Lipid Disorders and Investigations Flashcards
What are major classes of Lipoproteins?
- Chylomicrons
- Very Low Density Lipoproteins (VLDL)
- Intermediate Density Lipoproteins (IDL)
- Low Density Lipoproteins (LDL)
- High Density Lipoproteins (HDL)
What are complications from Lipoproteins?
- Increased LDL or Reduced HDL - can cause Atheroma (CHD)
- Increased chylomicrons / VLDL - can lead to Pancreatitis
What are secondary causes of Lipid Disorders?
- Diabetes Mellitus
- Hypothyroidism
- EtOH
- Nephrotic syndrome
- CRF
- Atypical antipsychotics
- Cortiscosteroids
- Oral oestogens
- Ciclosporin
- Beta blockers, retinoids and
- HIV/antiretroviral drugs
- Anabolic steroids
What are investigations of secondary lipid disorders to exclude secondary lipid disorders?
- U+E (Na, K, urea, creatinine, eGFR) - Exclude renal failure
- Liver profile (Tpro, Alb, ALP, ALT, GGT) - Exclude cholestasis
- TFTs - Exclude hypothyroidism
- HbA1c - Exclude diabetes
- Urine Protein - Exclude nephrotic syndrome
What are investigations for Lipid Disorders?
- Fasting lipid profile: Total cholesterol, Triglycerides, LDL cholesterol (Friedwald equation*), HDL cholesterol, Non-HDL cholesterol, Risk Ratio (TC:HDL)
- Direct LDL
- Apo B
- Lipoprotein (a)
- Apo E genotype
- FH genotype
What is Friedwald equation?
LDL-cholesterol = Total cholesterol – HDL cholesterol – (Total triglyceride/2.19)
How is Familial Hypercholesteronaemia treated?
- Statins (HMG CoA reductase inhibitors)
- Ezetimibe (Bile acid sequestrants)
- PCSK9 inhibitors
- Apheresis
What is Severe Hypertriglyceridaemia?
Serum triglycerides often >10 mmol/L
- Primary causes include FCS, Familial dysbetalipoproteinaemia
- Secondary causes include diabetes and alcohol
- Can cause Recurrent pancreatitis
What are physical features of Sever Hypertriglyceridaemia?
- Eruptive xanthomata
- Hepatosplenomegaly due to fat accumulation
- Lipaemia retinalis, milky eyes (FCS)
What are familial Dysbetalipoproteinaemia?
- Increased circulating chylomicron remnants/IDL
- Increase in both serum cholesterol & triglyceride
- Caused by Mutation of apoE gene – E2 phenotype
- Low apoB concentration and apoB/total cholesterol ratio <0.15 g/mmol raises suspicion
- Leads to accelerated atherosclerosis including peripheral arteries
What are physical hallmarks of Familial Dysbetalipoproteinaemia?
- Palmar xanthomata
- Eruptive xanthomata
What is the prevelance of Familial Hypercholesteronaemia?
- Dominantly inherited, 50% offspring affected. Incidence approx 1 in 250 (240,000 in UK)
- Serum cholesterol up to 15 mmol/L
- 15% die before 60 years
- 50% men have MI by 50, 60% women by 60y
- Homozygous form is rare (1/1000000). Can lead to MI and angina in childhood. TC up to 20 mmol/L
What are clincal signs of Familial Hypercholesteraemia?
Clinical signs in 30%:
- Tendon xanthomata
- Corneal arcus
- Xanthelesma
What is the Simon Broome Diagnostic Criteria for Definite Familial Hypercholesteraemia?
Definite Familial Hypercholesteraemia
- TC >7.5 mmol/L or LDL-C >4.9 mmol/L (adult)
- TC >6.7 mmol/L or LDL-C >4.0 mmol/L (<16y)
AND
- Tendon xanthomas or evidence in 1st /2nd degree relative OR
- DNA-based mutation in LDL-receptor, apo-B100 or PCSK9
What is the Simon Broome Diagnostic Criteria for Possible Familial Hypercholesteraemia?
Possible Familial Hypercholesteronaemia
- TC >7.5 mmol/L or LDL-C >4.9 mmol/L (adult)
- TC >6.7 mmol/L or LDL-C >4.0 mmol/L (<16y)
AND
- Family history of MI <50y in 2nd degree or <60y in 1st degree relative OR
- Family history of TC >7.5 mmol/L in 1st or 2nddegree relative
What are criteria for Familial Hypercholesteronamia?
- Dutch Lipid Clinic Network Score
- Simon Broome Diagnostic Criteria
What is the cause of familial hypercholesteronaemia?
Mutation affecting LDL receptor pathway (>1000 mutations described)
3 genes
- LDL-receptor (LDLR),
- Apolipoprotein (apo) B100 (the LDL-receptor ligand)
- Proprotein convertase subtilisin/kexin type 9 (PCSK-9)
What is Polygenic Hypercholesteronaemia?
Overproduction of VLDL by liver which is converted to LDL
- Type IIa or IIb phenotype
- Exacerbated by high fat diet and obesity
- 12 genes tested
What is Familial Chylomicronaemiasyndrome?
- Fredrickson Type 1 (Rare, 1 in a million)
- Autosomal Recessive, >180 mutations identified
- Lipoprotein lipase or Co-factor deficiency: ApoA5,GPIHBP1, ApoC2 and LMF1
- Leads to Recurrent episodes of pancreatitis
What are physical features of Familial Chylomicronaemiasyndrome?
- Eruptive xanthomata
- Hepatosplenomegaly due to fat accumulation
- Lipaemia retinalis
- Milky eyes
How is Familial Chylomicronaemiasyndrome diagnosed?
- Raised Total Cholesterol and Triglycerides (3 episodes >10mmol/L)
- Chylomicronaemia
- Apo B < 1g/L
What is the treatment for Familial Chylomicronaemiasyndrome?
- Low fat diet
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What is Familial Combined Hyperlipidaemia?
- Incidence 1 in 100
- Combined increase in cholesterol and triglyceride (Fredrickson type IIb)
- Family history of premature CHD
- No specific clinical hallmarks, but may have corneal arcus or xanthelasmata
What are biochemical markers of Familial Combined Hyperlipidaemia?
- Suspect if total cholesterol levels are in the range 6.5–10.0 mmol/L and/or triglycerides between 2.3 and 6.0 mmol/L
- Raised VLDL and ApoB (>1.2g/L)
What is the treatment for Familial Combined Hyperlipidaemia?
- Statins - HMG CoA reductase inhibitors
- Fibrates
- Healthy eating pattern, lifestyle changes and weight control are also essential
What is Abetalipoproteinaemia?
- Autosomal recessive
- Due to defect in microsomal triglyceride transfer protein (MTP) involved in assembly of TG-rich lipoproteins
- TC <1.3 mmol/L ( almost all is HDL-C)
- Very low serum triglycerides
What are Abetalipoproteinaemia associated with?
- Retinitis pigmentosa
- Ataxia
- Acanthocytes
- Steattorrhoea
What is Tangier’s Disease (Analphalipoproteinaemia)?
- Virtual absence of HDL (apo A1 <1%, ApoA2 <5%) due to defect in ABCA1 (autosomal recessive).
- ABCA1 is involved in efflux of cholesterol to HDL
- Deposition of cholesterol in foam cells in Reticulo-endothelial System. enlarged orange-yellow tonsils
- Premature atherosclerosis
What are features of Tangier’s Disease (Analphalipoproteinaemia)?
- Lymph node enlargement
- Hepatosplenomegaly
- Bone marrow infiltration – low platelets
What are the phenotypes of Lipid Disorders?
Class I: Affects Chylomicrons
- Normal to increased cholesterol
- Increased Triglycerides
Class IIa: Affects LDL
- Increased cholesterol
- Normal Triglycerides
Class IIb: Affects LDL & VLDL
- Increased cholesterol
- Increased Triglycerides
Class III: Affects IDL
- Normal to increased cholesterol
- Increased Triglycerides
Class IV: Affects VLDL
- Normal to increased cholesterol
- Increased Triglycerides
What are associated clinical disorders of phenotypes of Lipid Disorders?
- Class 1: Familial chylomicronaemia syndrome (lipoprotein lipase deficiency, apolipoprotein C-II deficiency)
- Class 2a: Familial hypercholesterolemia (1/250), Polygenic hypercholesterolemia (1/50), Nephrotic syndrome, Hypothyroidism
- Class 2b: Familial combined hyperlipidemia(1/100)
- Class 3: Familial Dysbetalipoproteinemia
- Class 4: Familial hypertriglyceridemia (1/100), Familial combined hyperlipidemia, sporadic hypertriglyceridemia, Diabetes
