Masterclass 8

Report
Massive Hypertriglyceridaemia:
A complete white-out,
INTESTINE
Chylomicrons
B -48
B
LIVER
E
LPL CII
CII
LCAT AI
CE
FC
CE
Other
tissues
F
C
AII
LCAT
B
LDL-R
E
B
CETP
HDL
LDL
FC
Macrophage
FC
ABCA1
LPL
E
LRP
SRCE+FC B1
AI E
AII
VLDL
CIII
R
AI
B -100
SR-A
CD-36
Lox-1
SR-PSOX
IDL
CIII
HL
.
O
B
OxLDL
DAVIGNON 2006
Metabolic Relationships
Among Lipoproteins
1.
VLDL
LDL
3.
HDL
TG
2.
 TRIGLYCERIDES
Lipoprotein
Lipase`
 HDL
SMALL
DENSE LDL
Chylomicrons and their remnants may
be less likely to cause atherosclerosis
(smaller numbers and larger size)
Fatty Acid and Triglyceride Flux
FATTY
ACIDS
(ALBUMIN)
TG (VLDL)
LIPOPROTEIN
LIPASE
TG
(CHYLO-MICRONS)
Pancreatic Lipase Movement
Most pancreatic
lipase is secreted
into the pancreatic
duct, but some moves
back into capillaries.
Chylomicron Role in Pancreatitis
Pancreatic lipase acts
on chylomicrons
adherent to capillary
endothelium, producing
fatty acid anions, or
soaps. By detergent
action, cell membranes
are disrupted, releasing
more lipase, and
additional fatty acid
anions are produced in
a 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
Algorithm for Diagnosis of Apo B Dyslipoproteinemias
HyperApo B
> 1.2 g/L
NormoApo B
< 1.2 g/L
NormoTG
< 1.5 mmol/L
HyperTG
> 1.5 mmol/L
TG:Apo B >
0.12
NomoTG
> 1.5 mmol/L
Hyper TG
> 1.5 mmol/L
LDL
VLDL + LDL
TG:Apo B <
0.12
Apo B > 0.75
g/L
Apo B < 0.75
g/L
TC:Apo B >
6.2
TC:Apo B < 6.2
Chylo + VLDL
Chylo
Chylo + VLDL
Remnants
VLDL
■ Complete
(FHC)
or partial LPL
deficiency
associated
with
a secondary
factor
■ Complete LPL
deficiency
(FHC)
■ Primary apoCII
deficiency
■ Familial
dysbetalipoproteinemia
(type III)
■ Hepatic lipase
deficiency
■ (Primary cause
associated with
a secondary
factor)
Lipoproteins
Normal
Primary
Causes
■ Normal
■ Hypoalphalipoproteinemia
■ Familial
hyperTG
■ Partial LPL
deficiency
■ FH
■ Polygenic
■ FDB
■ PCSK9
deficiency
■ ARH
deficiency
■ CYP7A1
deficiency
■ Hypoalphalipoproteinemia
■ FCH
■ βSitosterolemia
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-
Relationship of Non-Fasting Triglycerides and
Cardiovascular Risk
Copenhagen City Heart Study(7587 women and 6394 men)
Nordestgaard BG, et al. JAMA. 2007;298(3):299-308
Relationship of Non-Fasting Triglycerides and
Cardiovascular Risk
Womens Health Study (n= 26,509)
Bansal S, et al. JAMA. 2007;298(3):309-316
Relationship of Non-Fasting Triglycerides and
Cardiovascular Risk
Copenhagen City Heart Study(7587 women and 6394 men)
Nordestgaard BG, et al. JAMA. 2007;298(3):299-308
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
Essential Fatty Acid Families
ω-3 family
ω-6 family
H3C
C18:2 ω-6
COOH
Linoleic
H3C
C18:3 ω-3
• Corn Oil
• Safflower Oil
• Sunflower Oil
H3C
H3C
COOH
C20:4 ω-6 Arachidonic
COOH
-Linolenic
• Flaxseed Oil
• Canola Oil
• Soybean Oil
COOH
C20:5 ω-3 Eicosapentaenoic
(EPA)
H3C
COOH
C22:6 ω-3 Docosahexaenoic
(DHA)
More thrombotic
and inflammatory
metabolites
Less thrombotic
• Oily Fish
and inflammatory • Fish Oil Capsules
metabolites
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):
•
N-3 > C20 (Marine)
• Too short for membrane
Phosphlipid
• Suitable for membrane
Phospholipid
• Full effect as antiarrhythmic
• Strongly anti- arrhythmic
• No effect on TG
• No effect on platelet
adhesion
• Effective precursor
• Reduce TG synthesis and
decrease TG by about 50%
• Reduce platelet adhesion.
Postprandial Lipoproteins affect FMD
after Oral Fat Load
7
6
Triglycerides
mmol/L
5
4
3
2
0h
2h
4h
6h
8h
TG & RLP-C increased
significantly and
continuously up to 4 & 6
hours respectively
1.0
0.9
Remnant-C
FMD revealed decreased
vasodilation at 4-6 hours
mmol/L
0.8
0.7
0.6
0.5
0.4
0h
2h
4h
6h
8h
2h
4h
6h
8h
% Dilation
18
16
14
12
Results vary, but postprandial
events, including secretion of
chylomicrons, exert strong
effects on vascular function
FMD
10
0h
Franco M et al. J Clin Endo & Metab 2004;89:2946-2950
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
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
• 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
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/l
Divide 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 C
Safety 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 paresthesias
D) 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 headaches
and dizziness with lightheaddedness and vertigo
independently of alcohol consumption. These
symptoms were accompanied by mood disturbances
including dysphoria and depression. Neurologic
examination 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”

similar documents