Cholesterol & Steroid Metabolism PDF

(003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20...

(003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 OUTLINE C.DISCUSSION Although cholesterol can be synthesized in almost all cells, the I. HYPERCHOLESTERLINEMIA liver, intestine, and the steroidogenic tissues such as the adrenal A. MAJOR CLASSES OF LIPOPROTEINS glands and reproductive tissues are the primary sites. B. HYPERLIPIDEMIA II. CHOLESTASIS OF PREGNANCY Cholesterol is synthesized by virtually all tissues in humans, A. BILE SALTS although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions to the body’s cholesterol pool. I. HYPERCHOLESTEROLINEMIA As with fatty acids, cholesterol is formed using the carbons of acetyl coenzyme A (CoA). Two acetyl CoA molecules condense A.CASE 1 to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added by HMG CoA synthase, producing HMG CoA A 48-year-old male presents to the clinic because of concerns (hydroxymethylglutaryl-CoA), a six-carbon compound. about heart disease. He reports that his father died from a heart attack at age 46, and his older brother has also had a heart REMEMBER THAT EACH ACETYL COA PROVIDES 2 attack at age 46 but survived and is on medications for elevated CARBONS cholesterol. The patient reports chest pain occasionally with HMG CoA is reduced then to mevalonate by HMG CoA ambulation around his house and is not able to climb stairs reductase. This is the very reason that HMG CoA is the rate- without significant chest pain and shortness of breath. The limiting step of cholesterol synthesis. It occurs in the cytosol, physical exam is normal, and the physician orders an uses two molecules of NADPH as the reducing agent. electrocardiogram (ECG), exercise stress test, and blood work. The patient’s cholesterol result comes back as 350 mg/dL Remember that dyslipidemia or problem with lipids can have (normal 200). The physician prescribes medication, which he different forms. It can be hypercholesterolemia meaning the total states is directed at the rate-limiting step of cholesterol cholesterol is elevated but it is not specified what type of biosynthesis. cholesterol is elevated. Hypertriglyceridemia is also a problem meaning elevated triglycerides but LDL and HDL can also be 1. What is the rate-limiting step of cholesterol normal in hypertriglyceridemia. Another problem aside from hypercholesterolemia and hypertriglyceridemia is low HDL and metabolism? elevated LDL The enzyme hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) catalyzes an early rate-limiting Among the four high LDL is the most worrisome is the one that step in cholesterol biosynthesis. gives us the most risk factors for atherosclerosis. 2. What is the class of medication prescribed? Notice that low HDL is actually a risked factor dyslipidemia. HMG-CoA reductase inhibitor, otherwise known as “statin” medications. In the liver, cholesterol is synthesized in the endoplasmic reticulum (ER) along with phospholipids, triacylglycerides, and B.CLINICAL CORRELATION apoproteins. Prelipoprotein particles are assembled in the ER and then transferred to the Golgi. Further processing and Hyperlipidemia is one of the most treatable risk factors of addition of cholesterol esters occur in the Golgi, culminating in atherosclerotic vascular disease. In particular, the level of the the formation of secretory granules containing lipoprotein low-density lipoprotein (LDL) correlates with the pathogenesis of particles. atherosclerosis. Exercise, dietary adjustments, and weight loss are the initial therapy of hyperlipidemia. If these are not These vesicles then fuse with the plasma membrane and export sufficient, then pharmacologic therapy is required. The exact cholesterol from the cell via exocytosis in the form of VLDLs (see below), which then enter the circulation. As the lipoprotein LDL targets depend on the patient’s risk of cardiovascular complexes are transported through the bloodstream they are disease. For example, if an individual has had a converted from VLDL to IDL to LDL by the removal of cardiovascular event previously (heart attack or stroke), the LDL triacylglycerides by lipoprotein lipase, which is located on the target is 100 mg/dL; 1 to 2 risk factors without prior events = 130 surface of capillary epithelial cells. Cholesterol and mg/dL; and no risk factors = 160 mg/dL. triacylglycerides (TAGs) are transported as complexes in the form of lipoprotein particles. Page 1 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 These lipoprotein particles contain a core of TAGs and Contain five different apoproteins cholesteryl esters surrounded by a monolayer of phospholipids, - VLDL is produced in the liver, mainly from dietary cholesterol, and specific proteins called apoproteins. The carbohydrate. apoproteins, specific to each type of lipoprotein, enable the hydrophobic lipids to be transported in the aqueous environment 3. Intermediate density lipoproteins (IDLs) of the bloodstream. They also contain signals that target the - IDL consists of the remains of VLDL after digestion of lipoprotein particles to the cells or activate enzymes. The some of the triacylglycerols. IDL can either be lipoprotein particles vary in density depending on the lipid/protein endocytosed by liver cells and digested by lysosomal enzymes or converted to LDL by further digestion of ratio and are named based on these densities. The higher the triacylglycerols. lipid/protein ratio, the lower the density of the particle. 4. Low-density lipoproteins (LDLs) Higher Protein Over Lipid ratio means there is more protein Primarily cholesteryl esters in that lipid particle; the safer the lipid is. Bigger and denser Apoprotein B-100 particle - LDL undergoes endocytosis and lysosomal digestion, Higher Lipid Over Protein ratio means there is more lipid in that particle; the uglier the lipid is and it is said that if you both in the liver and in the peripheral tissues. have more lipid over protein ratio the smaller the particle 5. High-density lipoproteins (HDLs) This is the very reason why VLDL and LDL are considered bad Secreted by liver and intestine cholesterol while HDL is considered good cholesterol Contains apoprotein A-1 “Good cholesterol,” high levels associated with low incidence Low HDL (Good Cholesterol and High LDL (Bad Cholesterol) are atherosclerosis risk factors for atherosclerosis - HDL transfers proteins (including an activator of lipoprotein lipase, apoC-II) to chylomicrons and VLDL. HDL also picks up cholesterol from peripheral tissues and from other blood lipoproteins. This cholesterol ultimately returns to the liver. The LDLs (containing cholesteryl esters) are taken up by cells by a process known as receptor-mediated endocytosis. The LDL receptor mediates this endocytosis and is important to cholesterol metabolism. LDLs bind to these receptors, which recognize apoprotein B-100. After LDL binding to the LDL receptor, the ligand-receptor complexes cluster on the plasma membrane in coated pits, which then invaginate forming coated vesicles. These coated vesicles are internalized and clathrin, the protein composing the lattice in membrane coated pits, is removed. These vesicles are now called endosomes and these endosomes fuse with the lysosome. The LDL receptor–containing membrane buds off and is recycled Figure 1. Major Classes of Lipoproteins to the plasma membrane. A, MAJOR CLASSES OF LIPOPROTEINS Fusion of the lysosome and endosome releases lysosomal proteases that degrade the apoproteins into amino acids. Major classes of lipoproteins and some of their properties: Lysosomal enzymes also hydrolyze the cholesteryl esters to free 1. Chylomicrons cholesterol and fatty acids. The free cholesterol is released into Lowest density the cell’s cytoplasm, and this free cholesterol is then available to Transport dietary lipids from the intestine to target tissues be used by the cell. - Chylomicrons are produced in intestinal cells from dietary lipid. Excess cholesterol is re-esterified by acyl CoA:cholesterol acyltransferase (ACAT), which uses fatty acyl-CoA as the source 2. Very-low-density lipoproteins (VLDLs) of activated fatty acid. Free cholesterol affects cholesterol By liver cells to transport endogenously synthesized lipids to metabolism by inhibiting cholesterol biosynthesis. Cholesterol target cells inhibits the enzyme β-hydroxy-β-methylglutaryl-CoA reductase Production controlled by lipid availability (HMG-CoA reductase), which catalyzes an early rate-limiting step Page 2 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 in cholesterol biosynthesis. HMG-CoA reductase is the target of 5. Type V the statin drugs in wide use for treating patients with elevated - An uncommon disorder, sometimes familial, cholesterol levels. In addition, free cholesterol inhibits the associated with defective clearance of exogenous synthesis of the LDL receptor, thus limiting the amount of LDLs and endogenous triglycerides and the risk of life- that are taken up by the cell. threatening pancreatitis. Having just the right amount of LDL even if they are considered The disease familial hypercholesterolemia results from a bad cholesterol, in the blood they will be still endocytose by the mutation in the LDL-receptor gene found on chromosome 19. cell in the body and they will still be used as a form of energy The overall phenotype of the inability to internalize the LDL receptor can be caused by three different types of defects. In the However, having an elevated LDL or excessive amount of first type, the LDL receptor is not produced. cholesterol in the body, these free cholesterols will inhibit the rest of the LDL receptors in the different types of cell and they will The second type is a result of a mutation in the terminal region of stay in the plasma in the blood and eventually become risk factor the receptor that results in an LDL receptor unable to bind LDL. for atherosclerosis The third type is caused by a mutation in the C terminal region that prevents the LDL-receptor complex from undergoing Most common reason for atherosclerosis is excessive intake of endocytosis. In the absence of a functioning LDL receptor, LDL cholesterol. Found among patient who are: cholesterol levels are greatly elevated in individuals with this Obese/ Central Obesity disease. This elevation results in premature atherosclerosis of With metabolic syndrome the coronary arteries. Hypertensive With Dyslipidemia Genetic defects in apoprotein B-100, the protein in the LDL With Familial hypercholesterolemia recognized by the LDL receptor, also exist and lead to elevated (*Patient who are on a vegetarian with familial LDL because the LDL complex is not recognized by the LDL hypercholesterolemia are still at risk for atherosclerosis) receptor. A diet low in fat and cholesterol, an exercise regimen, and anticholesterol medications are used in the treatment of this disease. B. HYPERLIPIDEMIA CLINICAL CORRELATION Hyperlipidemia is defined as elevated lipoprotein levels in the plasma, which may be primary or secondary. Several different In the hyperlipidemias, the blood levels of cholesterol or types of hereditary hyperlipidemias have been defined. triacylglycerols, or both, are elevated resulting from 1. Type I overproduction of lipoproteins or defects in various stages of their - A relatively rare inherited deficiency of either degradation. Elevations of blood lipid levels (particularly LDL) are lipoprotein lipase activity or the lipoprotein lipase- associated with a high incidence of heart attacks and strokes. In activating protein apo C-II. This results in the familial hypercholesterolemia, cellular receptors for LDL are inability to effectively remove chylomicrons and defective. Therefore, LDL is not taken up at a normal rate by the VLDL triglycerides from the blood. cells and degraded by lysosomal enzymes. The consequent increase of blood LDL (which contains a large amount of 2. Type II cholesterol and cholesterol ester) is associated with xanthomas - Includes familial hypercholesterolemia described in (lipid deposits often found under the skin) and coronary artery detail below. disease. The treatment may involve diets low in saturated fat and cholesterol, HMG-CoA reductase inhibitors (e.g., lovastatin), bile acid–binding resins, and nicotinic acid (niacin). 3. Type III - Associated with abnormalities of apolipoprotein E In hypertriglyceridemia due to deficiencies in LPL or apoC-II (apo E) and defective conversion and removal of (the lipoprotein lipase activator), triacylglycerol levels rise VLDL from the plasma. markedly because of decreased degradation of VLDL and chylomicrons. These deficiencies are associated with 4. Type IV characteristic xanthomas and an intolerance to fatty foods. Low- - A common disorder characterized by variable fat diets may be effective (see below). In diabetes mellitus elevations of plasma triglycerides contained (DM), VLDL levels are often elevated, which results in high blood predominantly in VLDL. This leads to a possible triacylglycerol levels. Cholesterol may also be elevated. predisposition to atherosclerosis and often has a familial distribution. In diabetes, elevated VLDL levels result from deranged carbohydrate and lipid metabolism caused by decreased insulin levels (Type 1 DM) or insulin resistance (Type 2 DM). The consumption of trans–fatty acids (trans fats) is also detrimental to overall lipid health. Trans fats (which occur when polyunsaturated Page 3 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 fatty acids are partially hydrogenated in order to increase their Cigarette Smoker shelf life; the act of reducing some of the double bonds in the Hypertension fatty acids results in some trans double bonds being created. Low HDL Recall that virtually all naturally occurring unsaturated fatty acids Family History of Premature Coronary Heart Disease (First are of the cis configuration.) raise LDL levels, and reduce HDL degree relative diagnosed with CHD at the age of 55 years levels, through an ill-defined mechanism. The recommended amount of trans fat consumption is no more than 1% of total old for male or less than 65 years old for female calories consumed, which covers the small amount of trans fats found in our foods. Determining Patient Risk C. COMPREHENSION QUESTIONS LOW RISK - Patient Has 0 to 1 Risk Factor MODERATE RISK- Patient at least 2 Risk factors and a 1) A patient presents in your office with very high levels of serum Framingham point score of at least 10-20% risk for CHD at cholesterol. After a series of tests, you conclude that the patient 10 years has high circulating levels of LDL cholesterol, but has normal HIGH RISK- Patient has History of stroke, Myocardial levels of the liver LDL receptor. One possible explanation for this infarction, Diabetic observation is which of the following? HIGH LDL A. The patient has a mutated form of apoprotein B-100. LDL TARGET LEVELS B. The inability to selectively remove cholesterol from the LDL complex. Low Risk - less than 160 mg/dL C. The absence of the enzyme lipoprotein lipase. Moderate Risk- less than 130 mg/dL D. Decreased levels of acyl-CoA: cholesterol acyltransferase. High Risk- less than 100 mg/dL E. Altered phosphorylation of the LDL receptor. TREATMENT (Apoprotein B-100 is the protein that is recognized by the LDL Treat first with Therapeutic Life Style change (Proper diet receptor since the test says that there is normal levels of liver and Exercise) LDL receptor it is right to assume that the problem is with the If patient is not able to comply medication is needed apoprotein B-100) Treatment of choice is “STATINS” (atorvastatin, simvastatin, rosuvastatin) Guidelines for Screening for Dyslipidemia using Lipid Profile Mechanism of action of statin it inhibits HMG CoA reductase Patient is 45 years unless patient is Common Side Effect Overweight/Obese Gastrointestinal Upset Has known Familial Hypercholesterolemia Muscle Pain/Weakness Diabetic or early Diabetes Rhabdomyolysis Hypertensive or has Hypertension (patient with systolic blood pressure of at least 140 or diastolic pressure with Elevated Liver Enzyme (Do not prescribe statins to patients at least 90) with history of hepatitis) Cigarette smoker *It is said Elevated liver enzyme levels at least 3 times of the Screening is done with Lipid Profile with at least 8 hours of upper limit of the normal value which is 40 IU/L fasting. Check the SGPT (Serum Glutamic Pyruvic Transaminase)/SGOT (Serum Glutamic Oxaloacetic Transaminase) if the SGPT is more Components of Lipid Profile than 120 IU/L do not give statin. Triglyceride ASSESSING THE RESPONSE TO THERAPY OF THE Cholesterol PATIENT HDL Assess after 6 weeks check the dose of the statin if it is LDL enough or if the patient is responding Ideally if the dose is adequate there is a 30-40% TREATMENT TARGETS decrease in the LDL level 5 Major Risk Factors If the patient is not responding increase the dose Age o Female at least 55 years old o Male at least 45 years old Page 4 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 C. Formation of mevalonate from hydroxymethylglutaryl- CoA D. Kinase that phosphorylates hydroxymethylglutaryl-CoA C. HYPERTRIGLYCERIDEMIA reductase E. Condensation of acetyl-CoA & acetoacetyl-CoA to Marked Elevation of TAG of at least 150 mg/dL hydroxymethylglutaryl-CoA Hypertriglyceridemia Levels β-hydroxy-β-methylglutaryl-CoA reductase (HMG-CoA reductase) Border line to High- 150- 199 mg/dL High- 200-499 mg/dL Enzyme responsible in forming Very High- 500 mg/dL or greater hydroxymethylglutaryl-CoA from mevalonate Treatment for Hypertriglyceridemia II. CHOLESTASIS OF PREGNANCY Advice for change of life style (Diet and Exercise) Medication of choice are FIBRATES (Fenofibrates) at a dose A. CASE of 45-145 mg A 26-year-old female at 35 weeks gestation presents to Niacin can also be use as medication the clinic with complaints of generalized itching. Patient reports no rash or skin changes. She denies any LOW HDL change in clothing detergent, soaps, or perfumes. She If the HDL level is less than >40 mg/dL denies nausea and vomiting and otherwise feels well. Also, considerd as an independent risk factor for CHD On physical exam, there are no rashes apparent on her skin and only some excoriations from itching. Blood Medication for Low HDL work reveals slightly elevated serum transaminase and Fish oil or Fish Oil capsules bilirubin levels. Niacin 1. What is the patient’s likely diagnosis? 2) A patient with hereditary type I hyperlipidemia presents with Cholestasis of pregnancy elevated levels of chylomicrons and VLDL triglycerides in the 2. What are treatment options? blood. The main function of the chylomicrons in circulation is to Oral antihistamines, cholestyramine, do which of the following? ursodeoxycholic acid 3. What is the cause of the patient’s generalized A. Transport lipids from the liver itching? B. Transport dietary lipids from the intestine to target Increased serum bile salts and accumulation of bile tissues salts in the dermis of the skin C. Transport cholesterol from IDL to LDL D. Act as a receptor for triacylglycerols in the liver B. CLINICAL CORRELATION E. Bind cholesterol esters exclusively 1. Cholestasis of pregnancy: - Cholestasis of pregnancy is a condition that Liver and intestines – main sources of the body’s circulating lipid slows or stops the normal flow of bile in the Liver: synthesize the lipids gallbladder. It can cause severe itching. This is Intestines: dietary lipids the most common symptom. CHYLOMICRONS - Intrahepatic cholestasis of pregnancy is a Carry TAGs and cholesterol esters from the syndrome of unknown etiology characterized intestines to the target tissues by a 100-fold increase in maternal and fetal VLDL blood bile salt levels. Bile salts are produced in Carry lipids from the liver into the circulation both the fetal and maternal liver. The fetus transfers the bile salts across the placenta for 3) Free cholesterol can affect cholesterol metabolism in the body disposal. When the function of the maternal by inhibiting cholesterol biosynthesis. The step at which free gallbladder is slowed (normal flow of bile from cholesterol inhibits its biosynthesis is by inhibiting which of the the gallbladder is impeded), bile salts can following processes? accumulate in the liver and bloodstream, ultimately resulting in the classical pruritus A. Cyclizing of squalene to form lanosterol symptom. B. Reduction of 7-dehydrocholesterol to form cholesterol - In pregnancy, it is expected that the gallbladder is slowed down. Page 5 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 o Reason why pregnancy is a risk factor surface/hydrophilic portion will be outside in contact of cholesterol gallstones with the aqueous environment > lipid will easily o When maternal gallbladder is slowed pass through the hydrophilic portion in the blood. down, bile salts now can accumulate - In the liver, bile salts are formed from in the liver and in the blood stream cholesterol by hydroxylation of the sterol ring, o Resulting in the classic pruritus oxidation of the side chain, and conjugation of symptom the carboxylic acid group with glycine or - Generalized itching and, possibly, jaundice taurine. may result. - The bile salts are stored in the gallbladder and - It is speculated that the hormones such as released during a meal to aid in lipid digestion. estrogen and progesterone, which are elevated 2 primary bile acids formed in the liver from cholesterol: in pregnancy, cause a slowing of the 1. Cholic acid gallbladder function (slow bile salt excretion 2. Chenodeoxycholic acid from the gallbladder), leading to this disorder. Secondary bile acids - Uncomplicated cholestasis is usually 1. Deoxycholate diagnosed clinically by generalized itching in a 2. Lithocholate pregnant woman, usually in the third trimester The formation of bile acids prevents cholesterol accumulation in without a rash. Elevated serum levels of organs; the body cannot break down the steroid ring of bile salts can help to confirm the diagnosis. cholesterol. At physiologic pH, bile acids will always be in the Elevated bilirubin levels or liver form of bile salts. transaminase enzymes may also be seen. Synthesis of bile salts: 2. Usual treatment: - Bile acids are conjugated with glycine or taurine in the - Antihistamine medications for the itching liver prior to excretion, forming Glyco- or - Some experts recommend ursodeoxycholic Tauroconjugates → Bile salts acid, a naturally occurring bile acid that seems to improve liver function and may reduce the serum bile acid concentration. o Relieves the pruritus and liver function abnormalities when administered - More severe cases may require bile salt binders such as cholestyramine or corticosteroids. C. DISCUSSION A. BILE SALTS - Secreted by the gallbladder that are essential for the Emulsification and absorption of fats - Salt forms of bile acids, which are the major product of cholesterol catabolism in the liver - They form micelles as their hydrophobic face contacts the fat (triacylglycerol), and their polar face maintains contact with the aqueous environment. This micelle formation allows water-soluble digestive enzymes to digest the entrapped triacylglycerol molecule, releasing fatty acids that are readily absorbed by the digestive system. Bile salts will cause emulsification of the dietary lipids increase in the surface area of lipids so that it will be easier for the small intestines to absorb it bile salts will form micelles > the TAGs portion of the lipid will be inside in contact with the fats > polar Figure 2. Synthesis of Bile Salts Page 6 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 Action of intestinal flora on bile salts: - Bacterial enzymes present in the intestine reduce the primary bile salts, produce the secondary bile salts, deoxycholate and lithocholate Metabolism of bile salts: Bile salts perform an important function and are recycled by the body. The body produces 400 mg of bile salts per day from cholesterol; this represents the fate of half of the cholesterol used daily in metabolism (800 mg). However, 20 to 30 g of bile acids is maintained in the enterohepatic circulation. Less than 0.5 g per day is lost to excretion. Bile salts are produced in the liver, stored in the gallbladder, and secreted through the bile duct into the duodenum where they act Figure 3: Comparison of the structures of isomers of on triacylglycerol molecules in the intestines. In the gut, the deoxycholate glycine or taurine moiety is removed from the bile salt. It is reabsorbed in the small intestine and returned to the liver for D. COMPREHENSION QUESTIONS: reuse via the portal vein. Bile salts are absorbed by passive diffusion along the entire small intestine, and a specialized Na+- 1. An 18-year-old male with sickle cell anemia develops bile salt cotransporter is present in the lower ileum. severe right upper-abdominal pain radiating to his lower right chest and his right flank 36 hours prior to Biochemical mechanism of action of Cholestyramine and admission to the ER. Twelve hours following the onset Ursodeoxycholic Acid: of pain, he began to vomit intractably. In the past year he has had several episodes of mild back and lower 1. Ursodeoxycholic acid extremity pain that he attributed to mild sickle cell crises. - The most successful therapy for cholestasis of He reported that the present pain was not like his usual pregnancy has been ursodeoxycholic acid. crisis pain. He also reports that his urine is the color of - a naturally occurring bile acid, which, when iced tea and his stool now has a light clay color. On administered, relieves both pruritus and liver examination, his temperature is slightly elevated, and function abnormalities heart rate is rapid. He is exquisitely tender to pressure - Experimental evidence suggests that it protects over his right upper abdomen. The sclerae of his eyes hepatocytes and cholangiocytes from bile acid- are slightly yellowish in color. What is the most likely induced cytotoxicity and improves hepatobiliary cause of this patient’s symptoms? excretion. Additionally, it decreases bile salt A. A cholesterol-rich gallstone transfer to the fetus and improves the secretory B. A defect in the synthesis of bile acids function of placental trophoblast cells. C. A defect in heme synthesis - Ursodeoxycholic acid is recycled through the D. A gallstone rich in calcium bilirubinate enterohepatic circulation. E. A sickle cell crisis brought on by overexertion 2. Cholestyramine 2 Types of Gallstones - Is another treatment option for cholestasis of 1. Pigment stones pregnancy High risk: - It is an oral medication that binds bile salts in the o Patients with sickle cell anemia intestine and promotes their excretion in the feces. 2. Cholesterol stones - As this drug is not absorbed, it most likely has little Most common type of gallstones effect on the fetus. Risk factors: - Effects on the fetus are still under evaluation. o Elevated cholesterol However, cholestyramine can interfere with the o Decrease in the motility of the gallbladder absorption of fat soluble vitamins, such as vitamins o Pregnancy A, D, E, and K. In rare cases, drug-induced vitamin o Obesity K deficiency is believed to contribute to haemorrhaging during childbirth. Note: Always check for the size of the gallstone. Significant size: 0.6 cm or 6mm Cholesterol gallstones with the size of 6mm or less can still be dissolved by the Ursodeoxycholic acid Page 7 of 8 CMED 1F  (003) CHOLESTEROL & STEROID METABOLISM DR. MARIA ALOIZA HADLOC | 12/15/20 Indications for surgery: Why is it important that Vitamin K is adequate among patients o Young patients with multiple gallstones who will undergo surgery? that start to experience symptoms of right It helps with the clotting factors upper quadrant pain radiating to the back Required for the blood clot formation o Complications of gallstones (cholestasis; Check prothrombin time for people who will inflamed gallbladder) undergo surgery o Polyp in the gallstone o If deranged, give Vitamin K through IV o Stone that is 2 cm (risk factor for infusion before surgery gallbladder cancer) 3. A 17-year-old female, whose parents were first cousins, Choledocholithiasis presents to a neurologist because of recurring seizures - (also called bile duct stones or gallstones in the despite being on anticonvulsive therapy. Nodules that bile duct) is the presence of a gallstone in the appeared to be fatty deposits were present on her common bile duct. Gallstones usually form in Achilles tendon and several of her joints. Plasma your gallbladder. The bile duct is the small tube cholesterol concentrations were elevated, and an assay that carries bile from the gallbladder to the of plasma sterols indicated elevated cholestanol. intestine. Cultured skin fibroblasts did not contain any sterol 27- Treatment: hydroxylase activity. A diagnosis of Cerebrotendinous o ERCP: Endoscopic procedure where an Xanthomatosis, a genetic disease inherited in an endoscope will be entering the mouth of autosomal fashion, was made. A deficiency in sterol 27- the patient up to the duodenum hydroxylase would lead to a decrease in the synthesis o Located in the duodenum is the ampula of which of the following compounds? (small hole where bile is going down from A. Chenodeoxycholate the common bile duct) B. Cortisol o Once endoscope is in the duodenum and C. 1,25-Dihydroxycholecalciferol ampula can already be seen, a wire will be D. Estradiol released inside the ampula to the common E. Testosterone bile duct to try to catch the stone and release it to the intestine Very high risk for infection o Stasis of bile in the common duct IV antibiotics 2. A patient has been on combination statin and cholestyramine therapy to lower his serum cholesterol levels. Prior to any surgery, this patient would be well advised to be supplemented with which of the following? A. Vitamin A B. Vitamin B12 C. Vitamin C D. Vitamin K E. Linolenic acid Cholestyramine - Oral Suspension is a cholesterol-lowering agent used to lower high levels of cholesterol in the blood, especially low-density lipoprotein (LDL) Bile acid sequestrant It also sequesters other fat-soluble vitamins in the intestine o Vitamins A, D, E, K Page 8 of 8 CMED 1F