Lipoprotein disorders and metabolic syndrome : obesity diabetes hypertension glucose tolerance statins weight insulin resistance

1. LIPOPROTEIN DISORDERS AND
METABOLIC SYNDROME
GUIDE : DR KALINGA B.E.
STUDENT : MOHAMMAD NIZAMUDDIN H ATTAR

2. NORMAL LIPOPROTEIN PHYSIOLOGY
PATHOPHYSIOLOGY
CLINICAL APPROACHES TO THE DIAGNOSIS
MANAGEMENT OF LIPOPROTEIN DISORDERS

3. These lipids are insoluble in blood plasma, so they
have to be transported through out the body in a
protein capsule known as Lipoprotein.

4. Lipoproteins are complexes of lipids and proteins
that are essential for transport of cholesterol,
triglycerides , and fat-soluble vitamins in the blood.

5. LIPOPROTEIN CLASSIFICATION AND
COMPOSITION

6. FIVE MAJOR CLASSES BASED ON THEIR
RELATIVE DENSITY
1. CHYLOMICRONS,
2. VERY-LOW-DENSITY LIPOPROTEINS (VLDLS),
3. INTERMEDIATE-DENSITY LIPOPROTEINS (IDLS),
4. LOW-DENSITY LIPOPROTEINS (LDLS),
5. HIGH-DENSITY LIPOPROTEINS (HDLS)

8. Rader DJ, Hoeg JM and BrewerHB Jr. Quantitationof plasma apolipoproteins in the primaryand secondarypreventionof coronaryarterydisease. Ann Intern Med. 1994Jun 15;120(12):1012-25.
LIPOPROTEIN SYNTHESIS, TRANSPORT
AND RECYCLING
Major
apolipoprotein
Function of the apolipoprotein
apoA-1 Structural protein - HDL
apoB-48 Structural protein - Chylomicron
apoB-100 Ligand for binding to LDL receptors
Structural protein in VLDL and LDL
apoE Ligand for binding to remnant apoE-receptor

9. TRANSPORT OF INTESTINALLY DERIVED
DIETARY LIPIDS BY CHYLOMICRONS
 Dietary lipids are hydrolyzed by lipases within the
intestinal lumen and emulsified with bile acids to form
micelles.
 Fatty acids are incorporated into TG and packaged with
APOB-48, to form chylomicrons.
 The TGS of chylomicrons are hydrolyzed by lipoprotein
lipase, and free fatty acids are released.

10. Dietary
lipids Deliver energy rich triglycerides to
cells throughout the body
Synthesis of steroid hormones
and cell membrane
50%

11. TRANSPORT OF HEPATICALLY DERIVED
LIPIDS BY VLDL AND LDL
 Triglycerides, which are packaged into VLDL particles along
with APOB-100.
 TG-depleted VLDL remnants dissociate from LPL, they are
referred to as IDLS, which contain roughly similar amounts
of Cholesterol and TG.
 Liver removes ~40–60% of IDL by receptor–mediated
endocytosis via binding to APOE, which is acquired through
transfer of this protein from HDL.
 The remainder of IDL is further remodeled by hepatic lipase
(HL) to form LDL

14.  Cholesterol in peripheral cells is transported to the liver
and intestine by a process termed “REVERSE
CHOLESTEROL TRANSPORT”

15. HDL METABOLISM AND REVERSE
CHOLESTEROL TRANSPORT

16. LDL vs HDL

17. DYSLIPIDEMIA
Disorders of lipoprotein metabolism are collectively referred
to as “DYSLIPIDEMIAS.”
Dyslipidemias are generally characterized clinically by
increased plasma levels of cholesterol, triglycerides or both.

18. Fredrickson classification is still
followed
Hyper-
lipoproteinemia
Name of the disease Increased lipoprotein Increased lipid
fraction
Type I Hyperchylomicronemia Chylomicrons Triglycerides
Type IIa Familial
hypercholesterolemia
LDL Cholesterol
Type IIb Familial combined
hypercholesterolemia
LDL and VLDL Cholesterol and
triglycerides
Type III Dysbetalipoprotenemia IDL Triglycerides and
cholesterol
Type IV Familial
hypertriglyceridemia
VLDL Triglycerides
Type V Familial lipoprotein
lipase deficiency
VLDL and
Chylomicrons
Triglycerides and
cholesterol

19. Type I Hyperlipoproteinemia or Hyperchylomicronemia
• 1 in 1 million
• Deficiency of lipoprotein lipase or apolipoprotien C-II (a lipase- activating
protein)
• Thus, inability to remove chylomicrons and triglycerides from blood
• Fasting TGS invariably > 1000mg/dl
• Plasma is turbid and forms a creamy supernatant layer
• Clinical features
 Acute pancreatitis
 Eruptive xanthomas
 Lipemia retinalis
 Premature ASCVD is rarely seen
 Hepatosplenomegaly

20. A. Xanthelasma
B. Lipemia retinalis
C. Achilles tendon
xanthomas.
D. Tendon xanthomas
E. Tuberous
xanthomas
F. Palmar xanthomas
G. Eruptive
xanthomas

21. Type IIa Hyperlipoproteinemia or Familial
hypercholesterolemia (increased LDL)
•Homozygous familial hypercholesterolaemia
•Mutations in LDL receptor (LDLR) gene.
•Receptor Negative and Defective Types
•Parents are heterozygous
•Markedly elevated (LDL-C)
•Range from 400 to >1000mg/dl

22. Type IIa Hyperlipoproteinemia or Familial
hypercholesterolemia
• Life-threatening condition (first decade of life)
• Accelerated ASCVD
• First in aortic root causing valvular or supravalular stenosis
• Extending in to coronary ostia .
• Cutanuos xanthomas .

23. Type IIa Hyperlipoproteinemia or Familial
hypercholesterolemia (increased LDL)
Heterozygous type
• 1 in 500
• AD
• Treatable life-threatening condition
• Heterozygous mutations in the LDLR gene
• Elevated (LDL-C) 190 -400 mg/dl.
• Clinical features similar to Homozygous condition

24. Type IIb Hyperlipoproteinemia or
combined hyperlipidemia
(increased VLDL and LDL)
• 1 in 100
• AD
• But molecular basis is yet to be deciphered
•
•
•
Leads to increased serum Triglycerides(200- 600mg/dl)
and LDL cholesterol (200-400mg/dl)
cutaneous xanthomas rare

25. Type III Hyperlipoproteinemia or
Dysbetalipoproteinemia
•1 in 1 million
•Mutation in apoE apoprotein
•AR
•Elevated plasma triglycerides and cholesterol
•Manifests earlier in males and usually after menopause in women
•Two distinctive types of xanthomas
• Tuberoeruptive
• Xanthomata striata palmaris
•Premature ASCVD
•Peripheral vascular disease

26. Type IV hyperlipoproteinemia or familial
hypertriglyceridemia (increased VLDL)
•1 in 100
•AD
•Mutations in Apolipoprotein C and Lecithin:cholesterol
acyltransferase (LCAT)
•Clinical features
• eruptive xanthomas,
• lipemia retinalis
• Hepatosplenomegaly
• Premature ASCVD
•May present as acute pancreatitis

27. Type V Hyperlipoproteinemia or Familial lipoprotein
lipase deficiency (increased VLDL and Chylomicron)
•1 in 600
•Mutation in the apoE apolipoprotein
•Patients overproduce triglycerides and defective clearance of
VLDL
•Clinical features similar to TYPE IV

28. SECONDARY
HYPERLIPIDEMIA
• Usually a “two hit phenomenon” is noticed
o “First hit” is the genetic predisposition
o “Second hit” are the secondary factors, which
worsen lipid levels.

29. SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA.

30. SITOSTEROLEMIA
 AR disease
 Mutations in the ATP-binding cassette (ABC) half transporter
family, ABCG5 and ABCG8
 The proteins transports plant sterols such as sitosterol
 Increase in hepatic sterol levels results in transcriptional
suppression of the expression of the LDL receptor.

31.  Clinical picture
a. Severe hypercholesterolemia,
b. Tendon xanthomas
c. premature ASCVD,
d. Anisocytosis and poikilocytosis
e. Megathrombocytes
f. Episodes of hemolysis
g. Splenomegaly
 Fails to respond to statin therapy

32. LYSOSOMAL ACID LIPASE DEFICIENCY (LALD)
 AR
 Also known as cholesteryl ester storage disease.
 Defect -lysosomal acid lipase (LAL).
 severe form - Wolman’s disease, presents in infancy and is rapidly fatal
• Suspect in nonobese patients with elevated LDL-C, low HDL-C,
• evidence of fatty liver in the absence of overt insulin resistance
• Progressive fatty liver ultimately leading to hepatic fibrosis.

33. Tangier Disease (ABCA1 Deficiency)
 Autosomal Dominant
 Defect in cellular transporter ABCA1
 This transporter facilitates efflux of unesterified cholesterol
and phospholipids from cells to apoA-I
 Extremely low plasma HDL-C levels
 Cholesterol accumulates in the reticuloendothelial system
 Hepatosplenomegaly
 Pathognomonic enlarged, grayish yellow or orange tonsils.

34. MANAGEMENT
 Intervene in patients with triglycerides >500 mg/ dl in order to reduce the risk of pancreatitis
 Dietary fat intake should be restricted to reduce the formation of chylomicrons in the intestine
 The excessive intake of simple carbohydrates should be discouraged because insulin drives tg
production in the liver.
 Aerobic exercise and even increase in regular physical activity can have a positive effect in
reducing tg levels and should be strongly encouraged

35. Pharmacologic Therapy
 Patients who persist in having fasting TG >500 mg/dl despite active lifestyle
management are candidates for pharmacologic therapy
 The two major classes - Fibrates And Omega-3 Fatty Acids (Fish Oil)
 In addition, statins can reduce plasma TG levels and also reduce CVD risk

36. HMG-COA REDUCTASE INHIBITORS (STATINS)
DRUG
• Lovastatin 20–40 mg daily
• Pravastatin 40–80 mg daily
• Simvastatin 20–40 mg daily
• Fluvastatin 20–40 mg daily
MAJOR INDICATIONS Elevated LDL-C; increased CV risk
MECHANISM Inhibit HMG-CoA reductase
Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on
hepatocytes
• modest reduction in triglyceride
COMMON SIDE
EFFECTS
Myalgias and myopathy ↑ transaminases, ↑ diabetes risk

38. CHOLESTEROL ABSORPTION INHIBITOR
DRUG
• Ezetimibe
• 10 mg daily
MAJOR INDICATIONS Elevated LDL, phytosterolemia
MECHANISM Blocks sterol transporter NPC1L1 in intestine brush border
Inhibits reabsorption of cholesterol excreted in bile • decreases LDL and phytosterols
Oral • duration 24 h •
COMMON SIDE EFFECTS
Toxicity: Low incidence of hepatic dysfunction, myositis

39. BILE ACID SEQUESTRANTS
DRUG • Cholestyramine 4 g daily
• Colestipol 5 g daily
• Colesevelam 3750 mg daily
MAJOR INDICATIONS Decreases LDL
MECHANISM Binds bile acids in gut
prevents reabsorption
increases cholesterol catabolism
up-regulates LDL receptors
COMMON SIDE EFFECTS Bloating, constipation, elevated triglycerides

40. PCSK9 INHIBITORS
DRUG • Evolocumab 140 mg SQ q 2 weeks
• Alirocumab 75 mg SQ q 2 weeks
MAJOR INDICATIONS Elevated LDL-C
MECHANISM ↓ PCSK9 activity, ↑ LDL receptors
COMMON SIDE EFFECTS Allergic reactions
flu like symptoms

41. Fewer LDL receptors on hepatocyte surface result in increased
plasma LDL-C
When PCSK9
binds to the
LDL receptor,
it targets the
complex for
degradation
Lysosomal degradation
Decreased LDLR surface concentration
LDLR recycling
LDLR/PCSK9 routed
to lysosome
PCSK9 secretion

42. OMEGA-3 FATTY ACIDS
DRUG Omega-3 acid ethyl esters 4 g daily
ecosapent ethyl 4 g daily
MAJOR INDICATIONS Elevated TG
MECHANISM ↑ TG catabolism
COMMON SIDE EFFECTS Dyspepsia, fishy odor to breath

43. FIBRIC ACID DERIVATIVES
DRUG Gemfibrozil 600 mg bid
Fenofibrate 145 mg qd
MAJOR INDICATIONS Elevated TG
MECHANISM Peroxisome proliferator-activated receptor-alpha (PPAR-α) agonists
Decrease secretion of very-low-density lipoproteins (VLDL) • increase lipoprotein
lipase activity • increase high-density lipoproteins (HDL)
COMMON SIDE EFFECTS Dyspepsia, myalgia, gallstones, elevated transaminases

44. Apo -B INHIBITOR
DRUG • Mipomersen
• 200 mg SC weekly
MAJOR INDICATIONS HoFH
MECHANISM
an antisense oligonucleotide against apoB
↓ VLDL and LDL-C production
COMMON SIDE EFFECTS injection site reactions, flu-like symptoms, increased hepatic fat

45. NIACIN
DRUG Dose of niacin 1–3 g/d
MAJOR INDICATIONS Low HDL • elevated VLDL, LDL, Lp(a)
MECHANISM Decreases catabolism of apo AI
Reduces VLDL secretion from liver
Increases hdl
decreases lipoprotein(a) [lp(a)], ldl, and triglyceride
COMMON SIDE EFFECTS Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity • may reduce
glucose tolerance

46.  Two different Recommendations
1. Adult Treatment Panel (ATP III) of the National
Cholesterol Education Program (NCEP)
 Beginning at age 20: Obtain a fasting (9 to 12 hour)
serum lipid profile consisting of total cholesterol, LDL,
HDL and triglycerides
 Repeat testing every 5 years for acceptable values
WHEN TO CHECK LIPID PANEL

47.  Non fasting lipid panel
Measures HDL and Total cholesterol
 Fasting lipid panel
Measures HDL, Total cholesterol and
Triglycerides
 LDL cholesterol is calculated:
 LDL cholesterol = Total cholesterol – HDL –
(Triglycerides/5)
Checking lipids

48.  LDL
 < 100 →Optimal
 100-129 → Near optimal
 130-159 → Borderline
 160-189→ High
 ≥ 190 → Very High
 Total Cholesterol
 < 200 → Desirable
 200-239 → Borderline
 ≥240 → High
Goals for Lipids

49.  HDL
 < 40 → Low
 ≥ 60 → High
 Serum Triglycerides
 < 150 → normal
 150-199 → Borderline
 200-499 → High
 ≥ 500 → Very High
Goals for Lipids

50.  CHD and CHD Risk Equivalents:
 Peripheral Vascular Disease
 Cerebral Vascular Accident
 Diabetes Mellitus
Determining Goal LDL

51.  0-1 Risk Factors:
 LDL goal is 160
 If LDL ≥ 160: Initiate TLC (therapeutic lifestyle
changes)
 If LDL ≥ 190: Initiate pharmaceutical treatment
LDL Goals

52.  2 + Risk Factors
 LDL goal is 130
 If LDL ≥ 130: Initiate TLC
 If LDL ≥ 160: Initiate pharmaceutical treatment
 CHD or CHD Risk Equivalent
 LDL goal is 100 (or 70)
 If LDL ≥ 100: Initiate TLC and pharmaceutical treatment
LDL GOAL

53. 2018 GUIDE LINES ON MANAGEMENT OF
BLOOD CHOLESTEROL
The ASCVD Risk Calculator is used to identify
patients who would benefit from primary prevention
strategies, not secondary.

54.  Patients 40 to 79 years of age without ASCVD
 Patients with LDL levels 70 to 189 mg/dL without
ASCVD and not on statin therapy
WHEN TO USE ASCVD CALCULATOR

55.  NOT for patients <40 years of age or >79 years of age
 NOT for patients with established ASCVD or with
symptoms suggestive of CVD
 NOT for patients on hemodialysis
 NOT for patients with advanced congestive heart failure
 NOT for subgroups of high-risk patients, such as those
with familial hypercholesterolemia
WHEN NOT TO USE ASCVD CALCULATOR

56.  The guideline identifies four major groups of
individuals (≥21 years old) as potentially
benefitting from statins.
 1. Individuals with clinical ASCVD.
 2. Individuals with primary elevations of LDL-C ≥190 mg/dl.

57.  3. Individuals 40–75 years of age with diabetes and
LDL-C 70–189 mg/dL without clinical ASCVD.
 4. Individuals without clinical ASCVD or Diabetes
who are 40–75 years of age and have LDL-C 70–189
mg/dL and an estimated 10-year ASCVD risk of
≥7.5%.
 (Clinician-patient discussion recommended before
initiation of statin therapy).

58.  DASH and Mediterranean-style eating plans
 Include fruits, vegetables, and whole grains in daily menu
 30-35% fat intake
 <6% saturated fats, no trans fats
 Low sodium (<2400 mg/day)
 Cut out processed or pre-prepared food
 Promote healthy eating for a lifetime
NUTRITION(AHA RECOMMENDATION)

59.  For Overall Cardiovascular Health:
 At least 30 minutes of moderate-intensity aerobic activity at least 5
days per week for a total of 150 minutes OR
 At least 25 minutes of vigorous aerobic activity at least 3 days per
week for a total of 75 minutes.
PHYSICAL ACTIVITY (AHA RECOMMENDATION)

60. The Metabolic
Syndrome

61.  The metabolic syndrome (syndrome X, insulin
resistance syndrome) consists of a constellation of
metabolic abnormalities that confer increased risk
of cardiovascular disease (CVD) and diabetes
mellitus

62. Epidemiology
• AHA estimates 47 million Americans have metabolic syndrome.
• It also affect children. Worldwide, incidence ranges from 15%
to 31% among children ages 6 to 16.
• 5 times higher risk for developing type 2 diabetes.

63. Epidemiology: India
 India has also seen a surge in obesity
 It had 0.4 million obese men, or 1.3% of the global obese
population in 1975, but in 2018, it zoomed into the fifth
position with 9.8 million obese men (3.7% of the global
population)
 Among women, India has jumped to the third rank with 20
million obese women (5.3% of global population).
63

65. RISK FACTORS
 Overweight/Obesity
 Sedentary Lifestyle
 Aging
 Diabetes Mellitus
 Cardiovascular Disease

66. ETIOLOGY
1.Insulin Resistance
2.Dyslipidemia
3.Increased Waist Circumference
4.Hypertension
5.Pro-Inflammatory Cytokines
6.Adiponectin
7.Leptin resistance

68.  Associated Diseases
1. CARDIOVASCULAR DISEASE
2. TYPE 2 DIABETES
 Other Associated Conditions
1. NAFLD
2. HYPERURICEMIA
3. PCOS
4. OSA

70. MANGEMENT
 LIFESTYLE
1. Diet therapy
2. Physical Activity
 BLOOD PRESSURE MANAGEMENT
 BEHAVIOR MODIFICATION
 DIABETES MANAGEMENT

71. ACCORDING TO THE TREATMENT GUIDELINES ISSUED BY
THE U.S. NATIONAL INSTITUTES OF HEALTH (NIH)
 Persons who are
 Overweight
 Have class I obesity
 If decrease their daily energy intake by approximately 500 kcal/day then it will reduction of
0.23 kg per week and that is about 5% at 6 months.
 Energy deficit of 500 to 1000 kcal/day -weight loss of approximately 0.45 kg/week and
result in an approximate 10% weight loss at 6 months

72. PHYSICAL ACTIVITY
Increasing physical activity alone is not an effective strategy for promoting initial weight
loss.
Most studies have shown that moderate endurance exercise (e.g., brisk walking for 45 to
60 minutes, four times a week, for up to 1 year) usually induces only minor weight loss.3
Weight-loss maintenance with exercise requires expending approximately 2500 kcal/
week
This level of energy expenditure can be accomplished through
Vigorous activity (aerobics, cycling, or jogging) for approximately 30
min/day
Moderate activity (brisk walking) for 60 to 75 min/day.

74. BEHAVIOR MODIFICATION
 These strategies include
i. stimulus control
ii. self-monitoring
iii. problem-solving skills
iv. cognitive restructuring,
v. social support
vi. relapse prevention

75. WEIGHT-LOSS DRUGS COME IN TWO MAJOR
CLASSES:
APPETITE SUPPRESSANTS
1. Phentermine/topiramate,
2. Lorcaserin,
3. Naltrexone/ bupropion
4. Liraglutide
FAT ABSORBTION INHIBITORS - Orlistat

76. PHEN/TPM
Combination drug that contains a
catecholamine releaser
(phentermine) and an anticonvulsant
(topiramate).
Weight loss for phen/tpm was 9.3% (15-
mg/92-mg dose) and 6.6% (7.5-mg/46-
mg dose)
MECHANISM • Modulation of γ-aminobutyric acid
receptors,.
• Inhibition of carbonic anhydrase,
• Antagonism of glutamate
COMMON SIDE EFFECTS paresthesias, dry mouth, constipation, dysgeusia,
insomnia. congenital fetal oral-cleft

77. LORCASERIN
Selective 5-HT2C receptor
agonist
weight loss was 3.6% and 3.0%,
respectively, in the BLOOM and
BLOSSOM trials
MECHANISM • By activating the 5-HT2C receptor,
lorcaserin is thought to decrease food intake
through the pro-opiomelanocortin (POMC)
system of neurons.
COMMON SIDE EFFECTS headache
dizziness
nausea.

78. NALTREXONE SR/BUPROPION SR (NB)
Combination of an opioid
antagonist and a mild reuptake
inhibitor of dopamine and
norepinephrine
4.8%, 5.1%, and 4.2%, respectively,
in the COR-I, COR-II, and COR-BMOD
trials.
MECHANISM
NB (8 mg/90 mg two tablets bid)
Bupropion stimulates secretion of α-
melanocyte stimulating hormone (MSH)
from POMC
Naltrexone blocks the feedback inhibitory
effects of opioid receptors
COMMON SIDE EFFECTS nausea, constipation, headache, vomiting,
dizziness, diarrhea, insomnia, and dry
mouth.

79. LIRAGLUTIDE
glucagon-like peptide-1 (GLP-1)
analogue
5.4%, and 6.1%, respectively, in the
SCALE and SCALE Maintenance trials.
MECHANISM
NB (8 mg/90 mg two tablets bid)
• Incretin hormone
• Inhibits both gastric emptying and
glucagon secretion.
• Stimulates GLP-1 receptors in the
arcuate nucleus of the hypothalamus to
reduce feeding
COMMON SIDE EFFECTS nausea, constipation, headache, vomiting,
dizziness, diarrhea, insomnia, and dry
mouth.

80. ORLISTAT (XENICAL)
Synthetic derivative of a naturally
occurring lipase inhibitor
lipostatin, produced by the mold
Streptomyces toxytricini.
Orlistat produces a weight
loss of ~9–10%
MECHANISM
120 MG TID
This drug reversible inhibitor of
pancreatic, gastric, and carboxyl
ester lipases and phospholipase A2 .
COMMON SIDE EFFECTS Adverse gastrointestinal effects, including
flatus with discharge, fecal urgency,
fatty/oily stool, and increased defecation.

81. METABOLIC OR BARIATRIC SURGERY
 It is an option for patients with the metabolic syndrome
who have a body mass index >40 kg/m2 , or >35 kg/m2
with comorbidities.
 Gastric bypass or vertical sleeve gastrectomy results in
dramatic weight reduction and improvement in most
features of the metabolic syndrome.

82. Types of Procedures
A. Roux-en-Y gastric
bypass (RYGB) 30%
weight loss,
B. laparoscopic adjustable
gastric banding 20%
weight loss
C. sleeve gastrectomy 30%
weight loss,
D. biliopancreatic
diversion35% weight
loss,
E. biliopancreatic
diversion with duodenal
switch35% weight loss.

83. COMPLICATIONS
 mortality rate is about 0.1% to 2%
 anastomotic leaks
 peritonitis
 pulmonary embolism.
 atelectasis
 pneumonia
 Postprandial Hypoglycemia
 deep vein thrombosis
 pulmonary embolism
 anastomotic leak with peritonitis
 wound infection
 gastrointestinal bleeding
 internal hernias
 dumping syndrome

84. Thank you