Dyslipidaemia

• Background

  Familial (primary) dyslipidaemia

  • Due to gene mutation(s).
  • Should be suspected in patients with premature IHD (age <55 in men, <60 in women).
  • WHO classifies them type 1-5 (T1-5).

  Acquired (secondary) dyslipidaemia

  Most cases of dyslipidaemia are acquired in later life. Obesity, sedentary lifestyle, and diabetes are common risk factors, though many cases are essentially idiopathic.

  Other causes:

  • Endocrine: hypothyroidism, hypopituitarism.
  • Hepatic: alcohol excess, cholestasis.
  • Renal: nephrotic syndrome, chronic kidney disease.
  • Others: pregnancy, anorexia, gout, antipsychotics.

• Signs and symptoms

  Usually detected through CVD risk assessment, or when presenting with complications such as IHD or stroke.

  The only specific sign is lipid deposits (xanthomas). Their presence and extent are a sign of disease severity. Locations:

  • Eyelids: xanthelasma (also seen in smoking).
  • Eyes: corneal arcus and retinal deposits.
  • Tendon xanthoma: achilles (run finger and thumb along to feel for lumps) and digital extensor tendons. Especially seen in T2 hyperlipidaemia.
  • Knees and elbows: xanthoma tuberosum and tuboeruptive xanthoma (with red papules). Seen in T3 hyperlipidaemia.
  • Palms and flexures: palmar xanthoma.

• Investigations

  Lipid profile

  A non-fasting sample is acceptable.

  Measured variables:

  • Total cholesterol (TC) = HDL + LDL + VLDL.
  • High density lipoprotein cholesterol (HDL): 'good' cholesterol.
  • Triglycerides (TG): not directly atherogenic but suggestive of lipoprotein size and ↑ in metabolic syndrome.

  Apolipoprotein levels may also help assess risk and guide treatment.

  Other

  Exclude secondary causes:

  • Kidney disease: U&E, urinalysis (especially proteinuria).
  • Others: LFT, TFT, glucose, uric acid.

• Management

  • First consider and treat secondary causes: excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease, and nephrotic syndrome.
  • Consider a familial syndrome if TC >7.5 or family history of premature IHD.
  • Carry out a full CV risk assessment e.g. with QRISK (if age <85) or the Framingham risk equation. The decision to treat should be based on the overall risk level rather than the cholesterol level alone.
  • For primary prevention, discuss benefits of lifestyle changes and manage other CV risk factors before offering a statin. Offer to re-assess risk if changes made.
  • After these steps are taken, most patients still require a statin e.g. atorvastatin 20 mg in primary prevention.

• Familial hyperchylomicronaemia (T1)

  Pathophysiology

  Lipoprotein lipase or ApoC2 deficiency → chylomicrons not cleared.

  Signs and symptoms

  • Eruptive xanthoma on buttocks and calves.
  • Lipaemia retinalis if severe.
  • Acute pancreatitis.
  • No increased risk of CVD.

  Investigations

  ↑↑TG, ↑chylomicrons, ↑VLDL, milky blood.

  Management

  Dietary

• Familial hypercholesterolaemia (T2a)

  Pathophysiology

  • Mutation in LDLR, ApoB or PCSK9 genes → less LDL removed from blood.
  • Prevalence 1/500.
  • The heterozygous form is, by definition, autosomal dominant. The homozygous form is rare but severe.

  Signs and symptoms

  • Early IHD.
  • Lipid deposits: xanthelasma, tendon xanthoma, corneal arcus.
  • Homozygous form: planar cutaneous xanthoma, aortic stenosis, MI in childhood (so avoid exercise).

  Investigations

  • Lipid profile: ideally fasting, but not hugely important. TC usually 9-12.
  • DNA testing for specific mutations.
  • Cascade testing of relatives: start with 1st degree relatives (including kids), moving on to next degree if found (and so on), checking LDL, and DNA if the mutation is known.

  Diagnostic criteria

  Broome criteria (after excluding secondary cause) for definite disease:

  • DNA +ve or...
  • TC >7.5 and LDL >4.9 (kids 6.7 and 4, respectively) and tendon xanthoma.
  • 'Possible FH': TC >7.5 and LDL >4.9 and family history of early MI or high cholesterol.

  Management

  • For adults, consider high-intensity statins to reduce LDL by 50%, ± ezetimibe, a cholesterol absorption inhibitor.
  • Refer kids to a specialist, but likely they will also need statins.

• Familial combined hyperlipidaemia (T2b)

  Pathophysiology

  • ↑VLDL and apolipoprotein B.
  • Heritable, but responsible gene(s) unknown.
  • Prevalence 1/100. Commoner but less severe than other familial dyslipidaemias.

  Signs and symptoms

  • Xanthelasma
  • Association with other features of metabolic syndrome e.g. HTN, central obesity, glucose intolerance.

  Investigations

  • ↑TC: usually 6.5-8.0.
  • ↑TG: usually 2.3-5.0.
  • ↑LDL.
  • Often ↓HDL.

  Diagnosis

  Suspect if ↑TC+TG and family history of hyperlipidaemia or premature IHD.

• Familial remnant hyperlipidaemia (T3)

  Aka familial dysbetalipoproteinaemia.

  Pathophysiology

  • ApoE replaced by defective ApoE2 form → ↓chylomicron remnant clearance via LDL receptor.
  • Autosomal recessive.
  • Prevalence 1/5000.

  Signs and symptoms

  • Early IHD.
  • Striate palmar and tuboeruptive xanthomas (knee, elbow).

  Investigations

  ↑↑TC, ↑TG, ↑VLDL.

• Familial hypertriglyceridaemia (T4)

  Pathophysiology

  • Autosomal dominant. Mild form is common.
  • ↑VLDL production.

  Complications

  Acute pancreatitis.

  Investigations

  ↑TG, ↑VLDL, ↑chylomicrons.

  Management

  Fibrates

• Statins

  Mechanism

  HMG-CoA reductase inhibitor → ↓cholesterol synthesis and ↑cholesterol uptake into liver via LDL receptor.

  Drugs

  • Simvastatin, atorvastatin, rosuvastatin.
  • NICE recommends atorvastatin as 1st line.

  Indications

  Isolated high cholesterol not sufficient, but rather given for people with ↑CVD risk or a familial syndrome.

  ↑CVD risk:

  • Existing CVD: IHD, stroke, TIA, PVD.
  • ≥10% 10 year risk (QRISK2).
  • Type 1 diabetes and any one of: >40 years old, >10 years duration, nephropathy, or other CVD risk factors.
  • Type 2 diabetes and >10% 10 year risk (QRISK2).
  • CKD

  Efficacy

  • For an individual aged 50-80, statins cause a relative risk reduction of roughly 20% in CVD and 10% in all cause-mortality over 5 years (and likely similar over 10 and 20 years), regardless of baseline cholesterol.
  • The absolute size of this benefit depends on baseline risk e.g. if 10% risk of CVD and 5% risk of death over 10 years, then statins would provide a 2% reduction in CVD (20% of 10%) and 0.5% reduction in all-cause mortality (10% of 5%).

  Management

  Start once daily in the evening, since that is when most cholesterol is synthesised.

  LFTs:

  • Check at baseline and 3 and 12 months.
  • Only stop if LFT rise >3x upper limit, or symptomatic.

  Lipid levels:

  • Check at 3 months, aiming for 40% reduction in non-HDL.
  • Consider increasing dose if not achieved.

  Myalgia:

  • Before starting statin: check CK if patient complaining of muscle pain. If 5x upper limit on 2 tests (1 week apart), don't start statin. For smaller elevation, use low dose.
  • After starting statin: check CK if patient complaining of muscle pain.
  • If myalgia or ↑CK occurs, rule out other causes – intense exercise, hypothyroidism, infection, trauma, alcoholism – before attributing to statins.
  • Stop if 5x upper limit or severe symptoms.

  Side effects

  • Myalgia/myositis (↑CK).
  • Hepatitis
  • Rash
  • GI symptoms.
  • Altered sleep.
  • Diabetes

  Contraindications and interactions

  • Macrolides
  • Azoles. Stop statin if course is required.
  • For simvastatin, max 20 mg daily if on amlodipine or rate-limiting CCBs.
  • Grapefruit juice.