Download SDL 2- Hyperlipidemia Lipoproteins (lipids + proteins) are

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