M2C Unit 2 Lesson 18

Lipid disorders or dyslipidemias

abnormalities in lipids (fats) or lipoproteins in the blood

2 types ((a) primary, (b) secondary.)

Primary lipid disorders

inherited disorders that directly cause defects in lipid metabolism.

• genetic diseases that lead to hypercholesterolemia or hypertriglyceridemia are not due to increased synthesis of these substance

• They are largely abnormalities of lipoprotein structure or of the receptors.

Secondary dyslipidemias

more common; elevations of cholesterol and TG are related to diabetes, chronic kidney disease, liver disease, hypothyroidism, obesity, smoking, medications (ie, hydrochlorothiazide), and excessive alcohol consumption

Lipoproteins role

transport cholesterol and TG in the blood between gut, liver, and tissues.

• TG and cholesterol are nonpolar and hydrophobic, so they do not dissolve in the blood.

Chylomicrons

deliver TG and cholesterol from the intestines into the blood and then deliver TG to peripheral tissues

VLDLs

deliver TG from the liver to the tissues

IDLs

deliver TG to the tissues and cholesterol to the liver.

LDL

“bad cholesterol,” associated with atherosclerotic disease, delivers cholesterol from the liver to the tissues.

HDL

“good cholesterol” delivers cholesterol from the tissues to the liver. Blood levels inversely related to cardiac disease.

The Fredrickson Classification of Primary Lipid Disorders

Each numbered type represents a pattern of lipoprotein elevation.

• Types IIa, IIb, and IV are the most common, accounting for >95% of patients with these primary lipid disorders.

What is elevated in Familial hyperchylomicronemia (type I)?

chylomicrons

What is elevated in Familial hypercholesterolemia (type IIa)?

LDL

What is elevated in Familial hyperlipidemia (type IIb)?

LDL and VLDL

What is elevated in Familial dysbetalipoproteinemia (type III)?

IDL and chylomicrons

What is elevated in Familial hypertriglyceridemia (type IV)?

VLDL

What is lipoprotein is abnormal in Familial hyperchylomicronemia (type I)?

low LPL or Apo C-2

What is lipoprotein is abnormal in Familial hypercholesterolemia (type IIa)?

low LDL receptors

What is lipoprotein is abnormal in Familial hyperlipidemia (type IIb)?

high Apo B-100

What is lipoprotein is abnormal in Familial dysbetalipoproteinemia (type III)?

APOE mutation

What is lipoprotein is abnormal in Familial hypertriglyceridemia (type IV)?

unknown abnormality

What is the cholesterol level in Familial hyperchylomicronemia (type I)?

Normal to ↑

What is the cholesterol level in Familial hypercholesterolemia (type IIa)?

↑↑

What is the cholesterol level in Familial hyperlipidemia (type IIb)?

↑↑

What is the cholesterol level in Familial dysbetaliproproteinemia (type IIb)?

↑↑

What is the cholesterol level in Familial hypertriglyceridemia (type IV)?

Normal to ↑

What is the Triglyceride level in Familial hyperchylomicronemia (type I)?

↑ ↑ ↑ ↑

What is the Triglyceride level in Familial hyperlipidemia (type IIa)?

Normal

What is the Triglyceride level in Familial hyperlipidemia (type IIb)?

↑ ↑

What is the Triglyceride level in Familial dysvetaliproproteinemia (type III)?

↑ ↑ ↑

What is the Triglyceride level in Familial hypertriglyceridemia (type IV)?

↑ ↑

What is Fredrickson Type IIa, another name?

Familial Hypercholesterolemia

The lipid profile in Type IIa typically shows very high?

LDL cholesterol levels, even at birth. TG levels are near normal. The resultant elevated LDL causes severe atherosclerosis

What is Fredrickson Type IIb another name?

Familial Combined Hyperlipidemia

In Fredrickson Type IIb, patients have moderately high levels of

both cholesterol and TG. They also demonstrate insulin resistance and obesity, like patients with metabolic syndrome or type 2 diabetes (but without the hyperglycemia).

What is Familial Combined Hyperlipidemia?

“Combined” hyperlipidemia Because all the bad lipids, LDL, VLDL, and TG are elevated. Liver overproduces apo B-100, the lipoprotein associated with small VLDL particles, dense LDL particles.

Another name for Fredrickson Type IV?

Familial Hypertriglyceridemia

Familial Hypertriglyceridemia has elevated?

VLDL and TG, with Tc and LDL relatively normal but low HDL.2

• These patients look similar to those with familial combined hyperlipidemia because they can also demonstrate insulin resistance and obesity

• NO strong association between familial hypertriglyceridemia and atherosclerotic heart disease, LDL not affected.

• Patients are at increased risk for acute pancreatitis because of their high TG levels

Another name for Fredrickson type I?

Familial hyperchylomicronemia

Familial hyperchylomicronemia patients have

ery high levels of TG, with near-normal cholesterol levels.

• The supernatant of spun blood is creamy due to the TG

• Patients are primarily at risk for pancreatitis, presumably because high levels of chylomicrons in the blood can obstruct capillaries in the pancreas and cause ischemia. The risk for ischemic heart disease is not increased

Another name for Fredrickson type III?

Familial dysbetalipoproteinemia

Familial dysbetalipoproteinemia have poor?

• lipoprotein clearance by the liver, causing chylomicrons and IDL to remain in circulation.

• Patients have moderate elevations in Tc and TG, have increased risk for heart disease

• Unique xanthomas, notably palmar xanthomas (yellow or pale patches in the palmar creases) and tuberoeruptive xanthomas (larger growths usually seen on the knees, elbows, and buttocks). Palmar xanthomas are only seen in this lipid disorder.

Clinical Presentations of Types IIa, IIb, and III (high LDL levels)

can all present with early or severe atherosclerotic disease, eg, ischemic heart disease, stroke, or peripheral artery disease (leg claudication)

Clinical Presentations of Types I and IV (high TG, near-normal serum cholesterol levels)?

do not lead to severe heart disease. Instead, patients are at risk for pancreatitis, especially if their TG are above 1000 mg/dL.

corneal arcus

lipid deposits in the cornea appear as a white ring around the edge of the iris

Xanthomas

build-up of lipids in the skin that lead to yellow-white papules and plaques, histologically composed of lipid-laden macrophages

Xanthelasma

eyelid plaques

Xanthomas key spots

eyelid plaques, extensor surfaces, and achilles tendon

Palmar Xanthomas: seen only in type?

III

Eruptive xanthomas associated with?

hypertriglyceridemia and familial chylomicronemia—are reddish bumps that appear suddenly over elbows, forearms, trunk, legs, or buttocks

Lipemia retinalis

occurs in patients with TG levels over 2000 mg/dL.

• Fundoscopic exam, the retinal arteries appear yellow or white rather than red because of an excessive accumulation of lipids.

Consume fish that have high levels of omega-3 fatty acids: a diet rich in omega-3 fatty acids has been shown to reduce the

rate of fatty acid incorporation into triglycerides, thus decreasing triglyceride levels.

Most patients with hypercholesterolemia benefit from what drugs?

a high-intensity statin. These drugs inhibit the enzyme HMG-CoA reductase, which is the key regulatory step in cholesterol biosynthesis

Those with marked elevations in blood triglycerides generally start with a?

fibrate

All patients with signs of ischemic heart disease (eg, chest pain) will need appropriate treatment, including?

aspirin, β-blockers, and nitrates

Lipid Lowering Drugs

• HMG CoA reductase inhibitors

• PCSK9 inhibitors

• Bile acid-binding resins

• Nicotinic acid

• Fibric acid derivatives (fibrates)

• Cholesterol absorption inhibitors

• Fish oils and Ω-3-FA

• Estrogen

Effect of Statins on LDL, HDL, TGs?

great decrease in LDL, increased HDL, and decreased TGs

Effect of Bile acid sequesters on LDL, HDL, TGs?

great decrease in LDL, increased HDL, and increased TGs

Effect of Cholesterol absorption inhibitors on LDL, HDL, TGs?

great decrease in LDL, increased HDL, and decreased TGs

Effect of fibrates on LDL, HDL, TGs?

decrease in LDL, increased HDL, and great decreased TGs

Effect of PCSK9 inhibitors on LDL, HDL, TGs?

great decrease in LDL, increased HDL, and decreased TGs

Effect of Niacin on LDL, HDL, TGs?

decrease in LDL, high increase in HDL, and decreased TGs

Effect of Fish oils and Ω3-FA on LDL, HDL, TGs?

increase in LDL, increase in HDL, and decreased TGs

Statin effect on Mechanism of Action (MOA)

Inhibition of HMG-CoA reductase

Bile acid sequesters effect on Mechanism of Action (MOA)

Remove intestinal bile acids; liver uses cholesterol to synthesize more bile acids

Cholesterol absorption inhibitors effect on Mechanism of Action (MOA)

Inhibit cholesterol absorption at the brush border

Fibrates effect on Mechanism of Action (MOA)

Upregulate LPL → TG clearance

Activates PPAR-a → HDL synthesis

PCSK9 inhibitors effect on Mechanism of Action (MOA)

inbit LDL-receptor degradation,

increases LDL removal from blood

Niacin effect on Mechanism of Action (MOA)

lipolysis (HsL, adipocytes),

decreases Hepatic VLDL

Fish oils and Ω3-FA effect on Mechanism of Action (MOA)

decreases delivery to liver

decreases TG synthesis

Statin effect on adverse drug reaction (ADR)

Hepatoxicity, increased LFTs, T2D

Myopathy,

Caution: DO NOT use with fibrates or niacin

What cannot be used with fibrates or niacin?

Statin ADR

Bile acid sequesters effect on adverse drug reaction (ADR)

GI upset, gas

low absorption of fat-soluble vitamins

Cholesterol absorption inhibitors effect on adverse drug reaction (ADR)

Diarrhea,

increased LFTs

Fibrates effect on adverse drug reaction (ADR)

Myopathy,

Caution: DO NOT use with statins,

Cholesterol gallstones (inhibit cholesterol 7- a-hydroxylase

PCSK9 inhibitors effect on adverse drug reaction (ADR)

Myalgias, Delirium, Dementia

Naicin effect on adverse drug reaction (ADR)

Flushed face, Hyperglycemia, Hyperuricemia

Fish oils and Ω3-FA effect on adverse drug reaction (ADR)

Nausea and Fishy taste

What globin chain is hemoglobin?

beta globin chain

On what chromosome is Hemoglobin gene?

Chromosome 11

What amino acid substitution takes place at position 6 on the beta globin chain?

Glutamic acid → Valine

Deoxygenated Hgb S is less soluble than deoxygenated?

Hgb A

Life span of sickled RBC

17 days

Howell jolly bodies

small, round remnants of nuclear DNA inside red blood cells (RBCs). (should be clearned out but remain is Sickle cell or defective spleen)

• sign for Chronic Sickle Cell disease