. Small cholesterol gallstones were collected from another two patients. Both native and ultrafiltered bile with or without added gallstones was analysed by polarized light microscopy for the presence of arc-like and needle-like anhydrous cholesterol crystals and classic cholesterol monohydrate crystals. Weight of the added stones was evaluated before and after 21 days of bile incubation.ResultsIn unfiltered bile, the presence of stones was associated with a trend towards less anhydrous cholesterol crystals, but significantly more aggregated cholesterol monohydrate crystals. In ultrafiltered bile, the presence of stones tended to inhibit the formation of arc-like or needle-like crystals and was associated with significantly greater amounts of both plate-like and aggregated cholesterol monohydrate crystals. After 21 days of the incubation, stone weight was decreased in both unfiltered (–4.5 ± 1.6%, P = 0.046) and ultrafiltered bile (–6.5 ± 1.5%, P = 0.002). Bile from pigment-stone patients was clear in the absence of stones, but showed early appearance of plate-like and aggregated cholesterol monohydrate crystals in all samples to which cholesterol gallstones were added.ConclusionsThe physical presence of cholesterol gallstones in both native and filtered bile greatly influences cholesterol crystallization pathways. Whereas cholesterol monohydrate crystals increase, anhydrous cholesterol crystals tend to be inhibited. Detachment of solid cholesterol crystals from the gallstone surface may explain these findings.

Role of the Free Radicals in Mechanisms of Gallstone Formation: An EPR Study.

The mechanism of gallstone formation is not well understood. Abnormal regulation of hepatic cholesterol, bile acid synthesis or esterification, deposition of cholesterol monohydrate crystals and gall bladder dysfunction are thought to be the principal metabolic aberrations that may cause gallstone formation. One plausible mechanism leading to these abnormalities is the role of free radicals, whose presence can be investigated using Electron Paramagnetic Resonance (EPR). Surgically removed gall bladder stones were used to obtain purified bilirubin, which was irradiated in vitro with visible light and measured with EPR in the presence of and without oxygen. EPR detected oxidized bilirubin free radical (BFR) (g=2.003, ΔH=1.0 mTl) in the gallstones. In vitro exposure of bilirubin to visible light in the presence of oxygen induced BFR formation; its intensity was radiation time dependent and decreased under the influence of β-carotene; irradiation in a vacuum did not generate BFRs. These results indicate the important role of oxidative processes (oxidation of bilirubin) in the gallstone formation. In oxidative stress, bilirubin acting as a second type photosensitizer undergoes rapid oxidation and free radical polymerization that plays an important role in the nucleation and deposition of gallstones.

Thyroid dysfunction, either hyper or hypothyroidism, promotes gallstone formation by different mechanisms

We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male C57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% (w/w) butter fat, 1% (w/w) cholesterol, and 0.5% (w/w) cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Trβ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxrα, Rxr, and Cyp7α1 were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in C57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. Hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxrα and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.

The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.

A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. To study whether the CCK-1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing the bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.

Cholesteryl palmitate crystals in bronchoalveolar lavage fluid smears as a possible prognostic biomarker for chronic interstitial pneumonia: A preliminary study.

We observed cholesterol-like crystals (Crystal X) in the bronchoalveolar lavage fluid (BALF) smears of patients with diffuse pulmonary disease. We analyzed the clinical data of patients with and without crystals, and elucidated the structure of Crystal X and its concentration in the BALF. Two hundred eighty-nine patients with diffuse pulmonary disease who underwent bronchoalveolar lavage (BAL) were analyzed. The relationships between the presence and number of Crystal X in BALF smears and clinical parameters were investigated. Furthermore, structure determination and quantitative analyses of the crystals were performed. Seventy-five (26.0%) patients had Crystal X in their BALF. The crystals were frequently observed in patients with chronic interstitial pneumonia (CIP, 60/160=35.3%). Patients with Crystal X exhibited significantly higher serum Kerbs von Lungren 6 antigen and surfactant protein-D levels (P<0.01) and lower percentage vital capacity (P<0.05) than patients without Crystal X. The number of crystals was significantly correlated with these parameters. The presence of crystals was also associated with a lower survival rate at 1 year after the BAL. The interfacial angles of the crystals were 126±2° and 144±2°, different from those of cholesterol monohydrate crystals. Infrared absorption spectrometry showed Crystal X was cholesteryl palmitate. Its concentration was significantly higher in BALF with crystals than in BALF without crystals (P<0.01). Crystal X in the BALF of patients with diffuse pulmonary disease was identified as cholesteryl palmitate, which may be a useful prognostic biomarker for CIP.

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

To distinguish the lithogenic effect of the classical estrogen receptor α (ERα) from that of the G protein-coupled receptor 30 (GPR30), a new estrogen receptor, on estrogen-induced gallstones, we investigated the entire spectrum of cholesterol crystallization pathways and sequences during the early stage of gallstone formation in gallbladder bile of ovariectomized female wild-type, GPR30((-/-)), ERα((-/-)), and GPR30((-/-))/ERα((-/-)) mice treated with 17β-estradiol (E2) at 6 µg/day and fed a lithogenic diet for 12 days. E2 disrupted biliary cholesterol and bile salt metabolism through ERα and GPR30, leading to supersaturated bile and predisposing to the precipitation of cholesterol monohydrate crystals. In GPR30((-/-)) mice, arc-like and tubular crystals formed first, followed by classical parallelogram-shaped cholesterol monohydrate crystals. In ERα((-/-)) mice, precipitation of lamellar liquid crystals, typified by birefringent multilamellar vesicles, appeared earlier than cholesterol monohydrate crystals. Both crystallization pathways were accelerated in wild-type mice with the activation of GPR30 and ERα by E2. However, cholesterol crystallization was drastically retarded in GPR30((-/-))/ERα((-/-)) mice. We concluded that E2 activates GPR30 and ERα to produce liquid crystalline versus anhydrous crystalline metastable intermediates evolving to cholesterol monohydrate crystals from supersaturated bile. GPR30 produces a synergistic lithogenic action with ERα to enhance E2-induced gallstone formation.

Pathogenetic features of the hepatobiliary system damage in patients with metabolic syndrome

A review of articles covering the modern views on the hepatobiliary system damage features in patients with clinical manifestations of metabolic syndrome. 196 original papers published over the last 6 years were found using PubMed, MEDLINE, E-library databases, from which 50 articles were picked out for the review. Considering high prevalence of metabolic syndrome, the studied problem seems important. The influence of obesity and associated insulin resistance at launching the systemic inflammation leading to activation of immunological cascade resulting in terget organs damage in such patients is highlighted. The pathogenesis of liver, gall bladder and bile ducts damage at presence of metabolic disorders is outlined. The role of inflammatory and anti-inflammatory cytokines in liver tissue damage is described. Based on the data of literature review and own data, it was shown that the lipid metabolism alterations are associated with liver functional damage, and liver in patients with metabolic syndrome is not only participating in atherogenic dislipoproteinemia development, but also damaged as the target organ. It was revealed that the key link in the gall bladder pathology in patients with metabolic syndrome is the lipid metabolism alterations that lead to the excess cholesterol bile excretion and cholesterol monohydrate crystals sedimentation. It was also shown that the functionally affected hepatocytes produce imperfect bile micelles with high cholesterol and low phospholipid levels, increasing the bile lithogenicity. High bile cholesterol level stimulating the mucin secretion by gall bladder wall, which is the important component of bile sediment and increases the bile crystalloids aggregation.

Comparative Proteomic Analysis of Gallbladder Bile Proteins Related to Cholesterol Gallstones

BackgroundNucleation of cholesterol monohydrate crystals following the aggregation and fusion of cholesterol-enriched vesicles is a critical procedure in the formation of cholesterol gallstone. Biliary proteins play important roles in the process. It is inefficient to screen pro-nucleating or anti-nucleating proteins with routine physiochemical techniques, by which we discovered several pro-nucleating proteins.Methodology/Principal FindingsBased on comparative proteomic technologies, we investigated the differentially expressed proteins between the cholesterol gallstone and control groups, and between the vesicular phase and micellar phase. There are 401±75 spots detected on the cholesterol gallstone group and 389±94 spots on the control group gels, 120±24 spots detected on vesicular phase and 198±37 on micellar phase gels, and accordingly 22 and 8 differentially expressed proteins were identified successfully, respectively. Three of them, HSA, Profilin and Retinol Binding Protein, were validated by Western blot.Conclusion/SignificanceSome of the identified proteins are in good agreement with proteins reported to be involved in the gallstone formation before. The information from this study might provide some important clues to uncover the key proteins involved in the formation of cholesterol gallstone.

Cholesterol nucleation-promoting potency of retinol binding protein

Objective To detect the nucleation-promoting potency of retinol binding protein (RBP) in the simulated bile system,and observe the process of cholesterol nucleation and crystallization.Methods Small and synthetic bile systems were synthesized.RBP (RBP group),α1-acid glycoprotein (AAG,AAG group) and albumin ( Alb,Alb group) were added into the Small bile respectively.The derived indices of nucleation time,crystal growth rate and final concentration of crystal were studied by Busch method.Alb ( control group) and RBP (experimental group) were added into the Small and synthetic bile systems respectively.The nucleation time was detected by polarizing microscopy according to the Holan method and the nucleation-promoting potency was calculated according to the Holzbach method. The morphological dynamics of cholesterol nucleation and crystallization were observed under a light microscope.All data were analyzed by using the analysis of variance or the t test.Results The derived indices of nucleation time,crystal growth rate and final concentration of crystal were 0.66,1.29 and 1.01 in the AAG group,and 0.73,1.02,0.95 in the RBP group,respectively.In the Small bile system,the average nucleation time of cholesterol monohydrate crrystals were ( 12.2 ± 1.2 )days in the control group and (8.2 ± 1.5)days in the experimental group,respectively,with a significant difference between the 2 groups (t =2.97,P ＜ 0.05 ).The nucleation activity of RBP was 0.67 in the Small bile system.In the synthetic bile system,the average nucleation time of cholesterol monohydrate crystals were (9.5 ± 1.1 ) days in the control group and (7.5 ± 1.1 )days in the experimental group,respectively,with a significant difference between the 2 groups ( t =2.35,P ＜ 0.05 ).The nucleation activity of RBP was 0.79 in the synthetic bile system.The process of cholesterol nucleation and crystallization was divided into 4 stages,and the split phenomenon appeared in the bile system at day 21.Conclusion RBP is a pro-nucleation factor in simulated bile system. Key words: Cholelithiasis; Cholesterol; Nucleating proteins

Rafting for gallstones by slowing mass transit

Rafting for gallstones by slowing mass transit

Characterization of Cholesterol Crystals in Atherosclerotic Plaques Using Stimulated Raman Scattering and Second-Harmonic Generation Microscopy

Cholesterol crystals (ChCs) have been identified as a major factor of plaque vulnerability and as a potential biomarker for atherosclerosis. Yet, due to the technical challenge of selectively detecting cholesterol in its native tissue environment, the physiochemical role of ChCs in atherosclerotic progression remains largely unknown. In this work, we demonstrate the utility of hyperspectral stimulated Raman scattering (SRS) microscopy combined with second-harmonic generation (SHG) microscopy to selectively detect ChC. We show that despite the polarization sensitivity of the ChC Raman spectrum, cholesterol monohydrate crystals can be reliably discriminated from aliphatic lipids, from structural proteins of the tissue matrix and from other condensed structures, including cholesteryl esters. We also show that ChCs exhibit a nonvanishing SHG signal, corroborating the noncentrosymmetry of the crystal lattice composed of chiral cholesterol molecules. However, combined hyperspectral SRS and SHG imaging reveals that not all SHG-active structures with solidlike morphologies can be assigned to ChCs. This study exemplifies the merit of combining SRS and SHG microscopy for an enhanced label-free chemical analysis of crystallized structures in diseased tissue.

Resolving the Structure of Ordered Domains in Single Hydrated Lipid Bilayers by New X-Ray Diffraction Methodology

Saturated lipids spontaneously form rigid domain in lipid membranes. X-ray scattering from these domains indicate that their sizes vary between 2-60nm and that the lipids within are well ordered. This research characterizes the lipid packing and phase behavior of such domains in bilayers composed of sphingomyelin, ceramide, DPPC, POPC and cholesterol.Over the past 30 years, X-ray studies were performed on either lipid monolayers, or multilayers. Several attempts have been made over the past 20 years, to perform experiments on single lipid bilayers, all of which have failed due to the strong scattering of the bilayer's surrounding water. In order to overcome this challenge we have developed a new system, which enables measurements of single hydrated lipid bilayers using synchrotron radiation.1This research provided, for the first time, knowledge on the interactions between the opposing lipids of each leaflet at the core of the bilayer. Comparisons with lipid monolayers made of the same lipid composition showed that the phase behavior of the ordered domains differs greatly, indicating strong correlation between the opposing leaflets of the bilayer.2Large quantities of cholesterol monohydrate crystals are found in atherosclerotic plaques. Studies have shown that these crystals are an early cause of inflammation. We managed to characterize the conditions under which cholesterol molecules nucleate at the lipid bilayer. Results demonstrate that cholesterol nucleation depends on the lipid composition.2,3The study was awarded the 2011 Barenholz Prize for basic research on sphingolipids.1. Ziblat, R.; Leiserowitz, L.; Addadi, L., Angewandte Chemie-International Edition 2011, Accepted for publication.2. Ziblat, R.; Leiserowitz, L.; Addadi, L., J Am Chem Soc 2010, 132, (28), 9920-9927.3. Ziblat, R.; Kjaer, K.; Leiserowitz, L.; Addadi, L., Angewandte Chemie-International Edition 2009, 48, (47), 8958-8961.

Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice

ObjectiveStudies in humans support a role for the oral pathogen Porphyromonas gingivalis in the development of inflammatory atherosclerosis. The goal of this study was to determine if P. gingivalis infection accelerates inflammation and atherosclerosis in the innominate artery of mice, an artery which has been reported to exhibit many features of human atherosclerotic disease, including plaque rupture. Methods and resultsApolipoprotein E-deficient (ApoE−/−) mice were orally infected with P. gingivalis, and magnetic resonance imaging (MRI) was used to monitor the progression of atherosclerosis in live mice. P. gingivalis infected mice exhibited a statistically significant increase in atherosclerotic plaque in the innominate artery as compared to uninfected mice. Polarized light microscopy and immunohistochemistry revealed that the innominate arteries of infected mice had increased lipids, macrophages and T cells as compared to uninfected mice. Increases in plaque, total cholesterol esters and cholesterol monohydrate crystals, macrophages, and T cells were prevented by immunization with heat-killed P. gingivalis prior to pathogen exposure. ConclusionsThese are the first studies to demonstrate progression of inflammatory plaque accumulation in the innominate arteries by in vivo MRI analysis following pathogen exposure, and to document protection from plaque progression in the innominate artery via immunization.

Cholesterol Embolization Syndrome

Cholesterol embolization syndrome refers to embolization of the contents of an atherosclerotic plaque (primarily cholesterol crystals) from a proximal large-caliber artery to distal small to medium arteries causing end-organ damage by mechanical plugging and an inflammatory response. Synonyms used in the medical literature include atheromatous embolization, cholesterol crystal embolization, and atheroembolism. Cholesterol embolization syndrome should be distinguished from the related and much more common syndrome of arterio-arterial thromboembolism in which fragments of a thrombus that forms atop an atheromatous plaque in the aorta or a large artery travel distally and occlude medium to large arteries.1 Cholesterol embolization syndrome is generally characterized by a multitude of small emboli (showers of microemboli) occurring over time. This is in contrast to arterio-arterial thromboembolism, which is usually characterized by an abrupt release of 1 or a few large emboli, leading to severe ischemia of target organs. Cholesterol embolization syndrome has a variety of clinical presentations. Cholesterol emboli originating in the descending thoracic and abdominal aorta may lead to renal failure, gut ischemia, and emboli to the skeletal muscles and the skin. Dermatologic manifestations (most commonly livedo reticularis and blue toe syndrome) are usually confined to the lower extremities but may extend to the abdomen and the chest. Cholesterol emboli originating in the ascending aorta may in addition cause neurological damage that is typically diffuse and due to small infarcts. Cholesterol embolization syndrome is also characterized by a nonspecific acute inflammatory response leading to constitutional symptoms (such as fever and malaise) and abnormalities in laboratory tests (such as hypereosinophilia and elevated erythrocyte sedimentation rate). These manifestations will be discussed in detail later in the text. Danish physician Fenger and his colleagues appear to have provided the first description of atheroembolism in the Danish medical brochure Ugeskrift for Laeger (Doctors’ Weekly).2 In 1844, they …

Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice

We investigated the effect of gallbladder hypomotility on cholesterol crystallization and growth during the early stage of gallstone formation in CCK knockout mice. Contrary to wild-type mice, fasting gallbladder volumes were enlarged and the response of gallbladder emptying to a high-fat meal was impaired in knockout mice on chow or the lithogenic diet. In the lithogenic state, large amounts of mucin gel and liquid crystals as well as arc-like and tubular crystals formed first, followed by rapid formation of classic parallelogram-shaped cholesterol monohydrate crystals in knockout mice. Furthermore, three patterns of crystal growth habits were observed: proportional enlargement, spiral dislocation growth, and twin crystal growth, all enlarging solid cholesterol crystals. At day 15 on the lithogenic diet, 75% of knockout mice formed gallstones. However, wild-type mice formed very little mucin gel, liquid, and solid crystals, and gallstones were not observed. We conclude that lack of CCK induces gallbladder hypomotility that prolongs the residence time of excess cholesterol in the gallbladder, leading to rapid crystallization and precipitation of solid cholesterol crystals. Moreover, during the early stage of gallstone formation, there are two pathways of liquid and polymorph anhydrous crystals evolving to monohydrate crystals and three modes for cholesterol crystal growth.