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HYPERLIPIDAEMIAS

HYPERLIPIDAEMIAS. Dr Danielle B Freedman April 2018. Causes of raised cholesterol Raised cholesterol caused by LDL Common Polygenic hypercholesterolaemia Drugs (eg, sertraline) Less common Hypothyroidism Nephrotic syndrome Cholestasis Familial hypercholesterolaemia *

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HYPERLIPIDAEMIAS

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  1. HYPERLIPIDAEMIAS Dr Danielle B Freedman April 2018

  2. Causes of raised cholesterol • Raised cholesterol caused by LDL • Common • Polygenic hypercholesterolaemia • Drugs (eg, sertraline) • Less common • Hypothyroidism • Nephrotic syndrome • Cholestasis • Familial hypercholesterolaemia* • Anabolic steroids

  3. Causes of raised cholesterol and Tg • Common • Type 2 diabetes mellitus/obesity • ETOH • Pregnancy • Drugs (eg, risperidone) • Less common • Familial combined hyperlipidaemia • Hypothyroidism • End stage renal disease

  4. Managing dyslipidaemia for the primary prevention of cardiovascular disease • Cardiovascular disease (CVD) is the most common underlying cause of death worldwide. 17.3 million out of 54 million total deaths per year. • 8.2/17.3 million due to ischaemic heart disease • 6.5/17.3 million due to stroke. • Mean total cholesterol, LDLc, and triglyceride have decreased over the past 20 years. • Long term exposure to modestly elevated cholesterol concentrations is associated with CVD in later life (some observational cohort evidence)

  5. Assess lipid status as part of an overall cardiovascular risk assessment using a risk calculator • Routinely record a family history of premature cardiovascular disease, and consider an underlying familial dyslipidaemia • Explain to patients their cardiovascular risk and the benefits and harms of treatment

  6. Primary Prevention of Cardiovascular Disease • Do a full formal risk assessment if estimated 10 year risk of CVD ≥10% • All CVD risk assessment tools provide only an approximate value for CVD risk and should not be used in patients with: type 1 diabetes, eGFR <60 +/or albuminuria, pre-existing CVD, FH/other inherited lipid disorder. • Measure non-fasting: Total-cholesterol, HDL-cholesterol, Non-HDL cholesterol and triglycerides • Exclude secondary causes of dyslipideamia • Consider familial lipid disorders where indicated incl FH • Suggest lifestyle modification/optimisation of other modifiable CVD risk factors • Offer statin if risk assessment shows this was ineffective • Treatment aim at 3 months: >40% reduction in non-HDL Cholesterol

  7. Secondary Prevention of Cardiovascular Disease • Do NOT use risk assessment tools – they are not valid, patients already high risk • Start Atorvastatin 80mg in people with CVD. Lower dose if potential drug interactions, high risk adverse events, patient preference • Do not delay statin treatment to manage modifiable risk factors • Type 1 diabetes and CKD have specific treatment guidelines • Treatment aim at 3 months: >40% reduction in non-HDL Cholesterol • Evidence that lowering non-HDL cholesterol <2.5 mmol/L (LDL-cholesterol <1.8 mmol/L) decreases CVD events

  8. NICE guideline (CG67)recommends using QRISK2 calculator and 10% threshold • US guidelines use 7.5% • European society cardiology use 10%, modify by pre-treatment LDLc • Factors associated with highest CVD risk for QRISK2 • AF • T2DM • FH CVD • Current smoker • Factors associated with lowest hazard ratios in QRISK2 • Lipid profile • Age (older) • Sex (Male) • Renal disease • Blood pressure medication • BMI

  9. Do patients needs to fast before a lipid profile blood test? • Fasting for a lipid profile is not routinely recommended • Unless Triglycerides >4.5 mmol/L – suggest repeat on fasting sample. These patients are likely to have variable response to food intake

  10. Familial dyslipidaemias associated with premature CVD • Heterozygous familial hypercholesterolaemia • Defined as LDLc >4.9 mmol/L in index case pluseither the same lipid profile in a first or second degree relative or premature ischaemic heart disease in same relative (Simon Broome criteria).

  11. QRISK 2 calculator • Information required to generate a QRISK/ CVD risk score (based on a UK patient cohort) • Personal details: age, sex, ethnicity, and postcode • Clinical information: smoking status, diabetes status, heart disease in 1st degree relative <60, CKD, AF, BP medication, RA • Examination and lab results: cholesterol/HDL ratio, systolic BP, height, weight (for BMI)

  12. Lipid lowering medication: mechanism of action • Statins • Inhibits HMG-CoA reductase, (rate limiting enzyme in cholesterol synthesis) • Leads to an increase in LDL receptor expression in the liver, which lowers LDL • Ezetimibe • Inhibits cholesterol absorption from the gut • PCSK9 • prevents LDL receptor degradation, lowers LDL

  13. Statin based treatment strategy NICE: High intensity statin aiming for 40% reduction in non-HDL cholesterol US: Moderate to high intensity statin aims for 30% to 50% LDL reduction European Society of Cardiology: Aim for LDLc <1.8 mmol/L in very high risk or <2.6 mmol/L in high risk or at least a 50% LDLc reduction NICE guidance on statin intensity HIGH: Atorvastatin 20mg (and above); rosuvastatin 10mg (and above) MEDIUM(31-40% LD reduction): Atorvastatin 10mg, rosuvastatin 5mg, sinvastatin 20-40mg LOW (20-30% LDL reduction): pravastatin 10-40mg, simvastatin 10mg

  14. NICE guideline Cardiovascular disease: risk assessment and reduction, including lipid modification CG181, 2014. The information used to make the table is from Law MR, Wald NJ, Rudnicka AR (2003) Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423.

  15. Statins and glycaemic control • Alternative evidence suggests that statins increase fasting blood glucose marginally • overall the benefits of treatment outweigh this risk of diabetes mellitus • Statins do not substantially affect glycaemic control in known diabetics

  16. Monitoring statin therapy • Baseline liver function tests are recommended in all relevant lipid guidelines • Follow-up testing at 8 wks and 12 months is recommended by NICE • Raised ALT occur in 0.5% to 2.0% of statins users, particularly in those with hepatic fat, • Mildly increased ALT not associated with hepatotoxicity • If ALT <3 time ULN – statin can continue • ALT >3 times ULN – more detailed investigation and statin cessation until investigations complete

  17. Advice and monitoring for adverse events • Do not measure CK levels in asymptomatic people who are being treated with a statin • Statins are contraindicated in pregnancy:Advise women of childbearing potential of the potential teratogenic risk of statins and to stop taking them if pregnancy is a possibility.Advise women planning pregnancy to stop taking statins 3 months before they attempt to conceive and to not restart them until breastfeeding is finished

  18. NICE TA394: Evolocumab for treating primary • hypercholesterolaemia and mixed dyslipidaemia • June 2016 • Evolocumab is recommended as an option for treating primary hypercholesterolaemia or mixed dyslipidaemia, only if: • The dosage is 140 mg every 2 weeks. • LDL is persistently above the thresholds in nexttable despite max tolerated lipid-lowering therapy.

  19. 58 year old female Referred with Hypercholesterolaemia CHOL = 9.1mmol/L Treated initially by GP with Atorvastatin for 1 month Blood test: Abnormal LFTs – Bil 12 umol/L ALP 524 IU/L [25-120] ALT 98 IU/L [40] Statin stopped

  20. FH Mother died aged 82 Father MI 70 Brother CHD 60 PMH Hysterectomy age 40 Basal cell ca 1999 SH Married 2 children Occasional alcohol Non smoker DH HRT Allergies Hayfever SQ Weight  BOR No thirst

  21. O/E Not anemic BMI = 25 No jaundice No xanthelasma Looked young for age No LK2S felt Nil b/p 130/98

  22. Q1 What laboratory investigations would you request? • LFTs • TFTs • Urine protein • CK

  23. Q1. Answer • LFTs • TFTs • Urine Protein

  24. Q2 What other laboratory investigations would you request? • Serum Ferritin • Immunoglobulins and EPS • ESR • Auto abs

  25. Answer b) Igs and eps d) Auto abs

  26. GT 118 IU/L [<70] ALP 402 [<120] ALT 90 [<40] BIL 14 umol/L IgG n IgM  3.2g/L [0.2 – 3.] IgA n EPS: diffuse inc 

  27. ANF A SMA A GPC Negative AMA 1 in 640

  28. U/S Gross abnormality of liver texture cirrhosis Refer liver specialist Further finding Proteinuia Nephritis Dx  chol – 9.1mmol/L Cholestyramine (Questran)

  29. Progress Rx Ursodeoxycholic acid - 600 mg bd Still on Questran Chol 9.0mmol/L

  30. Q3 Primary Biliary Cirrhosis is? • Associated with Pagets disease of bone • Osteoporosis is a complication • More common in men • Age range affected is the elderly [>75 yrs]

  31. Q3. Answer • Osteoporosis is a well recognised complication • Due to reduced bone formation • Evidence shows 11% patients affected

  32. Dexa scan PBC risk factor osteoporosis  Osteoporosis Alendronate (had been on HRT) DX Statin 12 months later ALP 508 IU/L [25 – 120] ALT 106 IU/L [<40] Stop Statin ALP 292 ALT 55 Chol 8.9 mmol/L HDL 3.0 mmol/L

  33. Q4 In primary biliary cirrhosis • Hypercholesterolaemia is not associated with cardiovascular risk • Fibrates normalise LFTs • Often associated with Sjögren’s syndrome • Pruritis is a rare symptom

  34. Q4. Answer • Evidence shows improvement in ALP, GT and 1gM • As autoimmune disease Sjögren’s syndrome most common extra hepatic autoimmine disease occurs in  75% patients 

  35. ALP <120 IU/L 416 264 344 264 ALT <60 IU/L 50 47 67 40 Chol Mmol/L 8.0 7.4 7.8 7.3 HDL Mmol/L 2.8 2.7 2.8 2.7 Dexa scan 12 months later - Improvement in bone density Feb 11 Chol = 7.2mmol/L ALP = 180 IU/L

  36. Learning points • PBC is a chronic cholestatic liver disease of adults • Aetiology unknown but dysregulation of immune system and genetic susceptibility important • 90% of those affected are women 40 – 50 years • Prevalence 7.5/100,000 • Mitochondrial antibodies present in 95% [>1/40 titre] • Hypercholesterolaemia in 85% of patients • ALP [2 – 10 x ULN] • ALT mild  • Bil normal

  37. ?? Is Hypercholesterolemia in PBC a cardiovascular risk • Studies suggest extreme hypercholesterolaemia related to cholestasis is not atherogenic[Longo et al GUT 2002] [Su et al NEJM 2007] • Other studies suggest patients with PBC need to be treated if they have another associated cardiovascular risk eg hypertension [Allocca et al GUT 2006] • Ursodeoxycholic acid [UDCA] reduces cholesterol and improves cholestasis and cholesterol biliary excretion • Fibrates improves LFTs better than UDCA

  38. Statins? Conflicting results • Suppressive effect on inflammation • Osteogenic properties and stimulate bone formation • ?  ALT • Need for Formal Trials

  39. Secondary causes of Hypercholesterolaemia include • Cholestasis (PBC) • Lipoprotein X - ?atherogenicity • [bile acids, apoC, apoD, ALB and chol] •  HDL • Hypothyroidism •  LDL • LDL receptors • clearance

  40. Secondary causes of Hypercholesterolaemia include – cont. Nephrotic Syndrome • Overproduction of Apo B – 100 •  HMG – co A reductase activityLDL  albumin[can get  chylomicrons and VLDL due  removal and  lipoprotein lipase activity

  41. Case 2 26 year old Female Attended her GP in February 2013 Tests requested were: FBC CRP Bone profile Liver Function Tests Lipid profile Renal function tests & eGFR Thyroid Function Tests Fasting glucose

  42. Blood test results Feb 2013: Lipid Profile Total Cholesterol 9.5 mmol/L Triglycerides 1.7 mmol/L HDL Cholesterol 1.73 mmol/L LDL Cholesterol 7.0 mmol/L Cholesterol/HDL ratio 5.5 Thryoid Function Tests Free T4 < 3 pmol/L TSH > 100 mU/L

  43. Thyroid function test history Oct 2009 Free T4 12 pmol/L TSH 6.29 mU/L Anti-TPO >1300 U/ml Actions GP d/w Dr Freedman and started on Levothyroxine Referral to Dr.Freedman’s clinic at the L&D

  44. Clinic appointment O/E Large diffuse goitre Blood test results March 2013 Lipid Profile Total Cholesterol 4.8 mmol/L HDL Cholesterol 1.00 mmol/L Cholesterol/HDL ratio 4.8 Thyroid Function tests Free T4 12.9 pmol/L TSH 14.73 mU/L Anti-TPO >1000 U/mL

  45. US Thryoid – April 2013 The thyroid is diffusely slightly enlarged and hypoechoic in echotexture. The appearances are consistent with Hashimoto's thyroiditis. No discrete nodules. No significant retrosternal extension. There are also prominent lymph nodes in both sides of the neck which would also be in keeping with a diagnosis of Hashimoto's. These nodes are not pathological in appearance. Thyroid Function Tests – May 2013 Free T4 13.6 pmol/L TSH 0.75 mU/L

  46. Familial Hypercholesterolaemia • Use Simon Broome criteria • Chol> 7.5 ( age16 and over) LDL > 4.0 • Chol > 6.7 ( age <16) LDL > 4.0mmol/L • And tendon xanthomas in patient or 1st or 2nd degree relative Or DNA based evidence

  47. ?? Possible FH • Cholesterol concentrations as before PLUS • Family history of MI in 2nd degree relative < 50yr or 1st degree relative <60 yr • OR • Family history of 1st or 2nd degree relative with Chol>7.5 or child,brother, sister<16 chol>6,7 mmol/L

  48. NICE Clinical Guideline 181 July 2014 Lipid measurement and referral • Arrange for specialist assessment of people with:- Total cholesterol > 9.0 mmol/litre or - Non-HDL cholesterol > 7.5 mmol/litre Even in the absence of a first-degree family history of premature coronary heart disease.

  49. Lipid measurement and referral cont… • Refer for URGENT specialist review if a person has a triglyceride concentration > 20 mmol/L that is NOT a result of excess alcohol or poor glycaemic control • In people with a triglyceride concentration 10 - 20 mmol/L: - Repeat the triglyceride measurement with a fasting test (after 5 days,but within 2 weeks) and- Review for potential secondary causes of hyperlipidaemia and- Seek specialist advice if the triglyceride concentration remains >10 mmol/L

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