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SDL 2- Hyperlipidemia Lipoproteins (lipids + proteins) are essential for transport of cholesterol, triglycerides, and fat soluble vitamins Classification of Disorders of Lipoprotein Metabolism Genetic mutations defective apolipoproteins, apolipoprotein receptors or activators (primary hyperlipoproteinemias) Secondary hyperlipidemias-- Diabetes mellitus, hypothyroidism, nephritic syndrome Disorders of Low Density Lipoproteins (LDLs) Familial Hypercholesterolemia Elevated plasma levels of LDL cholesterol, normal triglycerides, tendon xanthomas, premature coronary atherosclerosis Genetics LDL receptor located on short arm chromosome 19 Can be completely absent to 25% of normal receptor activity Homozygotes are more affected than heterozygotes (one parent affected) Due to increase in LDL production or delayed catabolism of LDL >900 mutations in LDL receptor gene (normally removes LDL from circulation or rarely ApoB) Epidemiology Autosomal dominant; 1/500 people in most countries (homozygous is rarer—1/1 million) Finnish, Lebanese, Ashkenazi Jews, Africaner, and French Canadians have higher prevalence Males and females equally affected LDL levels elevated at birth; the longer you live the higher risk of atherosclerosis and ischemic heart disease Homozygous--premature death usually before 2nd or possibly 3rd decades Heterozygous-- coronary events by 4th decade LDL-receptor Recognizes apoprotein B100 (apo-B100) in LDL particles Expressed in nearly all nucleated cells (not erythrocytes), mainly in the liver (removes 70% circulating LDL) SDL 2- Hyperlipidemia Pathogenesis Change in number and functional status of LDL receptors LDL particles are the major plasma carriers of cholesterol If the liver does not take up LDL particles, hepatic synthesis of cholesterol is not suppressed further cholesterol production despite high levels of circulating cholesterol High LDL increases cholesterol uptake in peripheral organs (scavenger pathways) Macrophages take up cholesterol foam cell formation, xanthelasma, a variety of xanthomas, early corneal arcus, atherosclerosis Clinical Manifestations Homozygous FH Classified into 2 groups based on amount of LDL receptor activity in skin fibroblasts >2% of normal LDL receptor activity—receptor negative 2-25% of normal LDL receptor activity—receptor defective Present in childhood with cutaneous xanthomas Total cholesterol levels are >500mg/dL (reference <200) and can be higher than 1,000 mg/dL Untreated have extremely high LDL-C levels (500-1000) Corneal arcus usually present, accelerated atherosclerosis can lead to childhood death or disability Aortic valvular stenosis typically extends to coronary ostia Develop symptomatic coronary atherosclerosis before puberty Receptor negative patients rarely survive beyond the 2nd decade Receptor defective LDL receptor defects have a better prognosis but develop atherosclerotic vascular disease by age 30 Heterozygous FH Blood tests typically report LDL-C (elevated usually 200-400 mg/dL) Development of coronary atherosclerosis and symptomatic ischemic heart disease (IHD) High penetrance (>90%), one parent and 50% of the patients siblings have hypercholesterolemia Family hx is positive for premature IHD, corneal arcus, tendon xanthomas (hands, elbows, knees, Achilles!!) Age of onset varies Elevated plasma levels of lipoprotein(a) Lp(a) appear to be at greater risk for CV complications Diagnosis: Based on severe LDL-C elevations in absence of secondary causes of hypercholesterolemia Triglycerides are in range or mildly high, HDL are within range or mildly low Heterozygous: LDL-C >330 mg/dL or If tendon xanthomas are present in pt above 95th percentile Homozygous: skin biopsy measuring LDL receptor activity in skin fibroblasts; molecular assays Familial Defective APO-B100 (FDB) Almost indistinguishable from heterozygous FH, tend to have more benign course than FH pt (short arm chrom 2) Rare, autosomal dominant Mutations in apo-B100 LDL receptor binding domain disruption of LDL receptor binding LDL is removed from circulation with a reduced rate, LDL receptors function normally Presentation: elevated plasma LDL cholesterol levels, normal plasma triglycerides, tendon xanthomas and an increased incidence of premature IHD Diagnosis: apoB100 gene mutation can be detected directly but is not currently used due to the fact that the treatment for it and heterozygous FH is identical Autosomal Dominant Hypercholesterolemia (ADH) Rare gain-of-function mutations in proprotein covertase subtilisin/kexin type 9 precursor (PCSK9) PCSK9 involved in inactivation and degradation of LDL receptor in liver Loss-of-function mutations in this gene produce low LDL levels Clinical presentation: increased LDL cholesterol in plasma, skin and tendon xanthomas and premature IHD SDL 2- Hyperlipidemia Autosomal Recessive Hypercholesterolemia (ARH) Rare, impaired LDL receptor function caused by mutations in phosphotyrosine binding domain protein LDLRAP1 gene codes for phosphotyrosine binding (PTD) domain LDL receptor malfunction LDL uptake in the liver is reduced to same extent as homozygous FH ARH protein is required for efficient LDL uptake in hepatocytes, lymphocytes 50 pts worldwide, Italian and Sardinian origin Clinically: resembles homozygous FH—hypercholesterolemia, tendon xanthomas, premature atherosclerosis, IHD Plasma cholesterol levels are intermediate between levels seen in FH hetero and homozygotes Sitosterolemia (STSL, phytosterolemia) Rare, autosomal recessive disease with elevated plasma sitosterol (plant sterol similar to cholesterol) Caused by mutations in ATP-binding cassette transporter family, ABCG5 and ABCG8 Expressed in the liver and intestine, form functional complex to limit intestinal absorption and promote biliary excretion of dietary plant sterols Mutations sterol accumulation (all sterols 50-200x increase) and atherosclerosis Most abundant sterols in human diet are: cholesterol (animal derived) and sitosterol (major plant sterol) Plasma levels of sitosterol are <1mg/dl in normal individuals Clinically: increased plasma levels of sitosterol, modest increases of plasma cholesterol Similar to FH—tendon and/or tuberous xanthomas usually involving Achilles tendon and xanthelasma Premature atherosclerosis becomes evident by early IHD Accelerated (sometimes fatal) atherosclerosis at young age with homozygous sitosterolemia Polygenic Hypercholesterolemia Due to combination of environmental (obesity and dietary choices) and genetic factors (multiple genes or one) Secondary causes: diabetes, obesity, alcohol, dialysis, jaundice, Cushings, anorexia, meds Most common cause of elevated serum cholesterol Clinically: elevated LDL cholesterol (140-300mg/dL) with normal plasma level of triglyceride in absence of secondary causes of hypercholesterolemia Serum triglyceride concentrations within reference range Tendon xanthomas are not present (if so, FH or FDB are more likely) Inherited forms of Low LDL Caused by genetic factors; uncommon Total cholesterol <120mg/dL (ref value <200) or LDL <50 mg/dL (ref range 60-80) Abetalipoproteinemia (ABL) Autosomal recessive—microsomal triglyceride transfer protein (MTP) mutations (body cannot crease chylomicron and VLDL) MTP ensures normal function of chylomicrons in enterocytes and of VLDL in hepatocytes Normal VLDL is 5-40 mg/dl Clinically: appear normal at birth, by 1 mo develop diarrhea with excessive amount of fat in feces (steatorrhea) Malnutrition, failure to thrive Lipoproteins absent from serum; total cholesterol <45mg/dl, triglycerides <20 mg/dl (ref range 30-90) LDL is undetectable Severe vitamin E deficiency retinitis pigmentosa (photoreceptor death by apoptosis) and spinocerebellar degeneration (loss of position and vibratory sense, DTRs, ataxia and spastic gait) Prognosis: Death occurs by 3rd decade; in early diagnosis use vitamin E (tocopherol) therapy and medium-chain fatty acid dietary supplementation Familial hypobetalipoproteinemia (FHBL) Mutations in gene coding for apo-B truncated apo-B that causes rapid LDL clearance (increased catabolism) Heterozygous pts have low total cholesterol (<120), low LDL (<80) but remain asymptomatic (normal lifespan) Homozygous: lower lipid levels (total cholesterol <80, LDL <20, absent apo-B) SDL 2- Hyperlipidemia Disorders of Remnant Lipoproteins Familial Dysbetalipoproteinemia (FDBL) High levels of plasma total cholesterol and triglycerides (mixed hyperlipidemia) in adults Accumulation in plasma of remnant lipoprotein particles (partly catabolized chylomicrons and VLDL) Pathophysiology: ApoE is present in multiple copies of chylomicron and VLDL remnants and mediates removal FDBL due to genetic variations in apo-E that interfere with its ability to bind lipoprotein receptors Apo-E has 3 isoforms: Apo-E2 (decreased affinity for apo-E receptor), Apo-E3 (most prevalent), Apo-E4 Apo-E2 phenotype: 1%pop, most asymptomatic FDBL develops due to decreased clearance of chylomicron and VLDL remnants 2 hit hypothesis (second hit due to: high fat diet, diabetes, obesity, hypothyroidism, renal disease, estrogen deficiency, alcohol use, certain drugs) Clinically: present in adulthood with xanthomas and premature IHD or peripheral vascular disease Total cholesterol levels 300-600, triglyceride levels are 400-800 Diagnosis: lipoprotein electrophoresis (remnants accumulate in broad band between pre-beta (VLDL) and beta (LDL) DDx: Hepatic lipase deficiency (rare autosomal recessive disease with elevated plasma cholesterol and triglyceride levels Confirm diagnosis by measuring HL activity in post-heparin plasma Disorders of Triglyceride-Rich Lipoproteins Familial Chylomicronemia Syndromes AKA Lipoprotein lipase deficiency, apo-C2 deficience, type 1 hyperlipoproteinemia Deficiency or defect in either enzyme lipoprotein lipase (LPL) or its cofactor (apolipoproten C2) Lipoprotein lipase: Main apolipoprotein component of chylomicrons is apo-B48 HDL donates apo-C2 and converts it to a mature chylomicron (responsible for LPL activation and is present in both chylomicrons and VLDL) LPL is found in endothelial cells of systemic capillaries (essential for metabolism of chylomicrons and VLDL, changing them into respective remnants) Genetics: LPL deficiency has autosomal recessive (1/1mil) Apo-C2 deficiency is also recessive LPL heterozygotes have normal or mild-moderate elevations in plasma triglyceride levels Apo-C2 heterozygotes have normal plasma triglyceride levels Pathophysiology: Elevations in plasma chylomicrons and VLDL Normally chylomicrons are removed within 12 hrs of last meal Familial chylomicronemia: persists for days, fasting plasma is turbid and forms a creamy supernatant Fasting triglyceride levels >1000 (ref 40-160), fasting cholesterol levels are also usually elevated Clinical presentation: Present in childhood with recurrent episodes of severe abdominal pain (acute pancreatitis) Fundoscopic exam shows retinal bv’s that are opalescent Eruptive xanthomas are small, painless, yellowish white papules (back, buttocks, extensor surfaces of limbs) Hepatosplenomegaly Premature atherosclerosis and IHD not usually seen Diagnosis: Deficiency is established enzymatically by assauing triglyceride-lipotic activity of plasma (LPL found reduced) Familial Hypertriglyceridemia (FHTG) AKA Type IV hyperlipoproteinemia Autosomal dominant, moderately elevated plasma triglyceride, accompanied by more modest elevations in cholesterol Fredrickson type IV phenotype (elevated TG and VLDL) Genetics: mutations in gene encoding apo-A5 (an activator of lipoprotein lipase) Epidemiology: Triglyceride and VLDL (not cholesterol) are elevated No association with premature coronary heart disease Risk for chylomicronemia syndrome (elevated chylomicrons in blood) Clinical presentation: children (10-15), elevated plasma levels of triglycerides and VLDL; Eruptive xanthomas, asymptomatic until another disorder (obesity or type II diabetes) presents and there is increased risk of IHD or pancreatitis SDL 2- Hyperlipidemia Familial Combined Hyperlipidemia (FCHL) Moderate elevations in plasma levels of VLDL and LDL, reduced plasma levels of HDL (<40) Epidemiology: most common genetic lipoprotein disorder (1/200) Genetics: poorly understood, likely with several different genes Enviornmental factors modulate; there is a genetic overlap between FCHL and metabolic syndrome (obesity, glucose intolerance, insulin resistance, hypertension, hyperuricemia) Clinically: elevation of triglycerides (200-800) and cholesterol (200-400) Do not develop xanthomas, have premature atherosclerosis and ischemic heart disease Disorders of High Density Lipoproteins Mutations in certain genes encoding HDL synthesis Genetic forms of hypercholesterolemia associated with premature coronary atherosclerosis Genetic forms of hypoalphalipoproteinemia not always associated with accelerated atherosclerosis Primary Hypoalphalipoproteinemia (primary HA) AKA isolated low HDL Low plasma levels of HDL cholesterol (alpha lipoprotein) Below the tenth percentile of cholesterol and triglyceride levels Genetics: AD, patients have family history of low HDL cholesterol levels (underlying apo-A1 defects) Pathogenesis: accelerated catabolism of HDL and apo-A1 Clinical manifestations: plasma triglyceride and total cholesterol levels are normal HDL cholesterol low (15-30 mg/dl) corneal opacities and xanthomas; increased risk of atherosclerosis and IHD Lecithin-Cholesterol Acyltransferase Deficiency (LCAT deficiency) Autosomal recessive disorder caused by mutations in lecithin-cholesterol acyltransferase Pathophysiology: LCAT synthesized in liver and secreted into the plasma Enzyme mediates esterification of cholesterol into cholesteryl ester Lack of normal cholesterol esterification impairs formation of mature HDL particles and leads to rapid catabolism of circulating apo-A1 Genetics: complete deficiency (classic) or partial deficiency (“fish eye disease”) Clinical presentation: progressive corneal opacification (deposition of cholesterol in the cornea) Very low plasma HDL (<10) and variable hypertriglyceridemia Complete: characterized by hemolytic anemia and progressive renal insufficiency Premature atherosclerosis is NOT a feature Diagnosis: specialized laboratory by assaying plasma LCAT activity Tangier Disease Very rare AD disorder that causes complete absence or extreme deficiency of HDL Genetics: mutations encoding ABC1 transporter (generates and stabilizes mature HDL particle) In its absence HDL is rapidly cleared from circulation Clinically: extremely low plasma HDL cholesterol levels (<5mg/dl) Hepatosplenomegaly and pathognomonic enlarged, yellow-orange tonsils Peripheral neuropathy (mononeuritis multiplex) Associated with increased risk of premature atherosclerosis and IHD SDL 2- Hyperlipidemia Secondary Causes of Hyperlipidemia Must be considered prior to initiation of lipid lowering therapy Hormonal Causes Hypothyroidism: Elevated plasma LDL due to reduction in hepatic LDL receptor function, delayed clearance, increased plasma TGs Metabolic syndrome: obesity, elevated blod pressure, peripheral insulin resistance often cluster with elevated plasma triglycerides and a reduced HDL cholesterol level Secondary hypertriglyceridemia correlated with increased risk of IHD Type 2 Diabetes: elevated plasma triglycerides, VLDL, and decreased HDL Elevated LDL cholesterol levels are not a feature of diabetes mellitus Renal Disorders: Nephrotic syndrome associated with hyperlipoproteinemia, usually mixed but can manifest hypercholesterolemia or hypertriglyceridemia Liver disorders: Liver failure associated w/ reductions in plasma triglyceride and cholesterol due to decreased synthesis Cholestasis (in gallstones, primary biliary cirrhosis) associated with hypercholesterolemia Extensive xanthoma formation can result Alcohol: elevated plasma VLDL and triglyceride levels due to increased lipolysis in adipose Xanthomas Deposition of yellowish cholesterol-rich material in skin or tendons Common manifestation of disorder of lipoprotein metabolism Accumulation of lipids in foam cells Cutaneous xanthomas are mostly cosmetic disorders Morbidity and mortality are related to premature atherosclerosis (IHD) and pancreatitis Classiciation: Xanthelasma: most common Sharply demarcated yellowish collection of cholesterol underneath the skin, usually on or around eyelids Any type of primary hyperlipoproteinemia can be present Tuberous xanthomas: over the joints Firm, painless, red-yellow nodules Lesions can coalesce to form multilobated tumors Generally on extensor surfaces of knees, elbows, and the butt Particularly associated with hypercholesterolemia and increased levels of LDL Tendinous xanthomas: slowly enlarging subcutaneous nodules related to the tendons or ligaments Most common locations are hands, feet, Achilles tendons Associated with severe hypercholesterolemia and elevated LDL levels, particularly in FH Eruptive xanthomas: buttocks, shoulders, extensor surfaces; eruptions of small, red-yellow papules on an erythematous base Pruritus is common and lesions may be tender Associated with hypertriglyceridemia, particularly high VLDL and chylomicrons Appear in diabetes Plane xanthomas: flat and macular (rarely elevated) in any site Associated with genetic hyperlipoproteinemias (familial hypercholesterolemia and familial dysbetalipoproteinemia Also associated with secondary hyperlipidemias (especially cholestasis) Principles of Treatment: Diagnosing and treating underlying lipid disorders is necessary to decrease size of xanthomas and prevent risks of atherosclerosis Eruptive resolve within weeks of treatment, tuberous resolve after months, tendinous take years or persist Can use surgery for unresponsive