1. Patient no 67
A 39 years old male is known to have high cholesterol and triglycerides at multiple occasions in the past. His two brothers have also similar pattern of lipid abnormality. His BMI is 28 Kg/m2. He is not hypertensive. His recent biochemical profile indicates:
Fasting Plasma Glucose: mmol/L (79 mg/dl)
Cholesterol : mmol/L (362 mg/dl)
Triglycerides : mmol/L (634 mg/dl)
LDL Chol (measured): mmol/L (164 mg/dl)
HDL Chol (measured): mmo/L (37 mg/dl)
Give TWO most important differential diagnosis
Name ONE laboratory test which can be very helpful in differentiating these two conditions.
Familial Combined Hyperlipidaemia and Metabolic Syndrome
Apolipoprotein B
Ref No 5
Practical guidelines for familial combined hyperlipidaemia diagnosis: an up-date
Vascular Health and Risk Management 2007:3(6) 877–886

2. Familial Combined Hyperlipidaemia (FCHL)
FCHL is characterized by hypercholesterolemia and/or hypertriglyceridemia in at least two members of the same family with intra- individual and intra-familial variability.
Its an important predisposing factor for premature CHD
FCHL is one of the most common genetic hyperlipidemias in the general population

3. Difference between Metabolic Syndrome (MS) and FCHL
Apo B is the main differentiating marker, it is high in FCHL, but not in MS.
LDL-C is usually normal or rather low in MS as compared to FCHL
The lipid phenotype is more variable in FCH than in MS (both in individuals and families)
The inheritance of the disorder is much more evident in FCH, and life style is much less relevant on FCH clinical manifestation and prognosis than on MS
Earlier clinical and laboratory manifestation in FCH

4. Climb National Information Centre for Metabolic Diseases
Patient no 68
A 3 months old male infant is somewhat restless probably due to abdominal pain. He has a papular rash and enlarged liver and readily palpable spleen. There is no evidence of jaundice and the child appears well.
His lipid profile revealed:
Serum appearance: ‘raspberry milkshake’
Overnight standing test at 40C: Creamy ring at the top
Cholesterol : mmol/L (131 mg/dl)
Triglycerides : mmol/L (2217 mg/dl)
LDL Chol (measured): mmol/L (190 mg/dl)
HDL Chol (measured): mmo/L (43 mg/dl)
Which type of hyperlipidaemia is present in this patient according to Fredrickson classification of hyperlipidemias?
Name ONE enzyme which may be deficient in this patient
Type 1
Lipoprotein Lipase
Ref No 8
Climb National Information Centre for Metabolic Diseases

5. Lipoprotein Lipase Deficiency
Type1 Hyperlipoproteinaemia
Characterized by very high triglycerides and normal cholesterol
In a Routine Chem Path lab can be diagnosed by overnight tube test i.e. putting the serum sample of the patient at 40 C.
A ring at the top of the tube indicates increased chylomicrons in the sample
Usually present in children < 1 y of age
Abdominal pain may be due to pancreatitis
Hepato-splenomegaly may also be present.

6. Patient no 69
A 1 month old infant has a highly chylous sample. Her lipid profile is as following:
Cholesterol : mmol/L
Triglycerides : mmol/L
LDL Chol (measured): mmol/L
HDL Chol (measured): mmo/L
Overnight incubation of serum sample at 40C shows a ring on the top of a clear sample
What is the most probable diagnosis?
Which type of hyperlipidaemia this infant is suffering from as per Frederickson Classification .
Lipoprotein Lipase Deficiency
Type I Hyperlipidaemia
Ref No 4
John D Brunzell. Familial Lipoprotein Lipase Deficiency
GeneReviews® [Internet] Available at:

7. Lipoprotein Lipase Deficiency
A childhood hyperlipidaemia
Severe hypertriglyceridaemia is the characteristic finding
It’s a type I hyperlipidaemia mainly due to hyperchylomicronaemia
Abdominal pain or pancreatitis may be the presenting feature.

8. Patient no 70 (Recent Updates)
A 57 years old male is a known patient of Ischaemic Heart Disease for which he underwent CABG about 5 years ago. He and many of his closed relatives had hypercholesterolaemia for which he is being given statins at the maximum does. Unfortunately his tolerance to this medicine is very poor and he experiences a lot of muscular pains. His recent biochemical profile shows:
Total Cholesterol: mmol/L
Triglycerides: mmol/L
LDL-C: mmol/L
HDL-C: mmol/L
ALT: U/L
CK: U/L
What is most likely diagnosis?
Name ONE very recently reported drug which can be helpful to this patient (Please write full biochemical name)
Familial hypercholesterolemia (FH) can be defined as a heritable disorder, caused by mutations in the LDL-receptor gene that result in receptor absence or malfunction.1,2 Inheritance may be autosomal dominant or recessive. Over 900 mutations in the LDL-receptor gene have been identified as causing FH.3
The common consequence of the possible genetic mutations is a decreased clearance of LDL from the plasma, resulting in a clinically recognisable pattern of severe hypercholesterolemia, cholesterol deposition in the tendons and skin, and high risk of atherosclerosis, which manifests mainly as coronary artery disease (CAD).2
Marais/50/col 1/para 1
Mahley/19/para 1
Rader/1797/col 2/para 1
Familial Hypercholesterolaemia
Evolocumab (PCSK9 Inhibitor)
Ref No 10
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015;372:

9. Familial Hypercholesterolaemia (FH): Basic Defect
Normal FH

10. Salient Features of FH Inheritable, autosomal dominant disorder
FH Presentations
Salient Features of FH
Inheritable, autosomal dominant disorder
Usually due to mutations in LDL receptor gene that result in decreased clearance of LDL particles from plasma
Other mutations include those in the Apo B and PCSK9 genes
Clinical manifestations include
Severe hypercholesterolemia due to accumulation of plasma LDL
May be accompanied by cholesterol deposition in tendons and skin (xanthomas) and in the eyes
Evidence of CVD early in life
Familial hypercholesterolemia (FH) can be defined as a heritable disorder, caused by mutations in the LDL-receptor gene that result in receptor absence or malfunction.1,2 Inheritance may be autosomal dominant or recessive. Over 900 mutations in the LDL-receptor gene have been identified as causing FH.3
The common consequence of the possible genetic mutations is a decreased clearance of LDL from the plasma, resulting in a clinically recognisable pattern of severe hypercholesterolemia, cholesterol deposition in the tendons and skin, and high risk of atherosclerosis, which manifests mainly as coronary artery disease (CAD).2
Marais/50/col 1/para 1
Mahley/19/para 1
Rader/1797/col 2/para 1

11. Visible Signs of FH A- Xanthelasma B – Corneal arcus (Arcus senilis)
FH Presentations
Visible Signs of FH
A- Xanthelasma
B – Corneal arcus (Arcus senilis)
C - Achilles tendon xanthomas
D - Tendon xanthomas
E - Tuberous xanthomas
F - Palmar xanthomas
Maley/19/Figure 36-22
What about arcus cornealis? Also can we note that tendon xanthomas [in asterix] may not be visible but detected through physical exam?
Mahley RW et al. In Kronenberg: Williams Textbook of Endocrinology 2008

12. The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations
FH Presentations
The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations
LDLR codes for the LDL Receptor, which clears LDL particles from the circulation by binding to surface Apo B
PCSK9 induces degradation of LDLR
FH may be caused by mutations in Apo B, LDL-R, or PCSK9
Extracellular Fluid
Apo B (site where receptor binds to LDL particle)
LDL Particle:
Cell membrane
PCSK9
Cytosol
LDL receptor

13. Normal Function of PCSK9
Regulates the surface expression of LDLRs by targeting for lysosomal degradation

14. PFD Patient No 10
FH Presentations
Normal function of PCSK9 is degradation of LDL Receptors (LDLR). So its action leads to increased LDL-C as occurs in other forms of FH. Why mutation in the gene forming PCSK9 leads to increased LDL-C?
Can there be Hypocholesterolaemia in a patient with PCSK9 mutation?
Name ONE feature which differentiates FH from Familial Combined Hyperlipidaemia.
Familial hypercholesterolemia (FH) can be defined as a heritable disorder, caused by mutations in the LDL-receptor gene that result in receptor absence or malfunction.1,2 Inheritance may be autosomal dominant or recessive. Over 900 mutations in the LDL-receptor gene have been identified as causing FH.3
The common consequence of the possible genetic mutations is a decreased clearance of LDL from the plasma, resulting in a clinically recognisable pattern of severe hypercholesterolemia, cholesterol deposition in the tendons and skin, and high risk of atherosclerosis, which manifests mainly as coronary artery disease (CAD).2
Marais/50/col 1/para 1
Mahley/19/para 1
Rader/1797/col 2/para 1

15. Inherited disorders of LDL­cholesterol metabolism
Patient no 71
A 19 year old male has strong family history of dyslipidaemia and Coronary Artery Disease. His biochemical investigations revealed:
Cholesterol : mmol/L (208 mg/dl)
Triglycerides : mmol/L (279 mg/dl)
LDL Chol (measured): mmol/L (83 mg/dl)
HDL Chol (measured): mmo/L (39 mg/dl)
Apolipoprotein B: g/L (0.7 – 1.74)
LDL-C / Apo B ratio: (>1.4)
Give TWO most important differential diagnosis
Name the most probable sub-type of LDL particles present in this patient in greater excess.
Familial Combined Hyperlipidaemia and Hyperapobetalipoproteinaemia
Small dense LDL
Ref No 6
Inherited disorders of LDL­cholesterol metabolism

16. Familial Combined Hyperlipidaemia (FCHL)
Metabolic disorder characterized by
Increased in triglycerides and / or cholesterol
levels in at least two members of the same family
Intra-individual or intra-familial variability of lipid phenotype
Increased risk of premature coronary heart disease

17. Metabolism of Lipoproteins in FCHL
Overproduction of hepatically derived Apolipprotein B­100 associated  with VLDL. 
LDL phenotype B (small, dense LDL particles) make it very strongly atherogenic
Raised LDL-C levels and Triglyceride levels
Reduced HDL -C
LDL-C / Apo B ratio < 1.2 (Normal > 1.4)

18. Variants of FCHL Hyperapobetalipoproteinemia
Characterized by over production of Apo-B
Normal concentration of LDL-C
LDL-C/Apo-B ratio < 1.2 (normal >1.4)
Lipoprotein Lipase (LPL) deficiency
Characterized by increased triglycerides
Confirmed by measuring LPL activity

19. Patient no 72 (Recent Updates)
A 51 years old male has recently returned from United States. He is a known patient of Coronary Heart disease. He has shown you his recent Lipid tests from a state-of-the-art US lab to seek your opinion:
Cholesterol: mg/dl
Triglycerides: 215 mg/dl
LDL-C: mg/dl
HDL-C: mg/dl
Non-HDL-C: mg/dl
Lipoprotein – Associated Phospholipase A2
(Lp-PLA2) Activity: 576 nmol/min/m (< 284)
What raised Lp-PLA2 indicates in this patient?
To which Lipoprotein this enzyme (Lp-PLA2) is bound to in circulation?
Lp-PLA2 is a marker of atherosclerosis
Mostly LDL but also to HDL
Ref No 10
Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality:
Lancet 2010; 375: 1536–44

20. Lipoprotein – Associated Phospholipase A2 (Lp-PLA2)
This marker is now available in the labs of developed countries as a part of the risk assessment of Coronary Artery Disease
It is implicated in many events leading to plaque formation and disruption
Secondly it is claimed to be an link between oxidative modification of LDL and inflammatory response.
Both activity and mass of this enzyme can be estimated.

21. Patient no 73 Ascorbic Acid intake before the test
A 45 years old woman had a blood sample sent to the lab by treating physician. No clinical details were given. No other samples were sent before or since, for comparison. Biochemistry results included the following:
Cholesterol mmol/L
HDL Cholesterol mmol/L
Triglycerides mmol/L
Gamma Glutammyl Transferase U/L
ALT U/L
CK U/L
a. Give ONE analytical reason for these lipid results
b. Name TWO more tests likely to be affected in this way
Ascorbic Acid intake before the test
Glucose (by glucose oxidase) and Uric acid
Ref No 1
Teitz Textbook of Clinical Chemistry and Molecular Diagnostics 5th Ed (Page 720 & 771)
(Ref not attached)

22. Analytical Interference with Ascorbic Acid
In analytical methods with H2O2 generation, this problem can arise
In the step when peroxidase enzyme acts on H2O2 to produce coloured compound, ascorbic acid can compete with chromogenic substances
So a very high dose of ascorbic acid immediately before sample collection (as in Patient No 1) can lead to very low results of certain anlylates.
Ascorbic acid can also produce ‘False Positive’ results in urine tests for glucose or occult blood