Revision of fundamental facts of lipid metabolism through clinical discussion, and simultaneous assessment of learning through multiple choice questions

1. Lipid Metabolism- Revision
Namrata Chhabra
MHPE, MD, MBBS, FAIMER FELLOW
19-Dec-20 1

2. 19-Dec-20 2
Case study-1

3. Case study-1
• A 45-year-old man presented to the emergency with chest pain.
• The chest pain lasted for approximately 15 minutes then subsided on
its own.
• He also noticed that he was nauseated and was sweating during the
pain episode.
• He had no medical problems and had not been to a physician for
several years.
19-Dec-20 3

4. Case study-1
• On examination, he was in no acute distress with normal vital signs.
• His lungs were clear to auscultation bilaterally, and his heart had a
regular rate and rhythm with no murmurs.
• An electrocardiogram(ECG) revealed slight ischemic changes.
• The blood biochemistry revealed raised serum total cholesterol and
LDL cholesterol levels.
• He was placed on a low-fat diet and Lovastatin therapy.
19-Dec-20 4

5. Case study-1
He was without complaints and was feeling well on his subsequent
follow-up visit. On repeat serum cholesterol screening, a decrease in
the cholesterol level was noted.
• What is the mechanism of action of this drug?
• What are the alternative options to treat this patient?
19-Dec-20 5

6. Case discussion
• The patients had an episode of IHD (Ischemic heart disease) and had
hyperlipidemia.
• Hyperlipidemia is one of the most treatable risk factors of coronary heart
disease.
• Initially, when the fasting low-density lipoprotein (LDL) cholesterol is found
elevated, lifestyle modification is recommended such as dietary
adjustments, exercise, and weight loss.
• If the LDL cholesterol level is again found above threshold, pharmacological
therapy is initiated.
• Since the patient in the given case had a mild attack of IHD, hence without
trial he had been put on low-fat diet and statins.
19-Dec-20 6

7. Hypolipidemic Drugs
1) Statins (Lovastatin)
Lovastatin is a member of a class of
drugs (Atorvastatin, fluvastatin,
pravastatin and Simvastatin are
others in this class) called statins
that are used to treat
hypercholesterolemia.
The statins act as competitive
inhibitors of the enzyme HMG-CoA
reductase.
19-Dec-20 7

8. Hypolipidemic drugs
a) Niacin
• Niacin acts to decrease VLDL and LDL plasma levels.
• It involves inhibition of VLDL secretion, which in turn decreases the
production of LDL.
• Niacin inhibits the release of free fatty acids from adipose tissue which
leads to a decrease of free fatty acids entering the liver and decreased
VLDL synthesis in the liver.
• This decreases the availability of VLDL for conversion to LDL (containing
cholesterol esters).
• Niacin also increases high-density lipoprotein (HDL) (the “good
cholesterol”) by an unknown mechanism.
19-Dec-20 8

9. Mechanism of action of Niacin
19-Dec-20 9

10. 19-Dec-20 10

11. 19-Dec-20 11
Case study-2

12. Case study-2
• A teenage girl was brought to the
medical center because of her
complaints that she used to get too
tired when asked to participate in gym
classes.
• A consulting neurologist found muscle
weakness in girl’s arms and legs.
• When no obvious diagnosis could be
made, biopsies of her muscles were
taken for test.
19-Dec-20 12

13. Case study-2
• Biochemistry revealed greatly
elevated amounts of
triglycerides esterified with
primary long chain fatty acids.
• Pathology reported the
presence of significant numbers
of lipid vacuoles in the muscle
biopsy.
19-Dec-20 13

14. Case study-2 (contd.)
• A chest X-ray showed moderate
enlargement of her heart.
• Her liver was moderately enlarged and
palpable.
• She was slightly hypoglycemic, and her
non-esterified fatty acids were slightly
higher than would be expected for an
overnight fast.
• Ketone bodies were not detectable.
19-Dec-20 14
What is the probable diagnosis?
What might be the cause of her
symptoms?

15. Case details
• The most likely cause of these symptoms is carnitine deficiency.
• Carnitine is required for the transport of long-chain fatty acyl
coenzyme esters into myocyte mitochondria, where they are
oxidized for energy.
19-Dec-20 15

16. Role of Carnitine in fatty acid oxidation
19-Dec-20 16
• Carnitine is obtained from
foods, particularly animal-
based foods, and via
endogenous synthesis.
• Carnitine deficiency
results from inadequate
intake of or inability to
metabolize the amino acid
carnitine.

17. Type of fatty acid oxidation affected by
Carnitine deficiency
It’s the Beta oxidation which is affected- Major mechanism, occurs in
the mitochondria matrix. 2-C units are released as acetyl CoA per
cycle.
19-Dec-20 17

18. Overview of Beta oxidation
A saturated acyl Co A is degraded by a
recurring sequence of four reactions:
1) Oxidation by flavin adenine
dinucleotide (FAD)
2) Hydration,
3) Oxidation by NAD+, and
4) Thiolysis by Co A
19-Dec-20 18

19. Causes of carnitine deficiency
19-Dec-20 19
Carnitinedeficiency
Inadequate intake
Defective
metabolism
Decreased
synthesis
Leak from renal
tubules
Increased
requirement

20. Clinical manifestations of Carnitine deficiency
Carnitine
deficiency
Myoglobin
uria
Muscle
necrosis
Muscle
aches
Fatty liver
19-Dec-20 20

21. Diagnosis of Carnitine deficiency
1) Extremely reduced carnitine levels in plasma and
muscle (1–2% of normal).
2) Fasting ketogenesis may be normal if liver carnitine
transport is normal, but it may be impaired if dietary
carnitine intake is interrupted.
3) Hypoglycemia is a common finding. It is precipitated by
fasting and strenuous exercise.
4) Muscle biopsy reveals significant lipid vacuoles.
19-Dec-20 21
Supply
Demand

22. Treatment
• Oral carnitine is highly effective in correcting
the cardiomyopathy and muscle weakness as
well as any impairment in fasting ketogenesis.
• Avoidance of fasting and strenuous exercise.
• Supplementation with medium-chain
triglycerides and essential fatty acids (e.g.,
Linoleic acid, Linolenic acid).
• A high-carbohydrate, low-fat diet.
19-Dec-20 22

23. 19-Dec-20 23
Case study-3

24. Case study-324
• A three-month-old male infant
presented with facial
dysmorphism, hypotonia,
psychomotor retardation, and
hepatomegaly.
• He had an elder brother with
the same facial features and
hypotonia who died of hepatic
failure at four months of age.

25. Case study-3
• Biochemical studies revealed elevation of
blood VLCFAs, compatible with
peroxisomal disorder.
• Electron microscopy of liver biopsy
revealed absence of peroxisomes.
• What might be the most probable
diagnosis ?
19-Dec-20 25

26. Case details
• Zellweger syndrome, also called
cerebrohepatorenal syndrome is a
rare, congenital disorder (present at
birth),
• characterized by the reduction or
absence of peroxisomes in the cells
of the liver, kidneys, and brain.
19-Dec-20 26

27. Biochemical Defect
• Zellweger syndrome is a peroxisome
biogenesis disorders (PBD).
• It is characterized by an individual’s
inability to beta-oxidize very-long
chain fatty acids in the peroxisomes of
the cell, due to a genetic disorder in
one of the several genes involved with
peroxisome biogenesis.
19-Dec-20 27

28. Clinical Manifestations
• Enlarged liver, vision disturbances(glaucoma) and prenatal growth
failure.
• Symptoms at birth may include a lack of muscle tone, an inability
to move.
• Other symptoms may include mental retardation, seizures, and an
inability to suck and/or swallow.
19-Dec-20 28

29. Clinical Manifestations
• Jaundice and gastrointestinal
bleeding may also occur.
• Of central diagnostic importance
are the typical facial
appearance(high forehead,
unslanting palpebral fissures,
hypoplastic supraorbital ridges,
and epicanthal folds.
19-Dec-20 29

30. Laboratory
Diagnosis
• Several noninvasive
laboratory tests
permit precise and
early diagnosis of
peroxisomal
disorders.
• The abnormally high
levels of VLCFA (Very
long chain fatty acids),
are most diagnostic.
19-Dec-20 30

31. Treatment
• There is no cure for Zellweger syndrome, nor is there a standard
course of treatment.
• Since the metabolic and neurological abnormalities that cause the
symptoms of Zellweger syndrome are caused during fetal
development, treatments to correct these abnormalities after birth
are limited.
• Most treatments are symptomatic and supportive.
19-Dec-20 31

32. Prognosis
• The prognosis for infants with Zellweger syndrome is poor.
• Most infants do not survive past the first 6 months, and usually
succumb to :
• respiratory distress,
• gastrointestinal bleeding, or
• liver failure.
19-Dec-20 32

33. 19-Dec-20 33
Case study-4

34. Case study-4
• A 6-year-old child with progressive hearing loss was brought for
consultation.
• History revealed that the child was born normal but progressively
developed loss of hearing and loss of smell.
• From the past few months, the child was finding it difficult to locate
the things at nighttime.
19-Dec-20 34

35. Case study-4
• The child had dysmorphic
features,
• a flat bridge of nose, and
• low-set ears.
19-Dec-20 35

36. Case study-4
• On examination, pulse was irregular, and the liver was enlarged.
• Laboratory investigations revealed low levels of plasma cholesterol,
HDL and LDL.
• A diagnosis and Refsum disease was made.
• What is the defect in Refsum disease?
19-Dec-20 36

37. Review of clinical and lab profile
Hearing loss
Visual
impairment
Loss of
smell
Irregular pulse
Enlarged
liver
Dysmorphic
features
Low Cholesterol
Low LDL
Low HDL
19-Dec-20 37

38. Refsum disease (RD)
• A neurocutaneous syndrome that is characterized biochemically by
the accumulation of phytanic acid in plasma and tissues.
• Refsum first described this disease.
• The symptoms evolve slowly and insidiously from childhood through
adolescence and early adulthood.
19-Dec-20 38

39. Biochemical Defect
• Refsum disease is a recessive disorder characterized by defective
peroxisomal alpha-oxidation of phytanic acid.
• Phytanic acid is almost exclusively of exogenous origin and is delivered
mainly from dietary plant chlorophyll and, to a lesser extent, from
animal sources.
19-Dec-20 39

40. Alpha oxidation
• Phytanic acid is metabolized by an
initial α- hydroxylation followed by
dehydrogenation and
decarboxylation.
• Beta oxidation can not occur
initially because of the presence of
4- methyl groups, but it can
proceed after decarboxylation.
• The whole reaction produces three
molecules of propionyl co A, three
molecules of Acetyl co A, and one
molecule of iso butyryl co A
19-Dec-20 40

41. Clinical manifestations
• Classic Refsum disease manifests
in children aged 2-7 years;
however, diagnosis usually is
delayed until early adulthood.
• Infantile Refsum disease makes its
appearance in early infancy.
• Symptoms develop progressively
and slowly with neurologic and
ophthalmic manifestations.
19-Dec-20 41

42. Clinical
manifestations
42
• Night blindness due to degeneration
of the retina (retinitis pigmentosum)
• Concentric constriction of the visual
fields
• Cataract
• Loss of the sense of smell (anosmia)
• Deafness

43. Clinical manifestations
• Signs resulting from cerebellar ataxia –
oProgressive weakness
oFoot drop
oLoss of balance
• Some individuals will have shortened
bones in their fingers or toes.
• The children usually have moderately
dysmorphic features that may include
epicanthal folds, a flat bridge of the
nose, and low-set ears.
• Ichthyosis
19-Dec-20 43

44. Laboratory Diagnosis
• Blood levels of phytanic acid are increased, 10 to 50 mg/dL (normal
values ≤ 0.2 mg/dL, and account for 5 to 30 percent of serum lipids.
• Cerebrospinal fluid (CSF) shows a protein level of 100-600 mg/dL.
• Phytanic oxidase activity estimation in skin fibroblast cultures is
important
• Imaging
• Skeletal radiography shows bone changes.
19-Dec-20 44

45. Treatment
• Eliminate all sources of chlorophyll
from the diet.
• The major dietary exclusions
are green vegetables (source of
phytanic acid) and animal fat
(phytol).
• The aim of such dietary
treatment is to reduce daily
intake of phytanic acid from the
usual level of 50 mg/d to less
than 5 mg/d.
19-Dec-20 45

46. Treatment
Plasmapheresis – Patients may
also require plasma exchange
(Plasmapheresis) in which blood
is drawn, filtered, and reinfused
back into the body, to control the
buildup of phytanic acid.
19-Dec-20 46

47. Prognosis
• In early diagnosed and treated cases, phytanic acid decreases slowly,
followed by improvement of the skin scaling and, to a variable degree,
reversal of recent neurological signs. Retention of vision and hearing
are reported.
• Prognosis in untreated patients generally is poor.
• Pharmacological up regulation of the omega-oxidation of phytanic
acid may form the basis of the new treatment strategy for adult
Refsum disease in the near future.
19-Dec-20 47

48. Multiple choice question-1
Which of the following is the best marker for the diagnosis of Acute
pancreatitis?
a) Lactase
b) Amylase
c) Cholesteryl esterase
d) Υ- Glutamyl trans peptidase
e) Sucrase
19-Dec-20 48

49. Answer
b) Amylase
19-Dec-20 49

50. Multiple choice question-2
A gall stone that blocked the upper part of the bile duct would cause
an:
a) Increased formation of chylomicron
b) Increased recycling of bile salts
c) Increased excretion of bile salts
d) Decreased excretion of fats in the feces
e) Incomplete lipid digestion and absorption
19-Dec-20 50

51. Answer
e) Incomplete lipid digestion and absorption
19-Dec-20 51

52. Multiple choice question-3
A molecule of Palmitic acid attached to carbon 1 of glycerol moiety of a
triacylglycerol is ingested and digested. Which of the following
molecular complexes in the blood carries the palmitate residue from
the lumen of the gut to the surface of the gut epithelial cell?
a) VLDL
b) LDL
c) IDL
d) HDL
e) Bile salt
19-Dec-20 52

53. Answer
e) Bile salt
19-Dec-20 53

54. Multiple choice question-4
Which of the following supplies all the carbon atoms that are needed
for de novo synthesis of cholesterol?
a) Glucose
b) Acetyl co A
c) Malonyl co A
d) Succinyl co A
e) Citrate
19-Dec-20 54

55. Answer
b) Acetyl co A
19-Dec-20 55

56. Multiple choice question-5
Which of the following is not needed for the de novo synthesis of fatty
acids?
a) NADPH
b) Acetyl co A
c) Bicarbonate
d) ATP
e) Folic acid
19-Dec-20 56

57. Answer
e) Folic acid
19-Dec-20 57

58. Multiple choice question-6
Which of the following enzymes is required for releasing the newly
synthesized fatty acid from the fatty acid synthase complex?
a) Thiolase
b) Thiophorase
c) Thioesterase
d) Thiokinase
e) Hydratase
19-Dec-20 58

59. Answer
c) Thioesterase
19-Dec-20 59

60. Multiple choice question-7
Which of the following is the key regulatory enzyme of fatty acid
synthesis?
a) ATP citrate lyase
b) Keto acyl synthase
c) Acetyl transacylase
d) Acetyl co A carboxylase
e) Thiolase
19-Dec-20 60

61. Answer
d) Acetyl co A carboxylase
19-Dec-20 61

62. Multiple choice question-8
Which of the following is a break down product of odd chain fatty
acids?
a) Acetyl co A only
b) Acetyl co A and Butyryl co A
c) Acetyl co A and Propionyl co A
d) Propionyl co A only
e) Butyryl co A only
19-Dec-20 62

63. Answer
c) Acetyl co A and Propionyl co A
19-Dec-20 63

64. Multiple choice question-9
A 4-month-old infant presents with a seizure. His mother reports that her
infant has been irritable and lethargic over the past several days. The infant
is found to have a profoundly low serum glucose and ketone body level. The
infant is diagnosed with medium chain acyl co A dehydrogenase deficiency.
What is the biochemical basis of infant's symptoms?
a) Beta oxidation of fatty acid is impaired
b) Fatty acid synthesis is impaired
c) Adipolysis is inhibited
d) TCA cycle is inhibited
e) Pyruvate to acetyl co A conversion is inhibited
19-Dec-20 64

65. Answer
a) Beta oxidation of fatty acid is impaired
19-Dec-20 65

66. Multiple choice question-10
Which of the following is not an intermediate of pathway of cholesterol
synthesis ?
a) Mevalonate
b) Squalene
c) Lanosterol
d) Desmosterol
e) 7- dehydrocholesterol
19-Dec-20 66

67. Answer
e) 7- dehydrocholesterol
19-Dec-20 67

68. 19-Dec-20 68
Revision of fatty acid
synthesis

69. Fatty acid synthesis and fatty acid oxidation
19-Dec-20 69

70. 19-Dec-20 70

71. Fatty acid synthesis
Reaction catalyzed by Acetyl co A carboxylase
19-Dec-20 71

72. Components of Acetyl co A carboxylase
The enzyme is a multienzyme protein containing a variable number of
identical subunits, each containing-
1) Biotin
2) Biotin carboxylase,
3) Biotin carboxyl carrier protein
4) Transcarboxylase,
5) A regulatory allosteric site.
19-Dec-20 72

73. Regulation of Acetyl Co A carboxylase
19-Dec-20 73

74. Regulation of Acetyl Co A carboxylase
Allosteric modification
Feedback inhibition
Covalent modification
Induction and repression
19-Dec-20 74

75. 19-Dec-20 75
Fatty acid
synthase
complex

76. Multiple choice question-11
An 18-year-old female is diagnosed obese. She maintains a sedentary
lifestyle and eats a high-fat, high-sugar diet. Maintenance of this diet
and lifestyle has led to lipogenesis and obesity. Which of the following
affects excessive fatty acid synthesis?
a) Glycerol is obtained through glycolysis
b) Fatty acids are excessively synthesized from Acetyl co A
c) NADPH is excessively obtained from HMP pathway
d) Triglycerides are excessively synthesized
e) All of the above.
19-Dec-20 76

77. Answer
e) All of the above.
19-Dec-20 77

78. Multiple choice question-12
A 30- year-old pregnant woman has a sugar craving and consumes a hot
fudge sundae. Her serum glucose level increases, which causes release of
Insulin. Insulin is known to increase the activity of acetyl co A carboxylase ,
the rate limiting enzyme of fatty acid biosynthesis. Which of the following
best describes this regulatory enzyme?
a) It is activated by carboxylation
b) It catalyzes a reaction that condenses an acetyl group with malonyl group
c) It catalyzes a reaction that requires biotin and ATP
d) It converts Malonyl co A to Acetyl co A
e) It is activated by malonyl co A.
19-Dec-20 78

79. Answer
c) It catalyzes a reaction that requires biotin and ATP
19-Dec-20 79

80. 19-Dec-20 80
Ketogenesis and ketolysis

81. Ketogenesis and Ketolysis
19-Dec-20 81

82. Multiple choice question-13
Which of the following are the ketone bodies?
a) Acetyl co A and Propionyl co A
b) Lecithin and Lysolecithin
c) Acetoacetate and Beta-hydroxy butyrate
d) Pyruvate and lactate
e) Succinyl co A and succinate
19-Dec-20 82

83. Answer
c) Acetoacetate and Beta-hydroxy butyrate
19-Dec-20 83

84. Multiple choice question-14
Which of the following is not a cause of ketogenesis?
a) High carbohydrate diet
b) High fat diet
c) Starvation
d) Uncontrolled diabetes mellitus
e) Chronic alcoholism
19-Dec-20 84

85. Answer
a) High carbohydrate diet
19-Dec-20 85

86. 19-Dec-20 86
lipoproteins

87. Multiple choice question-15
Which of the following is the most important structural component of
VLDL?
a) Apo B48
b) Apo B 100
c) Apo A
d) Apo C
e) Apo E
19-Dec-20 87

88. Answer
b) Apo B48
19-Dec-20 88

89. Lipoproteins
• Lipoproteins consist of a nonpolar core
and a single surface layer of amphipathic
lipids
• The nonpolar lipid core consists of
mainly triacylglycerol and cholesteryl
ester and is surrounded by a single
surface layer of amphipathic
phospholipid and cholesterol molecules
19-Dec-20 89

90. Classification of Lipoproteins- based on density
• Lipoproteins may be classified
according to their density:
• Chylomicrons
• Very-low-density lipoproteins
(VLDL),
• Intermediate-density
lipoproteins (IDL),
• Low-density lipoproteins (LDL),
and
• High-density lipoproteins (HDL).
19-Dec-20 90

91. Classification of Lipoproteins- based on electrophoretic pattern
• Lipoproteins may also be separated by
electrophoresis into :
• Beta (LDL),
• Prebeta (VLDL),
• Broad beta (IDL)and
• Alpha (HDL) lipoproteins.
19-Dec-20 91

92. Classification of Lipoproteins
3) Based on nature of Apo- protein content
❑One or more apolipoproteins (proteins or polypeptides)
are present in each lipoprotein.
❑The major apolipoproteins of HDL (α-lipoprotein) are
designated A.
❑The main apolipoprotein of LDL (β -lipoprotein) is
apolipoprotein B (B-100), which is found also in VLDL.
❑Chylomicons contain a truncated form of apo B (B-48)
that is synthesized in the intestine, while B-100 is
synthesized in the liver.
❑Apo E is found in VLDL, HDL, Chylomicons, and
chylomicron remnants.
19-Dec-20 92

93. Multiple choice question-16
Chylomicrons, intermediate- density- lipoproteins (IDLs), low- density-
lipoproteins (LDLs), and very low-density lipoproteins (VLDLs) are all
serum lipoproteins.
What is the correct ordering of these particles from the lowest to the
highest density?
A. LDLs, IDLs, VLDLs and chylomicrons
B. Chylomicrons, VLDLs, IDLs, LDLs
C. VLDLs, IDLs, LDLs and Chylomicrons
D. LDLs, VLDLs, IDLs, Chylomicrons
E. Chylomicrons, IDLS, VLDLs and LDLs.
19-Dec-20 93

94. Answer
B. Chylomicrons, VLDLs, IDLs, LDLs
19-Dec-20 94

95. Multiple choice question-17
A 40 -year-old man presents with severe pain in his legs upon walking. He is
diagnosed with atherosclerotic plaques in the arteries of his legs.
High levels of cholesterol and LDL contribute to the formation of
atherosclerosis.
The oxidized form of LDL triggers the process of atherosclerosis.
Which of the following is the most important structural component of LDL?
a) Apo B48
b) Apo B 100
c) Apo A
d) Apo C
e) Apo E
19-Dec-20 95

96. Answer
b) Apo B 100
19-Dec-20 96

97. Metabolism of
Lipoproteins
Exogenous
pathway
Chylomicrons
(Intestinal
lipoprotein)
Endogenous
pathway
VLDL(LDL)&HDL
(Liver
Lipoproteins)
19-Dec-20 97

98. Metabolism of chylomicron
19-Dec-20 98

99. Metabolism of VLDL
19-Dec-20 99

100. Metabolism of HDL
19-Dec-20 100

101. Summary of Lipoprotein metabolism
19-Dec-20 101

102. Hyperlipidemia(hyperlipoproteinemia)
• Hyperlipoproteinemia is a
metabolic disorder characterized
by abnormally elevated
concentrations of specific
lipoprotein particles in the
plasma.
• Hyperlipidemia (i.e., elevated
plasma cholesterol or triglyceride
levels or both) is present in all
hyperlipoproteinemia.
19-Dec-20 102

103. Primary disorders
Alterations in
lipoproteins result from
genetic mutations that yield
defective Apo lipoproteins
19-Dec-20 103

104. • Alterations in lipoproteins occur from some
other underlying systemic disorder, such as:
o pregnancy,
o hypothyroidism,
o cholestasis, oral contraceptive use,
o diabetes mellitus, alcoholism,
o pancreatitis, gout and type I glycogen
storage disease.
Secondary disorders
19-Dec-20 104

105. Primary Disorders of
Plasma Lipoproteins
(Dyslipoproteinemias)
❑Inherited defects in lipoprotein
metabolism lead to the primary
condition of either hypo- or
hyperlipoproteinemia .
❑All of the primary conditions
are due to a defect at a stage in
lipoprotein formation,
transport, or degradation.
19-Dec-20 105

106. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Name Defect Characteristics
Hypolipoproteinemias
Abetalipoproteinemia No chylomicrons, VLDL, or LDL are
formed because of defect in the
loading of apo B with lipid.
Rare, blood acylglycerols low;
intestine and liver accumulate
acylglycerols. Intestinal
malabsorption.
Familial alpha-lipoprotein
deficiency
All have low or near absence of
HDL.
Hypertriacylglycerolemia due to
absence of apo C-II, Low LDL levels.
Atherosclerosis in the elderly.Tangier disease
Fish-eye disease
Apo-A-I deficiencies
19-Dec-20 106

107. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Name Defect Characteristics
Hyperlipoproteinemia
Familial lipoprotein lipase deficiency
(type I)
Hypertriacylglycerolemia due to
deficiency of LPL, abnormal LPL, or
apo C-II deficiency causing inactive
LPL.
Slow clearance of chylomicrons and
VLDL. Low levels of LDL and HDL. No
increased risk of coronary disease.
Familial hypercholesterolemia (type
II a)
Defective LDL receptors or mutation
in ligand region of apo B-100.
Elevated LDL levels and
hypercholesterolemia, resulting in
atherosclerosis and coronary
disease.
19-Dec-20 107

108. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)- contd.
Name Defect Characteristics
Familial type III
hyperlipoproteinemia (broad beta
disease, remnant removal disease,
familial dysbetalipoproteinemia)
Deficiency in remnant clearance by
the liver is due to abnormality in
apo E.
Increase in chylomicron and VLDL
remnants , Causes
hypercholesterolemia, xanthomas,
and atherosclerosis.
Familial Hypertriacylglycerolemia
(type IV)
Overproduction of VLDL often
associated with glucose intolerance
and hyperinsulinemia.
High cholesterol, VLDL, Subnormal
LDL and HDL. Associated with
Alcoholism, diabetes mellitus and
obesity.
Hepatic lipase deficiency Deficiency of the enzyme leads to
accumulation of large
triacylglycerol-rich HDL and VLDL
remnants
Patients have xanthomas and
coronary heart disease.
19-Dec-20 108

109. Multiple choice question-18
A 34-year-old female has been diagnosed with type 1 hyperlipidemia.
Which of the following lipoprotein concentration is elevated in such
disorder ?
a) HDL
b) IDL
c) VLDL
d) Chylomicrons
e) Both c and d
19-Dec-20 109

110. Answer
Both c) and d)
19-Dec-20 110

111. Multiple choice question-19
A 30 -year-old man has been diagnosed with familial
hypercholesterolemia; a disorder caused by a deficiency of LDL receptors.
Which of the following statements best describes the status of these
patients ?
a) Serum cholesterol decreases
b) Excessive cholesterol is released by HDL
c) Cholesterol synthesis by hepatocytes is increased
d) Number of LDL receptors on the surface of hepatocytes increase
e) After binding to LDL receptors, LDL is rapidly degraded
19-Dec-20 111

112. Answer
c) Cholesterol synthesis by hepatocytes is increased
19-Dec-20 112

113. Case study-5
19-Dec-20 113

114. Case study-5
• Two sisters, aged 19 & 17 years, were
referred to the dermatologist because they
had large number of yellowish spots on
the exposed parts of the body.
• On thorough examination and after
conducting a series of laboratory
investigations they were advised to
increase physical activity and reduce the
intake of fats
• What is the cause of yellow spots?
• How are the medical advices going to help
these patients?
19-Dec-20 114

115. Case Discussion
• Both the sisters are having
xanthomas.
• Xanthomas are lesions
characterized by accumulation of
lipid-laden macrophages.
• Most of the disorders of
hyperlipidemia
(hyperlipoproteinemia) are
associated with xanthomas.
19-Dec-20 115

116. Types of Xanthomas
• Cutaneous xanthomas associated with
hyperlipidemia can be clinically
subdivided into following types:
• Xanthelasma palpebrum
• Tuberous xanthomas
• Tendinous xanthomas
• Eruptive xanthomas
• Plane xanthomas
19-Dec-20 116

117. Laboratory Investigations of
hyper lipoproteinemia
• Measurement of plasma lipid and
lipoprotein levels while the patient is on a
regular diet after an overnight fast of 12-
16 hours.
• Visual inspection of the plasma sample
(stored at 4°C).
• Electrophoresis and ultracentrifugation of
whole plasma specimens
19-Dec-20 117

118. Treatment
• Dietary modifications
• Lipid-lowering agents such as
statins, fibrates, bile acid–binding
resins, probucol, or nicotinic acid.
• Xanthomas are not always
associated with underlying
hyperlipidemia, but when they are,
diagnosing and treating underlying
lipid disorders is necessary to
decrease the size of the xanthomas
and to prevent the risks of
atherosclerosis.
19-Dec-20 118

119. Treatment
• Weight reduction and a diet low
in saturated fat and cholesterol
are advocated.
• Patients should avoid alcohol
and estrogen in certain types of
hyperlipoproteinemia.
• Prognosis- Prognosis is good if
the underlying cause is treated.
19-Dec-20 119

120. Case study-6
19-Dec-20 120

121. Case study-6
• A 42-year-old executive complained of
fatigue and some recent alterations in
mental status, such as forgetting
appointments.
• He confessed to frequent drinking from
the past few years.
• He had vague right upper quadrant pain
on deep palpation and borderline
enlargement of the liver
19-Dec-20 121

122. Laboratory Investigation report
• AST(aspartate amino transferase) = 120
U/L
• ALT(alanine amino transferase) = 80 U/L
• ALP(alkaline phosphatase) = 68 U/L
• GGT(gamma glutamyl transpeptidase)=
170U/L
• S. Total bilirubin = 1.2 mg/dl
• S. Glucose = 60 mg/dL
• S. Uric acid = 9.8 mg/dL
• CBC and urinalysis results are normal.
19-Dec-20 122

123. Case discussion
• The patient is suffering from
alcohol related liver
disease.
• Excessive alcohol intake can
lead to:
ofatty liver,
ohepatitis, and
ocirrhosis.
19-Dec-20 123

124. Fatty Liver (steatosis)
• Fatty liver (steatosis) is an abnormal
accumulation of fats (triglycerides)
inside liver cells.
• Imbalance in the rate of
triacylglycerol formation and export
(impaired VLDL formation or
secretion leads to non-mobilization
of lipid components from the liver)
causing fatty live.
Increased
Triglyceride
synthesis
Decreased
VLDL
synthesis and
secretion
19-Dec-20 124

125. Causes of Fatty liver
A) More synthesis of
Triglycerides
oHigh Carbohydrate diet
oStarvation
oDiabetes Mellitus
oHigh Fat diet
Triglyceride
Synthesis
High
Carbohyd
rate diet
Starvation
Diabetes
Mellitus
High Fat
diet
19-Dec-20 125

126. Causes of Fatty liver
B) Defective export (metabolic
block)- Defective VLDL
synthesis
(a) Block in apolipoprotein
synthesis
i. Protein energy
Malnutrition
ii. Impaired absorption
iii. Presence of inhibitors of
endogenous protein
synthesis
iv. Hypobetalipoproteinemia
- Defective apo B gene
19-Dec-20 126

127. Causes of Fatty liver
(2) A failure in provision of phospholipids
oA deficiency of choline (a lipotropic
factor)
oMethionine deficiency can also cause
impaired choline synthesis
oInositol deficiency, and
oDeficiency of essential fatty acids
19-Dec-20 127

128. Causes of Fatty liver
• Impaired glycosylation- Orotic
aciduria, Orotic acid is believed
to interfere with glycosylation of
the lipoprotein, thus inhibiting
release.
• Impaired secretion of VLDL-
oxidative stress is a common
cause for membrane disruption
of lipoproteins
19-Dec-20 128

129. Clinical classification of fatty liver disease
Fatty liver
Non
alcoholic
Diabetes Starvation
High Carb
diet
Obesity
Drug
induced
Endocrino
pathies
Alcoholic
19-Dec-20 129

130. 2) Alcoholic fatty liver
disease
Impaired
fatty acid
oxidation
Increased
fatty acid
synthesis
Increased
production of
Glycerol
Increased TG
synthesis
Decreased
apoprotein
synthesis
Decreased
phospholipid
synthesis
Fatty liver
19-Dec-20 130

131. Lipotropic agents
• Choline,
• Inositol,
• Methionine and other essential amino acids,
• Essential fatty acids,
• Anti oxidant vitamins,
• Vitamin B12, folic acid and synthetic antioxidants have the apparent
effect of removal of fats from the liver cells, and thus prevent the
formation of fatty liver are called lipotropic agents.
19-Dec-20 131

132. Clinical manifestations
• Variable presentation from an asymptomatic hepatomegaly to a
rapidly fatal acute illness or end-stage cirrhosis.
• A recent period of heavy drinking, complaints of anorexia and
nausea, and the demonstration of hepatomegaly and jaundice
strongly suggest the diagnosis.
• Abdominal pain and tenderness, splenomegaly, ascites, fever, and
encephalopathy may be present.
19-Dec-20 132

133. 19-Dec-20 133

134. Laboratory Findings
• Enzyme profile:
• Serum AST is greater than ALT, usually by a
factor of 2 or more. This enzyme
relationship is characteristic of alcohol-
related liver disease.
• Serum ALP(alkaline phosphatase) is
generally elevated, but seldom more than
three times the normal value.
• GGT-Alcohol also stimulates the
cytochrome P-450 system, increasing the
synthesis of G-glutamyl transferase.
19-Dec-20 134

135. Laboratory Findings
• Serum bilirubin: >10 mg/dL and marked prolongation of the
prothrombin time (>6 seconds above control) indicates severe
alcoholic hepatitis with a mortality rate as high as 50 percent.
• Serum proteins: The serum albumin is depressed, and the γ-globulin
level is elevated in 50 to 75 percent of individuals, even in the
absence of cirrhosis.
• Iron indices: Increased transferrin saturation, hepatic iron stores, and
sideroblastic anemia are found in many alcoholic patients.
• Folic acid deficiency may coexist.
19-Dec-20 135

136. Laboratory Findings
• Hypoglycemia
• Ketosis
• Hyperuricemia
• Metabolic acidosis
• Liver biopsy: Liver biopsy demonstrates macrovesicular fat
• Other studies: Ultrasound helps exclude biliary obstruction and
identifies sub clinical ascites.
• Computed tomography (CT) scanning or MRI
19-Dec-20 136

137. Laboratory Findings
AST ALT ALP GGT
Serum Total
Protein
Prothrombin
time
Blood
glucose
Serum Uric
acid
Plasma pH
Blood Ketone
bodies
ALP GGT
Serum Total
Protein
Prothrombin
time
Blood
glucose
Serum Uric
acid
Plasma pH
19-Dec-20 137

138. Treatment
General Measures:
• Abstinence from alcohol
• Nutritional support (40 kcal/kg with 1.5–2 g/ kg as protein) improves
survival in patients with malnutrition.
• Supplementation with Vitamins
• Glucose administration with thiamine supplementation
Pharmacological interventions:
Methyl Prednisolone & Pentoxifylline reduce mortality in severe cases.
19-Dec-20 138

139. Case study-7
19-Dec-20 139

140. Case study-7
• A 70-year-old man is brought to
emergency with :
• acute onset of chest pain,
• dyspnea and
• sweating.
• On examination
• Pulse- 120/min
• B.P. - 100/70 mm Hg
19-Dec-20 140

141. Case study-7
• ECG changes
An electrocardiogram (ECG) reveals
ST segment elevation and peaked T
waves in leads II, III, and aVF.
• What is the most probable
diagnosis?
Laboratory Investigations
Serum CPK-MB – High
Serum LDH- High
Serum Troponins I and T
levels are elevated.
Serum Total cholesterol-
400 mg/dl
HDLc- 15 mg/dl
19-Dec-20 141

142. Case discussion
• The patient is most probably suffering
from ‘Acute myocardial Infarction’
evident from clinical manifestations,
laboratory report and the ECG changes.
• Myocardial Infarction (MI) is the rapid
development of myocardial necrosis
caused by a critical imbalance between
oxygen supply and demand of the
myocardium.
19-Dec-20 142

143. Atherosclerosis
❑Atherosclerosis is a disease of large
and medium-sized muscular arteries
and is characterized by –
❑the buildup of lipids, cholesterol,
calcium, and cellular debris within the
intima of the vessel wall- atheroma
(also called Atheromatous or
atherosclerotic plaques),protrude into
vascular lumina.
19-Dec-20 143

144. Atherosclerosis
19-Dec-20 144

145. Risk Factors of
Atherosclerosis
Major risk factors (Non-Modifiable)
❑ Increasing Age
❑ Male gender
❑ Family history
❑ Genetic abnormalities

146. Risk Factors of Atherosclerosis
Lesser, Uncertain, or Nonquantitated Risks-
❑Obesity
❑Physical Inactivity
❑Postmenopausal estrogen deficiency
❑High carbohydrate intake
❑Lipoprotein(a)
❑Hardened (trans)unsaturated fat intake
❑Chlamydia pneumoniae infection
19-Dec-20 146

147. Risk Factors of
Atherosclerosis
Potentially Controllable-
❑Hyperlipidemia
❑Hypertension
❑Cigarette smoking
❑Diabetes
❑C-reactive protein

148. Non-traditional Risk
Factors
14
8
❑ Oxidative stress
❑Anemia
❑Hyperhomocysteinemia
❑Chronic inflammation
❑Left ventricular hypertrophy

149. 19-Dec-20 149