Massive Hypertriglyceridaemia: A complete white-out,

O.

BOxLDL

IDL

B

ECIII

VLDL

B

ECIII

-100

LPL

BLDL

HL

FCAI

AII

INTESTINE

B

Chy

lom

icro

ns

CII

-48

AI

LIVERLDL-R

LRP

Macrophage

Lox-1

CD-36SR-A

SR-PSOXABCA1

SR-B1CE+FC CE

TG

CETPAI

AII

EHDL

LCATFC

CE

Other tissues

LPLR

E

B

CII

FC

LCAT

FC

CE

DAVIGNON 2006

Metabolic RelationshipsAmong Lipoproteins

LDL

1.

3.

2.

LipoproteinLipase`

TGHDL

VLDL

TRIGLYCERIDES

HDL SMALLDENSE LDL

Chylomicrons and their remnants may be less likely to cause atherosclerosis

(smaller numbers and larger size)

FATTYACIDS

(ALBUMIN)

TG (VLDL)

TG (CHYLO-MICRONS)

LIPO-PROTEIN

LIPASE

Fatty Acid and Triglyceride Flux

Pancreatic Lipase Movement

Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

Chylomicron Role in Pancreatitis

Pancreatic lipase actson chylomicrons adherent to capillaryendothelium, producingfatty acid anions, or soaps. By detergentaction, cell membranesare disrupted, releasingmore lipase, and additional fatty acidanions are produced ina vicious cycle.

Pancreatic lipase actson chylomicrons adherent to capillaryendothelium, producingfatty acid anions, or soaps. By detergentaction, cell membranesare disrupted, releasingmore lipase, and additional fatty acidanions are produced ina vicious cycle.

Dietary management of lipoprotein lipase deficiency: Avoid dietary fat, except MCT’s and marine oil n-3

fatty acids

Other treatment options in lipoprotein lipase deficiency

• Fibrates and marine oil n-3 fatty acids: limitation of gene response

• Avoid insulin deficiency: Cofactor for lipoprotein lipase

• Temporary effect of plasmapheresis

• Temporary effect of plasma transfusion in apo C2 (cofactor) deficiency

• ? Xenical

• Future: DGAT1 inhibitors

• ?Gene therapy

■ Normal■ Hypoalpha- lipoproteinemia

■ Complete (FHC) or partial LPL deficiency associated with a secondary factor

■ Complete LPL deficiency (FHC)■ Primary apoC-II deficiency

■ Familial dysbeta- lipoproteinemia (type III)■ Hepatic lipase deficiency■ (Primary cause associated with a secondary factor)

Apo B > 0.75 g/L

Apo B < 0.75 g/L

TC:Apo B > 6.2

TC:Apo B < 6.2

■ Familial hyperTG■ Partial LPL deficiency

■ FH■ Polygenic■ FDB■ PCSK9deficiency■ ARH deficiency■ CYP7A1deficiency■ Hypoalphalipo-proteinemia

■ FCH■ β-Sitosterolemia

Normal Chylo + VLDL Chylo Chylo +

VLDL Remnants

VLDL LDL VLDL + LDL

NormoTG< 1.5

mmol/L

TG:Apo B > 0.12

NormoApo B< 1.2 g/L

TG:Apo B < 0.12

HyperTG> 1.5

mmol/L

NomoTG> 1.5

mmol/L

HyperApo B> 1.2 g/L

Hyper TG> 1.5

mmol/L

PrimaryCauses

Algorithm for Diagnosis of Apo B DyslipoproteinemiasAlgorithm for Diagnosis of Apo B Dyslipoproteinemias

Abbreviations: apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; CAPD, continuous ambulatory peritoneal dialysis; Chylo, chylomicrons; CP7A1, cytochrome P450 7A1; DM2, diabetes mellitus type 2; dysbeta; dysbetalipoproteinemia; FCH, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHC, familial hyperchylomicronemia; HAART, highly active antiretroviral therapy; LPL, lipoprotein lipase; PCOS, polycystic ovary syndrome; SLE, systemic lupus erythematosus; TC, total cholesterol; TG, triglyceride. de Graaf J et al. Nat Clin Pract Endocrinol Metab 2008;4:608-

18.

Lipoproteins

Nordestgaard BG, et al. JAMA. 2007;298(3):299-308

Relationship of Non-Fasting Triglycerides and Cardiovascular Risk

Copenhagen City Heart Study(7587 women and 6394 men)

Bansal S, et al. JAMA. 2007;298(3):309-316

Relationship of Non-Fasting Triglycerides and Cardiovascular Risk

Womens Health Study (n= 26,509)

Nordestgaard BG, et al. JAMA. 2007;298(3):299-308

Relationship of Non-Fasting Triglycerides and Cardiovascular Risk

Copenhagen City Heart Study(7587 women and 6394 men)

Rx and response

Fibrates and marine oil n-3 fatty acids: greater prospect of gene upregulation

Niacin: greater prospect of gene upregulation

Avoid insulin deficiency: Cofactor for lipoprotein lipase

Temporary effect of plasmapheresis

? Xenical

Future: DGAT1 inhibitors

COOH

C20:5 ω-3 Eicosapentaenoic(EPA)

H3C

Essential Fatty Acid Families

C18:3 ω-3

ω-3 family

-Linolenic• Flaxseed Oil• Canola Oil• Soybean Oil

C22:6 ω-3 Docosahexaenoic(DHA)

COOHH3C

• Oily Fish• Fish Oil

Capsules

H3CCOOH

ω-6 family

C20:4 ω-6

C18:2 ω-6 Linoleic

Arachidonic

H3CCOOH

More thrombotic and inflammatory metabolites

• Corn Oil• Safflower Oil• Sunflower Oil

Less thrombotic and inflammatory metabolites

H3C COOH

What happens in the food chain?:

Starting materials

Modification by herbivores

Accumulation by carnivores

Essential Fatty Acid Contrasts: Position of 1st double bond

N-6 :

– Greater availability in diet

– Greater availability in membranes.

– Main substrate for PG & LT

– Typical inflammatory response

N-3:

– Lower availability, so lesser substrate for PG & LT

– Highest potential number of double bonds.

– Less inflammatory response

Essential Fatty Acid Contrasts: Chain length

N-3 < 20C (Plant):

– Too short for membrane Phosphlipid

– Full effect as anti-arrhythmic

– No effect on TG

– No effect on platelet adhesion

– Effective precursor

N-3 > C20 (Marine)

– Suitable for membrane Phospholipid

– Strongly anti- arrhythmic

– Reduce TG synthesis and decrease TG by about 50%

– Reduce platelet adhesion.

Postprandial Lipoproteins affect FMD after Oral Fat Load

Franco M et al. J Clin Endo & Metab 2004;89:2946-2950

0h 2h 4h 6h 8h

0h 2h 4h 6h 8h

0h 2h 4h 6h 8h2

3

4

5

6

7

10

12

14

16

18

0.4

0.7

0.8

0.9

1.0

0.6

0.5

mm

ol/L

% D

ilati

onm

mol

/L

FMD

Remnant-C

Triglycerides TG & RLP-C increased significantly and continuously up to 4 & 6 hours respectively

FMD revealed decreased vasodilation at 4-6 hours

Results vary, but postprandial events, including secretion of chylomicrons, exert strong effects on vascular function

Summary and link to cases

Mrs N.S.• This 36 year old woman has not been able to conceive. She gained a large

amount of weight (BMI 38) when she stopped smoking in her mid 20’s. Unfortunately she resumed smoking in her early 30’s without any change in weight. Alcohol intake is less that 30 gms / week. Two years ago she became diabetic and now requires insulin to maintain HB A1C < 7.5%. Even then, associated lipid levels include triglyceride of 38 mmol/l, but she has not suffered pancreatitis.

Questions concerning Mrs N.S.

• What priority do you place on cessation of smoking in this case?

High / Low

• Your preferred strategy to achieve weight loss involves the use of A) Xenical B) Meal replacement C) gastric bypass D) Metformin

• If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include: A) Nil by mouth B) Consideration of plasmapheresis, C) Commencement of statin therapy D) Reduction in Insulin dose E) All of the above

• What priority do you place on cessation of smoking in this case?

High / Low

• Your preferred strategy to achieve weight loss involves the use of A) Xenical B) Meal replacement C) gastric bypass D) Metformin

• If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include: A) Nil by mouth B) Consideration of plasmapheresis, C) Commencement of statin therapy D) Reduction in Insulin dose E) All of the above

This 36 year old woman has not been able to conceive. She gained a large amount of weight (BMI 38) when she stopped smoking in her mid 20’s. Unfortunately she resumed smoking in her early 30’s without any change in weight. Alcohol intake is less that 30 gms / week. Two years ago she became diabetic and now requires insulin to maintain HB A1C < 7.5%. Even then, associated lipid levels include triglyceride of 38 mmol/l, but she has not suffered pancreatitis.

What priority do you place on cessation of smoking in this case?

• High

• Low

What priority do you place on cessation of smoking in this case?

A vexed problem. Theoretical reasons for “high”

Your preferred strategy to achieve weight loss involves the use of ...

• A) Xenical

• B) Meal replacement

• C) gastric bypass

• D) Metformin

Your preferred strategy to achieve weight loss involves the use of ...

Pro’s and con’s of each

If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate

intervention would include

• A) Nil by mouth

• B) Consideration of plasmapheresis,

• C) Commencement of statin therapy

• D) Reduction in Insulin dose

• E) All of the above

If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate

intervention would include...Pattern of the problem (a case for “A”)

Mrs N.S.• Although advice about diet and smoking fails to alter weight or glycaemic

control, your introduction of fenofibrate and fish oil reduces TG to 17 mmol/l. Mrs N.S. desperate to start a family and is actively pursuing IVF.

• Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute pancreatitis? Yes / No

• Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy itself affect triglyceride levels or risk of pancreatitis?

Yes / No

• Would you continue fenofibrate? Yes / No

• Your estimate on Mrs N.S’s risk of a cardiovascular event is:

A) Low now and in the future

B) Low now, but high in the future

C) High, even now.

Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute

pancreatitis?

• Yes

• No

Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute

pancreatitis? The case for “no”

TG in mg%For mmol/lDivide by 90

Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy itself affect triglyceride levels or the risk of

pancreatitis?

• Yes

• No

Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy

itself affect triglyceride levels? The case for “yes”

Obstet Gynecol. 1993 May;81(5 ( Pt 2)):890-2.Recurrent pancreatitis associated with in vitro fertilization.Steinmetz OK, Hashim E, Falcone T, Hemmings R, Bourque J.BACKGROUND:We report the possible association between in vitro fertilization (IVF) and recurrent acute pancreatitis.CASE:A patient developed acute pancreatitis during each of two cycles of IVF. On a spontaneous cycle, serum triglycerides were as follows: early follicular phase 2.34 mmol/L, mid-follicular phase 4.17 mmol/L, and late follicular phase 6.6 mmol/L. During an episode of acute pancreatitis, the serum triglyceride level was 38.45 mmol/L.CONCLUSION:Acute pancreatitis may occur in patients with a family or personal history of hypertriglyceridemia who are candidates for IVF.

Would you continue fenofibrate?

• Yes

• No

Would you continue fenofibrate?Uncertain teratogenicity versus

manifest risk.

Pregnancy: Teratogenic Effects, Pregnancy Category CSafety in pregant women has not been established. Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose (MRHD) and embryocidal in rabbits when given at 9 times the MRHD (on the basis of mg/meter2 surface area). There are no adequate and well-controlled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Your estimate on Mrs N.S’s risk of a cardiovascular event is:

A) Low now and in the future

B) Low now, but high in the future

C) High, even now.

Your estimate on Mrs N.S’s risk of a cardiovascular event is:

The tentative case for “C”

Mr G.T.• Mr G.T. is 32 years old. He is Chinese and he consumes an Asian diet. He is

not overweight, but his business and social obligations involve occasional Asian banquets. He rarely drinks more than 20 gms alcohol per week. He suffered occasional episodes of abdominal pain in adolescence and early adulthood, and recently he was admitted to an intensive care unit with his first episode of acute pancreatitis. Fasting plasma lipids included plasma triglyceride level of 56 mmol/l but plasma glucose is within normal limits.

Questions concerning Mr G.T.

• What physical findings might accompany an episode of this severity?(More than 1 possible) A) Tendon Xanthomas B) Lipaemia Retinalis C) Tuberous Xanthomas D) Eruptive Xanthomas E) Corneal Arcus

• How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? A) Plasma LPL mass B) Plasma LPL activity C) Plasma LPL activity after a heparin bolus D) Protein iso-electric focussing for Apo C3 E) Genetic testing

• What diet advice would you give on discharge? A) Low fat diet < 10% energy B) Medium chain triglycerides to minimumize carbohydrate C) Extra fish oil (>15 gms) D) All of the above E) Low fat diet < 25% energy

• Mr G.T. is 32 years old. He is Chinese and he consumes an Asian diet. He is not overweight, but his business and social obligations involve occasional Asian banquets. He rarely drinks more than 20 gms alcohol per week. He suffered occasional episodes of abdominal pain in adolescence and early adulthood, and recently he was admitted to an intensive care unit with his first episode of acute pancreatitis. Fasting plasma lipids included plasma triglyceride level of 56 mmol/l but plasma glucose is within normal limits.

• What physical findings might accompany an episode of this severity?(More than 1 possible) A) Tendon Xanthomas B) Lipaemia Retinalis C) Tuberous Xanthomas D) Eruptive Xanthomas E) Corneal Arcus

• How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? A) Plasma LPL mass B) Plasma LPL activity C) Plasma LPL activity after a heparin bolus D) Protein iso-electric focussing for Apo C3 E) Genetic testing

• What diet advice would you give on discharge? A) Low fat diet < 10% energy B) Medium chain triglycerides to minimumize carbohydrate C) Extra fish oil (>15 gms) D) All of the above E) Low fat diet < 25% energy

What physical findings might accompany an episode of this severity? (More than 1 possible)

• A) Tendon Xanthomas

• B) Lipaemia Retinalis

• C) Tuberous Xanthomas

• D) Eruptive Xanthomas

• E) Corneal Arcus

What physical findings might accompany an episode of this severity? (More than 1 possible)

The case for “B” and “D”

How would you investigate the possibility of lipoprotein lipase (LPL) deficiency?

• A) Plasma LPL mass

• B) Plasma LPL activity

• C) Plasma LPL activity after a heparin bolus

• D) Protein iso-electric focussing for Apo C3

• E) Genetic testing

How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? The case

for “C”, but “E” is becoming possible

What diet advice would you give Mr G.T. on discharge?

• A) Low fat diet < 10% energy

• B) Medium chain triglycerides to minimize carbohydrate

• C) Extra fish oil (>10 gms/day)

• D) All of the above

• E) Low fat diet < 25% energy

What diet advice would you give Mr G.T. on discharge?

The case for “D”, but the dilemma re CHO

More questions about Mr G.T.• Despite your dietary advice, Mr G.T. suffers a recurrence of pancreatitis 5

months later.

• When massive hypertriglyceridaemia is present, which of the following symptoms may occur? A) Risk of pancreatitis, Abdominal pain, hepatosplenomegaly B) Confusion C) Peripheral paresthesiasD) Dyspnea E) All of the above

• If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest? A) Continuation of current diet B) Gene therapy C) Total pancreatectomy plus pancreatic transplant D) Biliary diversion E) Plasmapheresis

When massive hypertriglyceridaemia is present, which of the following

symptoms may occur?

A) Risk of pancreatitis, Abdominal pain, hepatosplenomegaly

B) Confusion

C) Peripheral paresthesias

D) Dyspnea

E) All of the above

When massive hypertriglyceridaemia is present, which of the following symptoms

may occur? The case for “E”.

Accumulated case reports, eg “He reported recurrent headachesand dizziness with lightheaddedness and vertigoindependently of alcohol consumption. Thesesymptoms were accompanied by mood disturbancesincluding dysphoria and depression. Neurologicexamination was normal.

If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest?

• A) Continuation of current diet

• B) Gene therapy

• C) Total pancreatectomy plus pancreatic transplant

• D) Biliary diversion

• E) Plasmapheresis

If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest?

The case for “A”