Disorders of lipoprotein metabolism: Disorders of lipoprotein metabolism Dr. Nirav Panchani Slide 2: Frederickson phenotype Lipoprotein abnormality Typical lipid levels I Chylomicrons Triglycerides (TG) >99th percentile IIa LDL Total cholesterol (TC) >90th percentile; depending upon type, may also see TG and/or apolipoprotein B ≥90th percentile IIb LDL and VLDL Depending upon type, TC and/or TG ≥90th percentile and apolipoprotein B ≥90th percentile III Remnants of VLDL and chylomicrons TC and TG >90th percentile IV VLDL TC >90th percentile; depending upon type, may also see TG >90th percentile or low HDL V Chylomicrons and VLDL TG >99th percentile Slide 3: One definition of dyslipidemia is total cholesterol, LDL-C, triglyceride, or Lp (a) levels above the ninetieth percentile or HDL-C or apo A-1 levels below the tenth percentile for the general population (National Health and Nutrition Examination Survey (NHANES) III) prevalence of dyslipidemia in premature CAD is as high as 75 to 85 percent compared to approximately 40 to 48 percent in age-matched controls without CHD AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA: AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA Autosomal dominant hypercholesterolemia (ADH) is a clinical disorder characterized by elevated plasma LDL-cholesterol (due to reduced LDL particle clearance) and premature atherosclerosis. At least three unrelated genetic mutations with an autosomal dominant mode of inheritance lead to ADH. The clinical manifestations of these mutations are indistinguishable and genetic testing is required to differentiate one from the other. AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA: AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA Familial hypercholesterolemia is the most common of these and is caused by defects in the LDL receptor (LDLR) gene. 1 in 500 Familial defective apolipoprotein B-100, caused by mutations in the apolipoprotein B gene, is less common and leads to impaired binding of LDL particles to the LDL receptor. Mutations of the proprotein convertase subtilisin kexin 9 (PCSK9) gene are rare. FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA Familial hypercholesterolemia (FH) is a monogenic, autosomal disorder caused by defects in the gene that encodes for the apo B/E (LDL) receptor . This results in reduced clearance of LDL particles from the circulation and an elevation in plasma LDL-C(> 95 th percentile for age & gender). There is also increased uptake of modified LDL (oxidized or other modifications) by the macrophage scavenger receptors, resulting in macrophage lipid accumulation and foam cell formation FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA FH are classified into one of two major groups based on the amount of LDLR activity: patients with less than 2 percent (receptor-negative) and patients with 2 to 25 percent of normal LDLR activity (receptor-defective) . In general, plasma levels of LDL-C are inversely related to the level of residual LDLR activity. excess LDL-C is deposited in the arteries as atheroma and in the tendons and skin as xanthomata and xanthelasma and corneal arcus . The prevalence of xanthomata increases with age, eventually occurring in 75 percent of FH heterozygotes . Slide 8: Planar xanthoma in the antecubital fossa of a patient with homozygous familial hypercholesterolemia. Slide 9: Subperiosteal xanthomata in a patient with heterozygous familial hypercholesterolemia. Slide 10: A xanthoma of the Achilles tendon in a patient with heterozygous familial hypercholesterolemia. Slide 11: Tendon xanthomata on the dorsum of the hand in a patient with heterozygous familial hypercholesterolemia. Slide 12: Bilateral xanthelasmata (due to cholesterol deposits in the periorbital skin folds) FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA Homozygotes with familial hypercholesterolemia have a high incidence of aortic stenosis (about 50 percent) due to atherosclerotic involvement of the aortic root; the incidence is lower in heterozygotes . Coronary artery calcification, a marker of coronary artery disease, can be identified as early as 11 to 23 years of age in heterozygotes CAD in FH develops by 3 rd or 4 th decade in men, a decade later in females. FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA Diagnosis - Definite criteria require hypercholesterolemia, usually normal serum triglycerides, and either genetic or cellular confirmation of an LDL receptor defect. The presence of tendon xanthomata in the proband or first-degree relatives has been considered pathognomonic of FH, but these findings can also occur in familial defective apo B-100, the normal ligand for the apolipoprotein B/E (LDL) receptor . Clinical diag. based on elevated LDL, premature CAD in family and + nce of tendinous xanyhomas . FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA Differential diagnosis — Tendon xanthomata and premature atherosclerosis can also occur in two rare disorders not involving LDL metabolism: sitosterolemia and cerebrotendinous xanthomatosis . • Sitosterolemia - is an autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine . Mutation of ABCG5 & ABCG8 transportes on intestinal villous borders renders absn . Of palnt stanols rather than elimination. c/f – extensive xanthoma formation and premature atherosclerosis before adulthood. Diag. – elevated sitosterol , campesterol , cholestenol , sitostenol , campestenol . TC & TG are WNL. Ezetimibe appears to reduce plasma plant sterol concentrations in patients with sitosterolemia . • Cerebrotendinous xanthomatosis is characterized by a block in bile acid synthesis due to the absence of hepatic mitochondrial 27-hydroxylase (CYP27); it is associated with prominent neurologic abnormalities and usually normal serum cholesterol concentrations. FAMILIAL HYPERCHOLESTEROLEMIA: FAMILIAL HYPERCHOLESTEROLEMIA FH also needs to be distinguished from the other two common causes of hypercholesterolemia : familial combined hyperlipidemia ; and polygenic hypercholesterolemia. • The lipid profile is similar in familial and polygenic hypercholesterolemia but xanthomata are not seen in the latter disorder. • There is a reduced ratio of LDL-C to apo B (less than 1.2 versus greater than 1.4 in normals ), and triglyceride levels may be above the 90th percentile in familial combined hyperlipidemia . FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100: FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100 Familial defective apo B-100 is an autosomal dominant disorder which, like FH, is associated with impaired binding of LDL particles to the apo B/E (LDL) receptor. 1 in 500 This disorder differs from FH in that the defect is localized to the apo B-100 ligand on the LDL particle , not the apo B/E (LDL) receptor. The net effect is that the clearance of LDL is reduced and plasma levels increase by two- to threefold. LDL – c level upto 400 ; may be even N. Management of FH: Management of FH At present, high-dose atorvastatin , rosuvastatin , or simvastatin should be the initial regimen since these drugs are more effective than other statins as monotherapy . High-dose atorvastatin produced a larger reduction in LDL-C (308 to 149 mg/ dL [8 versus 3.9 mmol/L]) than conventional dose simvastatin (321 to 185 mg/ dL [8.3 to 4.8 mmol/L]). High-dose atorvastatin also produced a significant reduction in carotid intima media thickness, measured with B-mode ultrasound, compared to an increase with simvastatin . Management of FH: Management of FH The role of additional therapy with other lipid altering drugs such as ezetimibe , produce a further reduction in LDL-C but there have been no trials demonstrating either improved clinical or surrogate outcomes in patients already on high dose statin therapy. This point was illustrated in the ENHANCE trial of 720 adult patients with heterozygous FH who were randomly assigned to treatment with simvastatin (80 mg/day) with or without ezetimibe (10 mg/day). Decreases in LDL-C were significantly greater in patients treated with combination therapy (58 versus 41 percent), but there was no statistically significant difference in the primary outcome of change from baseline in carotid intima -media thickness Management of FH: Management of FH Homozygous children — The 2006 AHA scientific statement on cardiovascular risk reduction in high-risk pediatric patients recommends early initiation of combined therapy including LDL apheresis , high dose statin , and a cholesterol absorption inhibitor in children with homozygous FH . Consideration can be given to the addition of a bile acid sequestrant and/or nicotinic acid as necessary, although compliance with these agents tends to be difficult . Management of FH: Management of FH Heterozygous children with FH should be treated aggressively at an early age. Dietary therapy and bile acid sequestrants have traditionally been the lipid lowering therapies of choice in children, but the effect is modest (approximately a ten percent reduction in LDL-C and total cholesterol with dietary interventions) and long-term compliance is poor . Randomized trials have demonstrated that statins are effective in lowering LDL-C and appear to be safe; there is also some evidence of improvement in atherosclerosis with treatment hence accepted as 1 st line Rx. As in adults, the combination of ezetimibe plus simvastatin lowers LDL cholesterol to a greater extent than monotherapy with statin . Management of FH: Management of FH The optimal age at which to initiate treatment of children with heterozygous FH is unknown. It is recommended by the American Academy of Pediatrics, to initiate cholesterol-lowering therapy in children with significant elevations of LDL cholesterol (>190 mg/ dL without other risk factors, >160 mg/ dL in children with family history of early atherosclerotic disease or two or more other risk factors). If the elevations are severe and the family history is particularly concerning, and lifestyle modification is not effective, treatment can be started as young as age eight years, although preference is to wait until ten years of age in males and after the onset of menses in females. Consideration can be given to the initiation of therapy earlier in children perceived to be at particularly high risk, such as those with tendon xanthomata , aortic sclerosis, or worrisome family history. Slide 23: Resistant hypercholesterolemia — FH homozygotes and heterozygotes who are refractory to standard drug therapy have been treated with a variety of regimens. These include ileal bypass surgery, portacaval anastomosis , liver transplantation, LDL apheresis , and gene therapy. Slide 24: Fertile women - FH women who are on statin therapy and anticipate becoming pregnant should stop statins three months prior to attempting to conceive. • Contraceptive options should be explored with fertile FH patients. For those women who choose to use an oral contraceptive, the potential for an increased risk of a cardiovascular event needs to be discussed. • Cholesterol measurements should not be performed during pregnancy as no therapy is indicated. There are no contraindications to breastfeeding in these women, but no lipid-lowering therapies should be used, with the possible exception of resin agents. FAMILIAL COMBINED HYPERLIPIDEMIA: FAMILIAL COMBINED HYPERLIPIDEMIA Familial combined hyperlipidemia (FCHL) occurs in 1 to 2 percent(1 in 50) of the general population and accounts for one-third to one-half of familial causes of CHD and 10 - 20 percent of cases of premature CHD . Baseline triglyceride concentrations were not independently associated with an increased risk. FCHL is an autosomal disorder caused by overproduction of hepatically -derived apo B-100 associated with VLDL . Apo B levels are strongly correlated with LDL phenotype B in FCHL families ; LDL phenotype B levels are inherited as a Mendelian trait that is distinct from the apo B genotype LDL phenotype B is associated with increased serum concentrations of apo B and triglycerides, reduced serum HDL and a three-fold increase in risk of CHD . LDL phenotype A is associated with large buoyant LDL particles; in comparison, phenotype B is characterized by small, dense LDL particles. FAMILIAL COMBINED HYPERLIPIDEMIA: FAMILIAL COMBINED HYPERLIPIDEMIA FCHL can be represented by one of three Fredrickson phenotypes • Combined elevations of triglycerides and cholesterol resulting from increases in VLDL and LDL (type IIb ) • Hypercholesterolemia due to an increase in LDL (type IIa ) • Isolated hypertriglyceridemia induced by a rise in VLDL (type IV) Those patients with abnormal lipoprotein lipase (LPL) function have higher levels of triglycerides (due to decreased clearance) and lower levels of HDL-C (due to reduced production from triglyceride-depleted VLDL remnants) than those with normal LPL activity. FAMILIAL COMBINED HYPERLIPIDEMIA: FAMILIAL COMBINED HYPERLIPIDEMIA Because FCHL is phenotypically heterogeneous, and total cholesterol and triglyceride levels may vary within an affected individual over time , overlap exist among FCHL, familial dyslipidemis HTN, metabolic synd. And hyperapobetalipoproteinemia . Few C/F – corneal arcus , xanthoma , xanthelesma are infreq . Biochem . abN – high TC, LDL (> 90 – 95 th percentile) and/ or high TG (> 90 - 95 th percentile) For diag. of FCHL, it must be present in at least one 1 st degree relative. Treatment of FCHL : Treatment of FCHL Treatment decisions are based upon the relative concentrations of LDL-C and triglycerides. As an example, patients with severe hypertriglyceridemia (triglyceride level >500 mg/ dL [5.6 nmol /L]) plus moderate hypercholesterolemia will benefit more from triglyceride-lowering agents such as a fibrate or nicotinic acid. These drugs hydrolyze the triglyceride core of VLDL and convert the large, buoyant VLDL to a particle mass more easily cleared by the apo B/E (LDL) receptor. In comparison, gemfibrozil does not reduce the level of apo B in FCHL, despite reductions in VLDL- and LDL-C and triglycerides . To the contrary, gemfibrozil may actually elevate LDL-C levels when the baseline concentration of triglycerides is moderately to markedly elevated. Treatment of FCHL : Treatment of FCHL This paradoxical response may be countered by the addition of nicotinic acid or a statin ; alternatively, a bile acid sequestrant can be used if the triglyceride levels have normalized. Gemfibrozil must be used with caution with a statin because of an increased risk of muscle injury. This risk can be minimized by using a statin that is not metabolized by CYP3A4 ( eg , pravastatin or fluvastatin ) . Dosing of gemfibrozil and bile acid sequestrants requires separation by two hours due to sequestrant -induced impaired bioavailability of gemfibrozil HYPERAPOBETALIPOPROTEINEMIA: HYPERAPOBETALIPOPROTEINEMIA Hyperapobetalipoproteinemia is characterized by an overproduction of apo B and may be a variant of familial combined hyperlipidemia . The clinical manifestations include premature CHD (particularly in patients with concurrent hypertriglyceridemia ), xanthelasma (in 10 percent of cases), and obesity . Coexisting diabetes mellitus or impaired glucose tolerance is more common in patients who also have hypertriglyceridemia . This condition is characterized by LDL species that are enriched in apo B-100. It is manifested clinically by an elevation in the concentration of apo B, but a normal concentration of LDL-C. In most cases, the LDL-C level is less than 160 mg/ dL (4.1 mmol/L), the LDL apo B concentration is greater than 135 mg/ dL (3.5 mmol/L), and the LDL-to- apo B ratio is less than 1.2 (normal value >1.4) Lp(a): Lp (a) STRUCTURE AND FUNCTION — is a modified form of low density lipoprotein (LDL) in which a large glycoprotein, apolipoprotein (a) [ apo (a)] is covalently bound to apolipoprotein B. LP(a) consist of a protein homologous with the fibrin-binding domain of plasminogen . Because of this structural similarity to plasminogen , Lp (a) interferes with fibrinolysis by competing with plasminogen binding to molecules and cells. Lp (a) also binds to macrophages via a high-affinity receptor that promotes foam cell formation and the deposition of cholesterol in atherosclerotic plaques Slide 32: There is a strong inverse relationship between the size of the apo (a) isoforms and the Lp (a) concentrations According to the Framingham Heart Study, the 90th percentile of Lp (a) levels is 39 mg/ dL (1.01 mmol/L) in men and 39.5 mg/ dL (1.03 mmol/L) in women . Blacks have somewhat higher values than whites. The standard method for measuring Lp (a) is density gradient ultracentrifugation. ELISA techniques are now widely available. Lp (a) is modest independent risk factor for CVD, unfavourable outcome in ACS and stroke. Slide 33: SCREENING — At present, screening and treatment for Lp (a) excess levels should only be considered for: • Patients with CHD and no other identifiable dyslipidemia • Patients with a strong family history of CHD and no other dyslipidemia • Patients with hypercholesterolemia refractory to therapy with LDL cholesterol lowering therapies ( Lp (a) excess may account for significant component of the LDL-cholesterol level calculated by the Friedewald formula, and that standard LDL-cholesterol lowering therapies do not lower Lp (a) levels appreciably.) Slide 34: The primary goal of therapy for Lp (a) excess ( Lp (a) concentration above the 95th percentile) is LDL-C reduction to the patient's target LDL-C concentration based upon risk factors Aggressive LDL-C reduction — treating LDL-C more aggressively in the presence of Lp (a) excess has not been formally studied. In a post-hoc analysis of the Familial Atherosclerosis Treatment Study, elevated Lp (a) levels were associated with progression of coronary atherosclerosis and CHD events ONLY IF the LDL-C level was not reduced by more than ten percent. In a post-hoc analysis of the Familial Hypercholesterolemia Regression Study of LDL apheresis , Lp (a) reduction did not provide additional angiographic benefit if LDL-C lowering therapy reduced the LDL-C to <130 mg/ dL . These studies, although small , provide some evidence that Lp (a) is less important of a CHD predictor when LDL-C has been treated. Slide 35: Lp (a) reduction — If the LDL-C concentration cannot be reduced to the optimal LDL-C level for an individual patient, use of medications that lower Lp (a) (usually with nicotinic acid) may be initiated. This approach will lower Lp (a) levels and further reduce LDL-C, but this approach has not been shown to improve important outcomes such as death or myocardial infarction. If the decision is made to lower Lp (a) levels, one possible therapeutic goal is to lower Lp (a) cholesterol levels measured by ultracentrifugation to less than 30 mg/ dL (0.78 mmol/L) in white patients Slide 36: Statins and bile acid sequestrates do not reduce Lp (a) levels . Lp (a) levels may increase slightly on statins , however this has not been shown to mitigate their beneficial effects on CHD event reduction. Most fibric acid derivatives do not lower Lp (a) levels, except for bezafibrate which may produce up to a 39 percent reduction . Bezafibrate is not approved for use in the United States. Estrogen replacement therapy (ERT) reduces Lp (a) levels by up to 50 percent , an effect that was somewhat mitigated by concomitant progesterone therapy . However, the clinical role for HRT is uncertain and it is not recommended for CVD risk reduction. Slide 37: Nicotinic acid (2 to 4 g/day) is the most effective therapy for reducing Lp (a) levels . In addition to lowering Lp (a) levels, reduction in LDL-cholesterol, apo B-100, small LDL, and triglycerides, it raises HDL-cholesterol levels and in combination with statins , appears to reduce CHD and CHD risk. Nicotinic acid reduces Lp (a) levels by as much as 38 percent. Neomycin (2 to 3 g/day) also lowers Lp (a) levels by as much as 24 percent, but has many side effects and in general should not be used to lower Lp (a) Slide 38: There are no clinical trials that have adequately tested the hypothesis that Lp (a) reduction reduces the incidence of first or recurrent CVD events. Therefore, widespread screening for Lp (a) excess is not indicated and treatment of Lp (a) excess should only be considered in specific circumstances. When Lp (a) excess ( Lp (a) concentration above the 95th percentile) is identified, more aggressive LDL-C targets than those recommended for the general population may be considered. This is based upon the knowledge that there may be modest, excess residual CVD risk associated with high Lp (a) levels. Familial hypertriglyceridemia: Familial hypertriglyceridemia Familial hypertriglyceridemia (type IV hyperlipoproteinemia phenotype) is an autosomal dominant disorder associated with moderate elevations in the serum triglyceride concentration (200 to 500 mg/ dL [2.3 to 5.6 mmol/L]). After meal it may increase to 1000 mg/dl. Prevalence – 1 in 50 to 100. It is often accompanied by insulin resistance, obesity, hyperglycemia, hypertension, and hyperuricemia . Patients with familial hypertriglyceridemia are heterozygous for inactivating mutations of the LPL gene and typically have low serum HDL-C ( hypoalphalipoproteinemia ). LDL is low & TC ic normal or high. More marked elevations is seen with alcohol intake, carbohydrate or calorie intake or drugs such as estrogen. Slide 40: Asso . With CHD is not as strong as FCHL. Hepatic overproduction of VLDL and partial LPL defi cause Familial hypertriglyceridemia . Type V hyperlipoproteinemia (Mixed hypertriglyceridemia): Type V hyperlipoproteinemia (Mixed hypertriglyceridemia ) characterized by triglyceride levels above the 99th percentile in association with a creamy plasma supernatant and increases in chylomicrons and VLDL clinical manifestations include hepatosplenomegaly and occasional eruptive xanthomas . However, patients with marked hypertriglyceridemia (>1000 mg/ dL [11.3 mmol/L]) may develop the chylomicronemia syndrome. Manifestations of this disorder include recent memory loss, abdominal pain and/or pancreatitis, dyspnea , eruptive xanthoma , flushing with alcohol, and lipemia retinalis . Most patients have a secondary form in which some other dyslipidemia ( eg , familial hypertriglyceridemia due to partial LPL deficiency) is exacerbated by one or more of the acquired disorders noted above. There is also a primary form of type V hyperlipoproteinemia in which there is no deficiency in LPL or its ligand apo C-II . The underlying defect in this disorder is uncertain but apo E4, which is a ligand for the hepatic chylomicron and VLDL remnant receptor, may play a role . Milky plasma: Milky plasma Eruptive xanthoma: Eruptive xanthoma Xanthomata are seen on the extensor surface of the forearm in a patient with severe hypertriglyceridemia . Slide 44: Mixed hypertriglyceridemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on agarose gel electrophoresis or ultracentrifugal analysis. A simple technique is to refrigerate plasma overnight and examine the specimen for a creamy supernatant from chylomicrons and a turbid VLDL-rich infranatant . The latter finding is different from type I hyperlipoproteinemia , in which only chylomicrons accumulate and the infranatant is clear. Patients with type I hyperlipoproteinemia have complete absence of either LPL activity or apo C-II.