Vascular Disorders

Chapter 9 Vascular Disorders



I. Lipoprotein Disorders

A. Lipoprotein fractions

1. Chylomicron (Fig. 9-1A)

a. Transports diet-derived triglyceride (TG) in the blood

b. Composition

(1) Protein (2%)

(2) TG (87%)

(3) Cholesterol (CH; 3%)

(4) Phospholipid (8%)

c. Synthesized in intestinal epithelium

image

9-1 Schematics of lipid metabolism and hyperlipoproteinemias. A, Chylomicron metabolism. See text for discussion. B, VLDL, IDL, LDL, HDL metabolism. See text for discussion. CETP, cholesterol ester transport protein; CH, cholesterol; CPL, capillary lipoprotein lipase; HDL, high density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; TG, triglyceride; VLDL, very low density lipoprotein.


(From Pelley J, Goljan E: Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, pp 126, 127, Figs. 7-8, 7-9, respectively.)



Chylomicron: diet-derived triglyceride



(1) Requires apolipoprotein (apo) B-48 for assembly and secretion

(2) Nascent chylomicrons in the circulation obtain apo CII and apo E from high density lipoprotein (HDL)


Chylomicrons: absent during fasting


d. Absent during fasting


CPL: chylomicrons → chylomicron remnant


e. If increased, it forms a creamy supranate.

(1) Test tube must be left upright in a refrigerator overnight.

(2) Chylomicron floats on top of plasma because it has very little protein (low density).

f. Source of fatty acids and glycerol


Chylomicrons: turbid supranate


• Used to synthesize TG in the liver and adipose

g. Hydrolysis by capillary lipoprotein lipase (CPL) leaves a chylomicron remnant.


CPL: located in adipose, muscle, myocardium


• Chylomicron remnants are removed by apo E receptors in the liver.


CPL: induced by insulin CPL: activated by apo CII


2. Very low density lipoprotein (VLDL) (Fig. 9-1B)

a. Transports liver-synthesized TG in the blood


VLDL: liver-derived triglyceride


• Requires apolipoprotein B-100 for assembly and secretion

b. Composition

(1) Protein (9%)

(2) TG (55%)

(3) CH (17%)

(4) Phospholipid (19%)

c. Source of fatty acids and glycerol


Hypertriglyceridemia: causes turbidity in plasma


(1) Used to synthesize TG in the adipose tissue

(2) Hydrolysis by CPL produces intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL).


CPL: VLDL → IDL → LDL


(3) Some of the IDL is removed from blood by apo E receptors in the liver.

d. Cholesterol ester transport protein (CETP)

(1) Transfers CH from HDL to VLDL

(2) Transfers TG from VLDL to HDL

(3) An increase in VLDL always causes a decrease in HDL-CH.

e. If increased, it forms a creamy infranate in plasmaVLDL = TG ÷ 5

(1) Protein is greater in VLDL than in chylomicrons, so it sinks rather than floats in plasma.

(2) VLDL concentration can be calculated: VLDL = TG ÷ 5


LDL = CH – HDL – TG/5


f. TG levels

(1) Optimal level < 150 mg/dL

(2) Borderline high level 150 to 199 mg/dL

(3) High level 200 to 499 mg/dL

(4) Very high level > 500 mg/dL

3. Low-density lipoprotein (LDL) (see Fig. 9-1B)

a. Transports cholesterol in the blood

b. Derives from continued hydrolysis of IDL by CPL

c. Removed from blood by LDL receptors in peripheral tissue


LDL: transports cholesterol


d. Composition

(1) Protein (22%)

(2) TG (10%)

(3) CH (47%)

(4) Phospholipid (21%)

e. Calculated LDL = CH − HDL − TG ÷ 5 (VLDL)


LDL = CH – HDL – TG/5


(1) Presence of chylomicrons falsely lowers calculated LDL by increasing diet-derived triglyceride; hence, fasting is required for an accurate calculated LDL.

(2) To reduce the chance for a falsely low calculated LDL, LDL is directly measured if the serum TG > 400 mg/dL.

f. Functions of cholesterol

(1) Component of the cell membrane

(2) Synthesis of vitamin D, adrenal cortex hormones, bile salts and acids

g. Ranges of LDL

(1) Optimal level < 100 mg/dL.

• Risk for coronary heart disease (CHD) markedly reduced

(2) Near optimal level is 100 to 129 mg/dL.

(3) Borderline high level is 130 to 159 mg/dL.

(4) High level is 160 to 189 mg/dL.

(5) Very high level > 190 mg/dL.

• Greatest risk for CHD

h. Fasting is not required for an accurate serum CH.


Serum CH: fasting not required


• Note that the CH content in chylomicrons is <3%; hence, fasting does not have a medically significant effect on the serum level.



The intensity of treatment to lower cholesterol is directly related to the degree of risk for CHD. The LDL cholesterol goal < 100 mg/dL (some studies suggest <70 mg/dL) if the patient has known coronary heart disease, which invariably requires the use of hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors. For persons without CHD, the LDL cholesterol goal is subdivided into those with a 0−1 risk factor (goal < 160 mg/dL) or those with multiple (2+) risk factors (goal < 130 mg/dL). The risk factors include age (male ≥ 45 years, female ≥ 55 years); family history of premature CHD (e.g., family member with myocardial infarction before 55 years of age); LDL > 160 mg/dL; current cigarette smoking; blood pressure ≥ 140/90 mg/dL (or on antihypertensive medicine); and HDL < 40 mg/dL (if ≥60 mg/dL, subtract 1).


4. High-density lipoprotein (HDL) (see Fig. 9-1B)


HDL: “good CH”


a. “Good cholesterol”

• Increased by exercise, wine, estrogen

b. Composition

(1) Protein (50%)

(2) TG (3%; unless VLDL is increased)

(3) CH (20%)

(4) Phospholipid (27%)

c. Synthesized by the liver and small intestine


HDL: source of apolipoproteins CII and E


d. Functions of HDL

(1) Source of apolipoproteins for other lipoprotein fractions

(2) Removes cholesterol from atherosclerotic plaques


HDL: removes cholesterol from plaques for disposal in the liver


(a) Delivers CH from peripheral tissue to the liver

(b) CH is either excreted into bile or converted into bile acids/salts.

e. Measured in the laboratory as HDL-CH

(1) Inverse association of levels of HDL-CH and incidence and prevalence of CHD

(2) Decreased if VLDL is increased (see earlier)

(3) Ranges of HDL-CH

(a) High level (optimal) ≥ 60 g/dL

(b) Low level (suboptimal) < 40 mg/dL

(4) Fasting is not required for an accurate serum HDL-CH.

• Same reason as for serum CH.


↑ VLDL causes ↓ HDL


B. Lipoprotein disorders

1. Type I hyperlipoproteinemia

a. Epidemiology

(1) Autosomal recessive

(2) Rare childhood disease

b. Pathogenesis (see Fig. 9-1A and B)


Type I: ↓ CPL or ↓ apo CII


(1) Deficiency of CPL or

(2) Deficiency of apo CII

c. Clinical findings

(1) Chylomicrons are primarily increased in early childhood.

(2) VLDL increases later in life.

(3) Presents with acute pancreatitis

• Pancreatic vessels filled with chylomicrons rupture.

d. Laboratory findings

(1) Increase in serum TG > 1000 mg/dL (primarily chylomicrons)

(2) Turbid supranate (chylomicrons) and clear infranate (early childhood)

(3) Normal (usual case) to moderately increased serum CH

2. Type II hyperlipoproteinemia

a. Laboratory findings

(1) Serum LDL > 190 mg/dL

(2) Serum CH > 260 mg/dL

(a) Serum TG < 300 mg/dL (called type IIa)

(b) Serum TG > 300 mg/dL (called type IIb)

b Pathogenesis

(1) Decreased LDL receptors (see Fig. 9-1B)

(2) ↑ Synthesis or ↓ excretion of CH (e.g., obstructive jaundice)


Type II: ↑ LDL due to ↓ LDL receptors; ↑ CH synthesis, ↓ CH excretion in bile


c. Acquired causes of hypercholesterolemia

(1) Primary hypothyroidism

• Decrease in LDL receptor synthesis or function

(2) Nephrotic syndrome

• Increase in LDL correlates with the degree of hypoalbuminemia

(3) Extrahepatic cholestasis (obstruction of bile)

• Bile contains CH for excretion

d. Familial hypercholesterolemia

(1) Autosomal dominant (AD) disorder

(2) Deficiency of LDL receptors

(3) Clinical findings

(a) Premature coronary artery disease and stroke

(b) Tendon xanthomas (Fig. 9-2A)

• Cholesterol deposit located over tendons (e.g., Achilles) and extensor surfaces of joints

image

9-2 A, Achilles tendon xanthoma. Note the slightly yellow nodular lesions at the distal end of the Achilles tendon. B, Xanthelasma. Yellow, raised lesions are noted on the lower left eyelid. C, Palmar xanthomas. Note the yellow macules on the palm that are accentuated in the creases. D, Eruptive xanthomas. Note the numerous small yellow papular lesions distributed over the buttocks.


(A courtesy of A.F. Lant, MD, and J. Dequeker, MD, London; B from Yanoff M, Duker J: Ophthalmology, 3rd ed. St. Louis, Mosby, 2009, Fig. 12-9-18; C and D courtesy of R.A. Marsden, MD, St George’s Hospital, London.)



Achilles tendon xanthoma: pathognomonic for familial hypercholesterolemia


(c) Xanthelasma (Fig. 9-2B)

• Yellow, raised plaque on the eyelid

e. Polygenic hypercholesterolemia (type IIa)

(1) Most common hereditary cause (85% of cases)

(2) Multifactorial (polygenic) inheritance

(3) Alteration in regulation of LDL levels

(4) Normal serum TG

f. Familial combined hypercholesterolemia (type IIb)

(1) AD inheritance.

(2) Serum CH and TG begin to increase around puberty.

(3) Associated with metabolic syndrome (refer to Chapter 22)

(4) Increase in CH and TG and decrease in HDL


Pharmacologic treatment includes dietary modification, increasing activity with aerobic exercises, and cessation of smoking. Dietary modification consists of a low CH, low fat diet (fat intake < 30% of total caloric intake); polyunsaturated fat up to 10% of total calories; monounsaturated fat up to 20% of total calories; saturated fat < 7% of total calories; no more than 200 mg/day of CH; and dietary fiber 20 to 30 g/day. Pharmacologic treatment consists of the use of HMG-CoA reductase inhibitors (“statins”; most effective); nicotinic acid (least expensive lipid-lowering agent; also decreases TG, and increases HDL greater than other drugs); bile salt sequestrants; and cholesterol absorption inhibitors.


3. Type III hyperlipoproteinemia

a. Laboratory findings

(1) Serum CH and TG > 300 mg/dL

(2) Serum CH 250 to 500 mg/dL

(3) LDL < 190 mg/dL

b. Familial dysbetalipoproteinemia (“remnant disease”)


Type III:deficiency apo E; ↑ chylo remnants and IDL


(1) AD inheritance

(2) Deficiency of apo E (see Fig. 9-1B)

(3) Decreased liver uptake of chylomicron remnants and IDL

c. Clinical findings

(1) Palmar xanthomas in flexor creases (Fig. 9-2C)


Type III: palmar xanthomas


(2) Increased risk for coronary artery disease

(3) Increased risk for peripheral vascular disease (unlike type II disorders)

d. Laboratory findings

(1) Serum CH and TG > 300 mg/dL

(2) Serum CH 250 to 500 mg/dL

(3) LDL < 190 mg/dL

(4) Confirm diagnosis with ultracentrifugation to identify remnants

• Lipoprotein electrophoresis and identification of apo E gene defect are other studies that can be used.

e. Treatment

• Fibric acid derivatives

4. Type IV hyperlipoproteinemia

a. Laboratory findings

(1) Serum TG > 300 mg/dL

(2) Serum CH 250 to 500 mg/dL

(3) Serum LDL < 190 mg/dL

(4) Turbid infranate after refrigeration


Type IV: ↑ VLDL; most common lipid disorder


b. Increase in VLDL

• Due to increase in synthesis or decrease in catabolism (see Fig. 9-1B)

c. Acquired causes of hypertriglyceridemia


Type IV: most common cause is alcohol excess


(1) Excess alcohol intake

(2) Oral contraceptives (OCP)

• Estrogen increases synthesis of VLDL

(3) Diabetes mellitus

• Decreased muscle and adipose CPL


OCP: estrogen ↑ TG synthesis in liver


(4) Chronic renal failure

• Increased synthesis of VLDL


OCP: variable effects on LDL and HDL


(5) Thiazides, β-blockers

• Possible inhibition of CPL

d. Familial hypertriglyceridemia

(1) Autosomal dominant disorder

(2) Clinical findings

(a) Eruptive xanthomas (Fig. 9-2D)


Type IV: eruptive xanthomas


• Yellow, papular lesions

(b) Increased risk for coronary artery and peripheral vascular disease


Nonpharmacologic treatment is to reduce alcohol intake and carbohydrate intake. Increase intake of omega-3 fatty acids from fish, flaxseed oil, or other sources (up to 3 g/day). Pharmacologic therapy consists of nicotinic acid or fibric acid derivatives.



Type IV Rx: ↓ carbohydrate and alcohol intake


5. Type V hyperlipoproteinemia

a. Pathogenesis

(1) Increase in chylomicrons and VLDL

(2) Due to decreased activation and release of CPL (see Fig. 9-1A and B)

b. Familial hypercholesterolemia (type IV) + exacerbating disorder

• Exacerbating disorders—diabetic ketoacidosis (DKA; most common), alcohol

c. Increased serum TG > 1000 mg/dL; normal CH and LDL

d. Turbid plasma


Type V: ↑ VLDL + chylomicrons


(1) Supranate after refrigeration, due to increased chylomicrons

(2) Infranate after refrigeration, due to increased VLDL

e. Hyperchylomicronemia syndrome


Type V: hyperchylo-micronemia syndrome


(1) Eruptive xanthomas

(2) Increased incidence of acute pancreatitis

(3) Lipemia retinalis

• Retinal vessels look like milk; blurry vision

(4) Dyspnea and hypoxemia

• Impaired gas exchange in pulmonary capillaries

(5) Hepatosplenomegaly

(6) Increase in serum TG (usually >1000 mg/dL)

(7) Normal serum CH and LDL

(8) Turbid supranate and infranate after refrigeration

f. Treatment

(1) Treat exacerbating disorder (e.g., DKA)

(2) Nicotinic acid or fibric acid derivatives

6. Apolipoprotein B deficiency (abetalipoproteinemia)

a. Autosomal recessive

b. Deficiency of apolipoprotein B-48 and B-100


Apo B deficiency: ↓ chylomicrons, VLDL, LDL


(1) Deficiency of chylomicrons, VLDL, and LDL

(2) Decrease in serum CH and TG

c. Clinical findings

(1) Malabsorption

(a) Chylomicrons accumulate in villi and prevent reabsorption of micelles.

(b) Marked decrease in vitamin E

(2) Ataxia (spinocerebellar degeneration), hemolytic anemia with thorny RBCs (acanthocytes) related to vitamin E deficiency.

d. Treatment

• Vitamin E

II. Arteriosclerosis

• Arteriosclerosis is thickening and loss of elasticity of arterial walls.

A. Medial calcification

Medial calcification: dystrophic calcification in muscular arteries


1. Dystrophic calcification in the wall of muscular arteries

• Examples—calcification in uterine and radial arteries

Related posts:

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  2. Lymphoid Tissue Disorders
  3. Genetic and Developmental Disorders
  4. Red Blood Cell Disorders

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Jun 25, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Vascular Disorders

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