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Tissues > T14 - Disorders of TG Metabolism > Flashcards

T14 - Disorders of TG Metabolism Flashcards

1
Q

How are exogenously-derived ApoB-containing lipoproteins produced?

A

incorporation of dietary lipids into chylomicrons, which occurs in enterocytes

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2
Q

How are endogenously-derived ApoB-containing lipoproteins produced?

A

incorporation of liver lipids into VLDL

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3
Q

List the four major parallels of the exogenously-derived lipid and endogenously-derived lipid metabolism pathways.

A

formation of TG-rich particles (ApoB-48 in chylomicrons, ApoB-100 in VLDL)

both CMs and VLDLs acquire ApoE and ApoC

CMs and VLDLs both become cholesterol rich as TGs are unloaded into periphery

CMs and VLDLs both become remnants which are cleared from circulation by hepatic LDLR endocytosis

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4
Q

Describe the characteristics of a venous blood sample obtained from a fasting individual.

A

all CMs and CMrs have been cleared from circulation

VLDLr levels low

cholesterol in blood is exclusively in LDL and HDL, with smaller amounts in VLDL

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5
Q

Describe the steps of the most ocmmon test used to determine lipoprotein-cholesterol levels. (4)

A

venous blood sample obtained from fasting individual

plasma separated from blood cells via centrifugation

supernatant collected and TG + total cholesterol measured enzymatically

remaining ApoB-containing lipoproteins (VLDL, IDL, LDL) precipitated and remaining cholesterol that is measured is bound to HDL

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6
Q

HDL cholesterol can be measured directly from a lipid profile. How is VLDL cholesterol measured? What are the assumptions underlying this measurement?

A

it is estimated by dividing fasting TG level by 5

assumption is that all TG in a fasting sample is carried in VLDL

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7
Q

What is the equation to calculate LDL-cholesterol?

A

total cholesterol = VLDL-C + LDL-C + HDL-C

LDL-C = total cholesterol — (total TG/5 + HDL-C)

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8
Q

What criteria must be met for the LDL-C calculation to be considered accurate? (3)

A

fasting subject, so no CMs or CMRs present

TG is <300 mg/dL

person does not have Type 3 hyperlipoproteinemia

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9
Q

What is a normal plasma total cholesterol value?

A

120-200 mg/dL

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10
Q

What is a normal plasma total triglyceride value?

A

50-200 mg/dL

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11
Q

What is a normal plasma HDL cholesterol value?

A

35-80 mg/dL

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12
Q

What is a normal plasma LDL cholesterol value?

A

70-160 mg/dL

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13
Q

What is hypertriglyceridemia?

A

abnormal elevations of CMs or VLDLs [remember that triglyercides constitute the bulk of these particles] (with the exception of Type 3 hyperlipoproteinemia)

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14
Q

What is the major lipid carrie din LDL and HDL?

A

cholesterol

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15
Q

What fraction of plasma cholesterol is carried in LDL?

A

70%

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16
Q

What factors can contribute to combined hyperlipidemia (i.e. elevations in both TG and cholesterol)? (3)

A

increased remnants

elevated LDL + VLDL

elevated VLDL + chylomicrons

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17
Q

What is another name for hypertriglyceridemia?

A

chylomicronemia

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18
Q

What are the TG levels in a patient with chylomicronemia?

A

fasting TG: >700 mg/dL

normal TG: >1000 mg/dL

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19
Q

How does plasma appear in a patient with chylomicronemia?

A

milky-cloudy-“strawberry milk” appearance, because the large CM and VLDL particles are scattering light

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20
Q

Explain why a blood sample with excess CM refridgerated overnight will have a layer of “cream” the next morning.

A

CM and VLDL have a lower density than the plasma density, so they will float to the top

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21
Q

What is the clinical presentation of eruptive xanthomas?

A

nontender yellowish papules (little bumps) full of TG appear on extensor surfaces of arms and legs at pressure points

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22
Q

What is the underlying cause of eruptive xanthomas? How long do symptoms last?

A

caused by collection of TG-filled macrophages in the skin

appear suddenly and regress with resolution of chylomicronemia

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23
Q

Describe the clinical presentation of lipemia retinalis.

A

arteries in eye discolored on fundoscopic examination

instead of bright red blood, contains “strawberry milk” or “tomato soup”

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24
Q

When does lipemia retinalis occur?

A

when TG exceeds 4000 mg/dL

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25
Q

(T/F) Patients with lipemia retinalis suffer from vision loss.

A

False. Patients with lipemia retinalis do not have any visual problems.

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26
Q

What happens in pancreatitis? (2)

A

CMs accumulate in capillaries of pancreas and destroy it

digestive enzymes enter abdominal cavity and digest tissue

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27
Q

Prolonged chylomicronemia can result in enlargement of what two organs?

A

liver (hepatomegaly) and spleen (splenomegaly), because of uptake of CMs by nonspecific pathways

28
Q

Chylomicronemia is specifically NOT associated with what condition?

A

chylomicronemia is NOT associated with an increase in coronary atherosclerosis

29
Q

What are the four major diseases associated with chylomicronemia?

A

eruptive xanthomas

lipemia retinalis

pancreatitis

enlargement of liver/spleen

30
Q

What is lipoprotein lipase deficiency and what is its inheritance pattern?

A

rare autosomal recessive disorder due to inactivating mutations in LPL gene

31
Q

When does lipoprotein lipase deficiency present, and how? (3)

A

usually presents in infancy/childhood w/ failure to thrive and recurrent abdominal pain due to pancreatitis, soemtimes + eruptive xanthomas

32
Q

How is LPL activity measured? (6)

A

heparin injected into blood

heparin displaces LPL from GPIHBP1

LPL and hepatic lipase accumulate in circulation

incubate with TG to measure total lipase activity

add antibody to inactivate HL to all lipase activity is coming from LPL

incubate again w/ TGs and measure the amount of free fatty acids that come out

33
Q

How is LPL deficiency treated? (4)

A

patient is hospitalized and not allowed to eat or drink anything to stop new CM formation

IV fluids provided until TGs are <700 mg/dL

initiate low fat diet (<20 g fat/day) to minimize CMs entering circulation

levels of TG will gradually fall as CMs are slowly + non-specifically taken up by macrophages in spleen and liver

34
Q

Explain why a homogzygous loss of ApoCII functionality leads to chylomicronemia.

A

ApoCII required for CM to interact with LPL and digest TGs

therefore, TG levels rise

35
Q

How does ApoCII deficiency present clinically?

A

recurrent abdominal pain

chylomicronemia

no post-heparin LPL activity

36
Q

How is ApoCII deficiency treated?

A

whole blood transfusion — donor will have normal/functional ApoCII

37
Q

What is the difference between ApoCII deficiency and LPL deficiency in terms of patient care?

A

ApoCII deficiency can be treated with a plasma transfusion

But LPL deficiency is a genetic problem that can’t exactly be cured

38
Q

Describe the relationship between ApoCIII (not to be confused with ApoCII) and plasma TG levels.

A

unlike ApoCII deficiency (which causes increased plasma TG levels), mutations that inactivate ApoCIII result in lower plasma TG levels

39
Q

Describe the relationship between ApoCIII (not to be confused with ApoCII) and LPL activity.

A

Normally, ApoCIII inhibits LPL activity

40
Q

Write out the pathway of normal metabolism of VLDL (i.e. endogenous metabolism). (4)

A

ApoB-100 + TG + cholesterol = VLDL that is secreted into circulation → acquires ApoE and ApoC series → interacts with LPL which hydrolyzes its TGs and becomes an IDL, losing ApoC series → ApoE binds to LDLR of liver and causes endocytosis

41
Q

How does Type III hyperlipoproteinemia develop?

A

Type III hyperlipoproteinemia develops when clearance of CM and VLDL remnants is delayed

42
Q

What is the underlying cause of Type III hyperlipoproteinemia?

A

sequence variations in ApoE that interfere with binding to LDLR

43
Q

What are the three isoforms of ApoE? List their relative prevalence.

A

ApoE2 (least common isoform)

ApoE3 (most common isoform)

ApoE4 (second most common isoform)

44
Q

How does ApoE2, the least common isoform, differ from ApoE3 or ApoE4?

A

ApoE2 binds with lower affinity than either ApoE3 or ApoE4 to the LDLR

45
Q

Having the ApoE2 is a predisposition to what disease?

A

Type III hyperlipoproteinemia. Being homozygous (ApoE2/ApoE2) is necessary but not sufficient to develop Type III hyperlipoproteinemia

46
Q

ApoE2 homozygosity is a risk factor but is not sufficient to induce familial type III hyperlipoproteinemia. What further increases the probability of developing familial type III hyperlipoproteinemia?

A

first hit = ApoE2/ApoE2 homozygosity

second hit = increase in production of TG-rich lipoproteins (via high-fat diet, obesity, diabetes, etc.) or decrease in rate of clearance of remnants by LDLR (via high cholesterol downregulation, hypothyroidism, low estrogen)

47
Q

When do the symptoms of Type III hyperlipoproteinemia become apparent?

A

in adulthood

48
Q
A
49
Q

What three diseases/events does type III hyperlipoproteinemia eventually cause in adults?

A

coronary artery disease (atherosclerosis in arteries supplying heart)

peripheral vascular disease (atherosclerosis in vasculature to extremities)

cerebrovascular disease/stroke (atherosclerosis in arteries to brain)

basically, atherosclerosis

50
Q

What is xanthelasma?

A

accumulation of cholesteryl esters in skin around eyes

51
Q

What are tuberous/tuberoeruptive xanthomas?

A

bumps that appear at areas of pressure (elbows, ankle, hands) that are large and red

52
Q

What is striae palmaris? (2)

A

xanthomas of palmar creases in hand

palmar creases appear orange

53
Q

Are patients with type III hyperlipoproteinemia predisposed to pancreatitis?

A

No. These patients do not get pancreatitis.

54
Q

In terms of plasma concentrations, what is a hallmark of familial type III hyperlipoproteinemia?

A

cholesterol and TGs are elevated to approximately the same level (i.e. cholesterol @ 500, TGs @ 550)

55
Q

How is a diagnosis of familial type III hyperlipoproteinemia made?

A

made by a test that measures amounts of remnants in the plasma

56
Q

What are the six possible treamtnets for familial type III hyperlipoproteinemia?

A

low fat diet (reduce CM/CMr production)

low-cholesterol diet (increase LDLR expression)

statins to increase hepatic LDLR expression

ezetimibe to block cholesterol absorption

weight loss (reduce VLDL production)

fibric acids to reduce production/increase metabolism of VLDLs

57
Q
A
58
Q

Where on ApoB is the LDL receptor-binding domain?

A

on the C-terminus (therefore not present in ApoB-48)

59
Q

Compare the relative sizes of ApoE and ApoB.

A

ApoE (48 kDa) is much smaller than ApoB (~500 kDa)

60
Q

Give two examples of tissues that express high numbers of LDL receptors.

A

adrenal glands

gonads

[they need the cholesterol to synthesize hormones]

61
Q

(T/F) LDL levels in a normal individual change significantly between the fed and fasting states.

A

False. LDL levels do NOT change significantly.

62
Q

What is the relationsihp between CETP and HDL?

A

CETP deficiency leads to HDL elevation

63
Q

What is the target of ezetimibe?

A

the NPC1L1 transporter, which absorbs cholesterol into enterocytes

64
Q
A
65
Q

What is the clinical presentation of a patient with no functional GPIHB1?

A

chylomicronemia (extremely high TG content)

66
Q

How is the metabolism of chylomicrons and VLDL similar and how are they different?

A

similar: both digested by LPL, but VLDLs have a further metabolism step by hepatic lipase
different: ApoB-48 vs. ApoB-100

67
Q

What ApoB-containing lipoprotein do you think would accumulate in individuals with no functional hepatic lipase?

A

IDLs would accumulate because IDLs use hepatic lipase as a secondary metabolism enzyme

Tissues (23 decks)

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