INCLUDING GUIDELINES

1. LIPID DISORDERS
PRESENTER: DR. JITHIN GEORGE

6. APOLIPOPROTEINS
• The proteins associated with lipoproteins, called
apolipoproteins
• required for the assembly, structure, function,
metabolism of lipoproteins.
• activate enzymes important in lipoprotein
metabolism
• act as ligands for cell surface receptors.
• The human liver synthesizes apoB-100, and the
intestine makes apoB.
• ApoB :chylomicrons, VLDLs, IDLs, and LDLs.
• apoA-I: liver and intestine, HDL

13. Dyslipidemia Caused by Excessive Hepatic
Secretion of VLDL

14. PRIMARY CAUSES FOR RAISED VLDL

15. LIPODYSTROPHY

16. Partial lipodystrophy
• more common
• mutation most notably lamin A.
• characterized by increased truncal fat
accompanied by markedly reduced or absent
subcutaneous fat in the extremities and buttocks.
• generally have insulin resistance, often quite
severe, accompanied by type 2 diabetes,
hepatosteatosis, and dyslipidemia.
• The dyslipidemia is usually characterized by
elevated TGs and cholesterol

17. Dyslipidemia Caused by Impaired
Lipolysis of Triglyceride-Rich
Lipoproteins
• LPL : for hydrolyzing the TGs in chylomicrons
and VLDL.
• Individuals with impaired LPL activity
• elevated fasting TGs and low levels of HDL-C,
usually without elevation in LDL-C or apoB.
• Insulin resistance, in addition to causing
excessive VLDL production, can also cause

18. Secondary Causes of Impaired Lipolysis
• Obesity and insulin resistance
– due in part to the effects of tissue insulin
resistance leading to reduced transcription of LPL
in skeletal muscle and adipose
– increased production of the LPL inhibitor apoC-III
by the liver.

19. Primary (Genetic) Causes and Genetic
Predisposition to Impaired Lipolysis

22. Rx
• dietary fat restriction (to as little as 15 g/d)
with fat-soluble vitamin supplementation
• fish oils
• patients with apoC-II deficiency: infuse fresh-
frozen plasma
• gene therapy approach: alipogene tiparvovec:
multiple intramuscular injections of an adeno-
associated viral vector encoding a gain-of-
function LPL variant, leading to skeletal
myocyte expression of LPL.

23. ApoA-V deficiency
• ApoA-V, facilitates the association of VLDL and
chylomicrons with LPL and promotes their
hydrolysis.
• loss-of-function mutations in both APOA5
alleles develop hyperchylomicronemia

24. GPIHBP1 deficiency
• cause severe hypertriglyceridemia by
compromising the transport of LPL to the
vascular endothelium.

25. Familial hypertriglyceridemia (FHTG)
• Elevated fasting TGs without a clear secondary
cause, average to below average LDL-C levels,
low HDL-C levels, and a family history of
hypertriglyceridemia.
• Patients with plasma TG levels >500 mg/ dL
after a trial of diet and exercise should be
considered for drug therapy with a fibrate or
fish oil to reduce TGs in order to prevent
pancreatitis.

26. Dyslipidemia Caused by Impaired Hepatic Uptake
of ApoB-Containing Lipoproteins

27. Secondary Causes of Impaired Hepatic
Uptake of Lipoproteins

28. Primary (Genetic) Causes of Impaired
Hepatic Uptake of Lipoproteins
Familial hypercholesterolemia
• Autosomal dominant
• elevated plasma levels of LDL-C in the absence of
hypertriglyceridemia.
• loss-of-function mutations in the gene encoding
the LDL receptor.
• The elevated levels of LDL-C in FH are primarily
due to delayed removal of LDL from the blood;
• because the removal of IDL is also delayed, the
production of LDL from IDL is also increased.

29. • A family history of hypercholesterolemia
and/or premature coronary disease is
supportive of the diagnosis.
• Secondary causes of significant
hypercholesterolemia such as hypothyroidism,
nephrotic syndrome, and obstructive liver
disease

30. Rx
• Diet low in saturated and trans fats
• Statins
• a cholesterol absorption inhibitor and/or a bile acid
sequestrant are the next-line classes of drugs.
• heterozygous FH patients whose LDL-C levels remain
markedly elevated (>200 mg/dL with cardiovascular
disease [CVD] or >300 mg/dL without CVD) on
maximally tolerated drug therapy are candidates for
LDL apheresis, Once in 2 weeks
• PCSK9 inhibitors

31. HOMOZYGOUS FAMILIAL
HYPERCHOLESTROLEMIA
• classified into those patients with virtually no
detectable LDL receptor activity (receptor
negative) and those patients with markedly
reduced but detectable LDL receptor activity
(receptor defective).
• LDL-C levels in patients with homozygous FH
range from about 400 to >1000 mg/dL, with
receptor-defective patients at the lower end and
receptor-negative patients at the higher end of
the range.
• TGs are usually normal

32. • present in childhood with cutaneous xanthomas.
• Atherosclerosis often develops first in the aortic
root, where it can cause aortic valvular or
supravalvular stenosis, and typically extends into
the coronary ostia, which become stenotic.
• Homozygous FH should be suspected in a child or
young adult with LDL >400 mg/dL without
secondary cause.

33. • Receptor defective patients: respond to
statins and cholesterol absorption inhibitor or
a bile acid sequestrant, which upregulate the
LDL receptor activity.
• Two drugs that reduce the hepatic production
of VLDL and thus LDL, a small-molecule
inhibitor of the microsomal TG transfer
protein (MTP) LOMITAPIDE and an antisense
oligonucleotide to apoB: MIPOMERSEN
• liver transplantation is effective in decreasing
plasma LDL-C levels in this disorder

34. Familial defective apoB-100 (FDB )

35. • mutation predominates: substitution of
glutamine for arginine at position 3500.
• levated plasma LDL-C levels with normal TGs;
tendon xanthomas can be seen, although not
as frequently as in FH, and there is an
associated increase in risk of CHD.

36. Autosomal dominant hypercholesterolemia due to
mutations in PCSK9
(ADH-PCSK9 or ADH3

37. Autosomal recessive
hypercholesterolemia

38. Sitosterolemia

40. Cholesteryl ester storage disease (CE
SD)

41. • Genetic deficiency of LAL results in
accumulation of neutral lipid in the
hepatocytes, leading to hepatosplenomegaly,
microvesicular steatosis, and ultimately
fibrosis and end-stage liver disease.
• blood spot assay of LAL activity and confirmed
by DNA genotyping for the most common
mutation,
• Liver biopsy

42. Familial dysbetalipoproteinemia
(FDBL)
• also known as type III hyperlipoproteinemia.
• Recessive
• mixed hyperlipidemia (elevated cholesterol
and TGs) due to the accumulation of remnant
lipoprotein particles (chylomicron remnants
and VLDL remnants, or IDL).
• Due to genetic variants of Apo E : apoE3 (most
common), and apoE2 and apoE4

43. • hyperlipidemia, xanthomas, or premature
coronary or peripheral vascular disease.
• The most common precipitating factors are a
high-fat diet, diabetes mellitus, obesity,
hypothyroidism, renal disease, HIV infection,
estrogen deficiency, alcohol use, or certain drugs.
• The disease seldom presents in women before
menopause. Other mutations in apoE can cause a
dominant form of FDBL where the hyperlipidemia
is fully manifest in the heterozygous state.

44. • Two distinctive types of xanthomas, tuberoeruptive
and palmar, are seen in FDBL patients
• very high levels of remnant lipoproteins or by
identification of the apoE2/E2 genotype.
• methods are used to identify remnant lipoproteins in
the plasma, including “β-quantification” by
ultracentrifugation (ratio of directly measured VLDL-C
to total plasma TG >0.30), lipoprotein electrophoresis
(broad β band), or nuclear magnetic resonance
lipoprotein profiling.
• statins are the first line in management.

45. HEPATIC LIPASE DEFICIENCY

46. HDL DISORDERS: TANGIER DISEASE
• Tangier Disease (ABCA1 Deficiency)
• Autosomal co-dominant form of extremely low plasma
HDL-C levels
• mutations in the gene encoding ABCA1
• In the absence of ABCA1, the nascent, poorly lipidated
apoA-I is immediately cleared from the circulation.
• extremely low circulating plasma levels ofHDL-C (<5 mg/dL)
and apoA-I (<5 mg/dL).
• Cholesterol accumulates in the reticuloendothelial system
o
• hepatosplenomegaly
• pathognomonic enlarged, grayish yellow or orange tonsils.
• An intermittent peripheral neuropathy (mononeuritis
multiplex) or a sphingomyelia-like neurologic disorder

47. CETP DEFICIENCY
• Inherited Causes of Very High Levels of HDL-C
• Loss-of-function mutations in both alleles of the gene
encoding CETP cause substantially elevated HDL-C
levels (usually >150 mg/dL).
• CETP transfers cholesteryl esters from HDL to apoB-
containing lipoprotein
• Absence of this transfer activity results in an increase
in the cholesteryl ester content of HDL and a reduction
in plasma levels of LDL-C. The large, cholesterol-rich
HDL particles circulating in these patients are cleared
at a reduced rate.
• CETP deficiency is rare outside of Japan.
• Based on high HDL-C in CETP deficiency, pharmacologic
inhibition of CETP : new therapeutic approach to both
raise HDL-C levels and lower LDL-C levels.

52. Lower sodium intake: Consume no more than 2400 mg of sodium per
day
Aerobic exercise
Frequency: 3-5 days/week
Intensity: 50-80% of exercise capacity
Duration: 20-60 minutes
Modalities: Examples include walking, treadmill, cycling,
rowing and stair climbing

58. pharmacological treatment for secondary prevention:
The following management:
1- Age ≤75 y and no safety concerns: High-intensity statin
2- Age >75 y or safety concerns: Moderate-intensity statin

59. • If unexplained severe muscle symptoms or fatigue develop during statin therapy,
promptly discontinue the statin and address the possibility of rhabdomyolysis by
evaluating CK, creatinine, and a urinalysis for myoglobinuria.
• 2. If mild to moderate muscle symptoms develop during statin therapy:
A- Discontinue the statin until the symptoms can be evaluated.
• B- Evaluate the patient for other conditions that might increase the risk for muscle
symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic
disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency,
or primary muscle diseases).
• C- If muscle symptoms resolve, and if no contraindication exists, give the patient
the original or a lower dose of the same statin to establish a causal relationship
between the muscle symptoms and statin therapy.
• D- Once a low dose of a statin is tolerated, gradually increase the dose as
tolerated.
• E- If, after 2 months without statin treatment, muscle symptoms or elevated CK
levels do not resolve completely, consider other causes of muscle symptoms listed
above.
• F- If persistent muscle symptoms are determined to arise from a condition
unrelated to statin therapy, or if the predisposing condition has been treated,
resume statin therapy at the original dose.

60. Unexplained ALT elevations >3 times ULN.
• 1. Baseline measurement of hepatic
transaminase levels (ALT) should be performed
before initiating statin therapy. (I B)
• 2. During statin therapy, it is reasonable to
measure hepatic function if symptoms suggesting
hepatotoxicity arise (e.g., unusual fatigue or
weakness, loss of appetite, abdominal pain, dark
colored urine or yellowing of the skin or sclera).
Unexplained ALT elevations >3 times ULN.
• 1. Baseline measurement of hepatic
transaminase levels (ALT) should be performed
before initiating statin therapy. (I B)
• 2. During statin therapy, it is reasonable to
measure hepatic function if symptoms suggesting
hepatotoxicity arise (e.g., unusual fatigue or
weakness, loss of appetite, abdominal pain, dark
colored urine or yellowing of the skin or sclera).

67. NLA RECOMMENDATIONS

69. Primary prevention for:

70. Secondary prevention for

71. If a patient-specific risk calculator
cannot be accessed
suggest considering the following patients with diabetes
mellitus (DM) to have a similar risk those with known CV
disease:
• 1. Men over age 40 with type 2 DM and any other CHD
risk factor, or over age 50 with or without other CHD risk
factors
• 2. Women over age 45 with type 2 DM and any other CHD
risk factor, or over age 55 with or without other CHD risk
factors
• 3. Men or women of any age who have had DM (type 1 or
type 2) for more than 20 years if they have another risk
factor or more than 25 years without another risk factor

73. MONOCLONAL ANTIBODIES