THE CLINICAL BIOCHEMISTRY OF LIPID DISORDERS

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1 THE CLINICAL BIOCHEMISTRY OF LIPID DISORDERS

3 Hormonal regulation INSULIN lipid synthesis, lipolysis CORTISOL lipolysis GLUCAGON lipolysis GROWTH HORMONE lipolysis CATECHOLAMINES lipolysis LEPTIN catabolism GHRELIN hunger hormon anabolism

4 ROLE OF LIPIDS: SIMPLE FACTS Hyperlipidemia is associated with increase risk of atherosclerosis related diseases like IHD and stroke. Major plasma lipids cholesterol, TG, phospholipids, FFA. Cholesterol is a major component of cell membranes and a precursor of steroid hormones and bile acids. TG are bodies major energy store particularly in adipose tissues. Because lipid molecules (cholesterol and TGs) are water insoluble, they must be packaged in special molecular complexes known as lipoproteins in order to be transported in plasma. Nomenclature of the lipoproteins is based on their separation by density gradient. Lipoproteins may accumulate in the plasma due to overproduction and/or deficient removal.

5 The story of lipids

7 Lipid laboratory parameters Cholesterol HDL cholesterol LDL cholesterol Triglyceride (TG) Free fatty acid (FFA) <5,2 mmol/l >0,9 mmol/l (males) >1,15 mmol/l (females) <3,4 mmol/l <1,7 mmol/l <0,7 mmol/l Lp(a) <0,3 g/l or < 0,1% ApoA1 ApoB ApoB/ApoA1 ratio: <0,7 (high risk: >0,9)

8 Lipid analysis how? Cholesterol, HDL, LDL, FFA, Triglyceride: enzymatic assay (e.g. cholesterol esterase or lipase) ApoA1, ApoB : immunoassay Lp(a): immuno-assay (immuno-turbidimetry) or lipid electrophoresis

9 Lipid analysis how? Electrophoresis Ultracentrifugation

10 Lipoprotein electrophoresis HDL alfa VLDL (pre-beta) LDL (beta) Chylomicron (origin) (not present)

11 Lipoprotein electrophoretogram and densitometry evaluation Alfa: 11,8% Lp(a): 0% TG: 16,95 mmol/l, CHOL: 6,26 mmol/l Broad beta: 76,8% Chylomikron: 11,4%

12 Lipoprotein electrophoretogram and densitometry evaluation Lp(a) HDL VLDL LDL

13 Lipoprotein (a) or Lp(a) Produced by the liver Structure: LDL-like particle, contains rich in cholesterol apob apolipoprotein(a) Normal value: < 0,1% (of total lipoproteins) or < 0,3 g/l Diagnositic significance: The LDL-like particle contributes to atherosclerosis Apolipoprotein(a) has a similarity with plasminogen, leading to reduced fibrinolysis (competition). Test: recommended for: patients with a moderate or high risk of cardiovascular disease measured by immuno-assay (immuno-turbidimetry) or lipid electrophoresis

14 LDL Particle Size Subclass IDL L3 L2 L1 large, buoyant A AB small, dense B

15 Significance of Small, Dense LDL Associated with levels of TG and LDL-C, and levels of HDL 2 Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B) Measurement: ultracentrifugation, electrophoresis, HPLC Possible mechanisms of atherogenicity high endothelial permeability decreased LDL receptor affinity oxidation susceptibility

16 Case 1. Date of birth: Sex: Female Arrival : :44 Test Result Reference range Unit Sodium Potassium Calcium Glucose Bilirubin Urea Creatinine Triglyceride TSH LDH GOT GPT Alkalic phosphatase Gamma-GT Amilase Lipase Total protein CRP 151! mmol/l 4,42 3,50-5,10 mmol/l 1,41! 2,15-2,55 mmol/l 13,43! 3,90-7,00 mmol/l 16,7 2,5-21,0 umol/l 8,41! 2,14-8,21 mmol/l 148! umol/l 30,70! 0,00-1,70 mmol/l 1,050 0,270-4,200 mu/l 1425! U/l 71! <44 U/l 11 <50 U/l 29! U/l 132! 0-40 U/l 1360! U/l 2470! <60 U/l 41,2! 66,0-87,0 g/l 299,80! <5,00 mg/l

17 Checking lipids Nonfasting lipid panel measures HDL and total cholesterol Fasting lipid panel Measures HDL, total cholesterol and triglycerides Measure LDL or LDL cholesterol is calculated: LDL cholesterol = total cholesterol (HDL + triglycerides/5)

19 When to check lipid panel Two different Recommendations 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 United States Preventative Services Task Force Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 4.9 or HDL <1.0, then a fasting panel should be obtained Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesterol levels or premature cardiovascular disease.

20 High cholesterol

21 Figure 6. (a) Achilles tendon xanthoma; (b) tendon xanthomata on the dorsum of a hand (heterozygous familial hypercholesterolaemia); and (c) planar xanthoma in the antecubital fossa (homozygous familial hypercholesterolaemia). Courtesy of Professor PN Durrington. XANTHOMA

22 Triglycerides as a risk factor for CHD Copenhagen Male Study Cumulative incidence of CHD and all-cause mortality % 7.7% 11.5% >0.80 >1.10 >1.60 (n=951) Triglyceride level (mmol/l) N=2906; 8years

23 Elevated triglycerides: a synergistic risk factor 300 CHD cases / 1000 in 8 years TG < 2,3 mmol/l TG > 2,3 mmol/l 50 0 <3.40 >3.40 >4.10 >4.90 LDL-C (mmol/l)

24 THE RISK CHART Friedewald formula: LDL = TC HDL- TG/5

25 Fredrickson s classification

26 Hereditary Causes of Hyperlipidemia Familial Hypercholesterolemia (Type IIa) Codominant genetic disorder, coccurs in heterozygous form Occurs in 1 in 500 individuals Mutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout life High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous xanthomas and xanthelasmas of eyes. Familial Combined Hyperlipidemia (Type IIb) Occurs in 1 in 100 individuals Decreased LDL receptor Increased plasma LDL and VLDL Familial hypertriglyceridemia (Type IV) occurs in 1 of 100 increased VLDL production Can cause pancreatitis Dysbetalipoproteinemia (Type III) Affects 1 in 10,000 Results in apo E2, a binding-defective form of apoe (which usually plays important role in catabolism of chylomicron and VLDL) Tuberous xanthomas, striae palmaris

27 Secondary Causes of Hyperlipidemia Alcohol Diet Hypothyroidism Nephrotic syndrome Anorexia nervosa Obstructive liver disease Obesity Diabetes mellitus Pregnancy Acute hepatitis Systemic lupus erythematousus AIDS (protease inhibitors)

Central obesity Insulin Resistance Hyperinsulinaemia Impaired Glucose

28 The metabolic syndrome Prothrombotic state ( fibrinogen, Factor VIIa, fibrinolytic activity) Hyperuricemia Hypertension Microalbuminuria Central obesity Insulin Resistance Hyperinsulinaemia Impaired Glucose Tolerance Type 2 Diabetes Triglycerides HDL cholesterol Small dense LDL Dyslipidemia

29 Clinical Identification of the metabolic Syndrome (any 3 of the following) Risk Factor Abdominal Obesity Men Women Triglycerides HDL cholesterol Men Women Blood pressure Fasting glucose Defining Level Waist Circumference >102 cm (>40 in) >88 cm (>35 in) >1.70 mmol/l <1.04 mmol/l <1.30 mmol/l >130/>85 mmhg > 6.10 mmol/l NCEP guidelines

30 Case 2: 56-y-old woman Intermittent abdominal pain Weight gain (60 68 kg) Postmenopausal estrogen therapy Spastic colitis? Temperature: 38.5 C Hospitalization: dehydration Blood: strawberry milkshake Sodium 124 mmol/l ( ) Potassium 3.3 mmol/l (3.5-5) Glucose: 7.3 mmol/l ( ) Bilirubin 31 umol/l (2-19) Urate 482 umol/l ( ) Triglycerid 77 mmol/l ( ) Chol mmol/l (4-5.6) HDL Chol 0.31 mmol/l ( ) Amylase (serum) 580 U/l Diagnosis: Familial hypertryglyceridemia with secondary pancreatitis Autosomal recessive condition Manifest: only when other metabolic conditions appear simultaneously Other family members also affected?

31 Lowering cholesterol levels Lifestyle: limiting smoking, alcohol physical activity Diet: small to moderate effect. Recent recommendations don t mention limiting cholesterol intake Statins: HMG-CoA reductase inhibitors PCSK9 monoclonal antibodies

33 The cholesterol revolution: monoclonal PCSK9 inhibitors

34 Happy Halloween! and be aware of lipids! :)

Pathophysiology of Lipid Disorders

Pathophysiology of Lipid Disorders Henry Ginsberg, M.D. Division of Preventive Medicine and Nutrition CHD in the United States CHD is the single largest killer of men and women 12 million have history