Vascular profile of patient with familial hypercholesterolemia

IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 111–115

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Vascular profile of patient with familial hypercholesterolemia Arvind Kandoria a , Sachin Sondhi a,∗ , Kunal Mahajan a , Ayushi Mehta b a b

Department of Cardiology, Indira Gandhi Medical College, Shimla, HP, India Department of Anaesthesia, Indira Gandhi Medical College, Shimla, HP, India

a r t i c l e

i n f o

Article history: Received 30 July 2017 Received in revised form 6 October 2017 Accepted 12 October 2017 Keywords: Familial hypercholesterolaemia Xanthomas Premature atherosclerosis Carotid artery stenosis

a b s t r a c t Familial Hypercholesterolaemia is a common genetic cause of premature Coronary heart Disease (CHD). It is an autosomal, dominant, inherited disorder of lipoprotein metabolism that results in a raised Low Density Lipoprotein Cholesterol (LDL-C) plasma concentration. The current study presented a 36 year old female having angina on exertion class 2 for past 1 year. She had large xanthomas over dorsal aspect of both the hands and feet and xanthelasma over eyelid. She was diagnosed as case of familial hypercholesterolemia. Her vascular profile revealed aortic root calcification, left main with triple vessel disease, right common carotid artery stenosis and atherosclerotic narrowing of aorta distal to left subclavian artery. © 2017 Cardiological Society of India. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Case description 36 year old female with BMI of 20 kg/m2 presented to us with complaints of angina on exertion class 2 for past 1 year. She had blood pressure of 132/70 mmHg and pulse rate of 76/min. She had xanthomas over dorsal aspect of both the hands (Fig. 1a), dorsal aspect of feet (Fig. 1b) and lateral aspect of right foot (Fig. 1c). She also had xanthelasma below left lower lid. On cardiovascular examination she had soft systolic murmur over aortic area and carotid bruit was heard over right side of neck. Her father died at age of 47 years because of myocardial infarction. He had no xanthomas or xanthelasma. Her mother had no skin manifestations and her lipid profile was normal. She had one elder brother. Her elder brother had no skin manifestations and was on treatment for dyslipidemia with 20 mg rosuvastatin. His current lipid profile revealed total cholesterol 245 mg/dl, LDL cholesterol 168 mg/dl, triglycerides 191 and HDL 40 mg/dl. Laboratory tests including CBC, LFT, and RFT were normal. Her lipid profile revealed total cholesterol 608 mg/dl, LDL cholesterol 429 mg/dl, triglycerides 126 mg/dl and HDL 54 mg/dl. The physical examination, lipid profile and family history of CAD in father and dyslipidemia in brother, were compatible with diagnosis of FH (familial hypercholesterolemia). The genetic analysis was not performed. She may be found to have homozygous FH on genetic testing if this could be performed.

Her electrocardiogram was normal. 2D echocardiography revealed thickened calcified aortic valves and aortic root (Fig. 2a), Mild aortic regurgitation (PHT 408 ms, aortic flow velocity 1.9 m/s) (Fig. 2b), right common carotid artery shows significant stenosis (Fig. 2c and d). There was evidence of atherosclerotic narrowing of aorta distal to left subclavian artery with peak gradient of 42 mmHg (Fig. 3). The left ventricular systolic and diastolic functions were normal. On coronary angiography there was aortic root calcification, left main ostial stenosis, diseased proximal LAD, diseased proximal LCX and distal RCA (Fig. 4). On brachiocephalic trunk angiography, there was 50% stenosis of distal brachiocephalic trunk and around 70% stenosis of middle part of right common carotid artery, left common carotid showed only mild stenosis, and arch angio atherosclerotic narrowing of aorta distal to left subclavian artery with gradient of 40 mmHg (Fig. 5). She was managed with 40 mg of rosuvastatin and 10 mg of ezetimibe. For secondary prevention of coronary artery disease she was started on ecosprin 75 mg and metoprolol 50 mg. She was taken for angioplasty but it was abandoned because we were not able to cross the wire into right coronary artery as lesion was calcified and on hooking left main coronary artery there was dampening of pressures along with ST-segment elevation on electrocardiogram. So she was referred for CABG with carotid endartrectomy.

Discussion

∗ Corresponding author. E-mail address: [email protected] (S. Sondhi).

Familial hypercholesterolemia (FH) is an inherited condition resulting in high levels of low-density lipoprotein cholesterol (LDLC) and increased risk of premature cardiovascular disease in men

https://doi.org/10.1016/j.ihjccr.2017.10.003 2468-600X/© 2017 Cardiological Society of India. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

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Fig. 3. Echocardiogram showing coarctation of aorta distal to left subclavian with peak gradient of 42 mm Hg.

Fig. 1. Multiple skin xanthomas over hands (a) and feet (b,c). Note xanthelasma below the lower eyelid (d).

and women. Heterozygous FH (HeFH) is the most common monogenic disorder, affecting 1 in 200–250, twice as high as previously thought,1 with a penetrance of greater than 90%.2 If HeFH is left untreated, there is a significant likelihood of CHD onset prior to age 55 (men) and 60 (women). Half of all untreated HeFH men and 15% of women will die of CHD-induced myocardial infarction (MI) before these ages.3,4 Homozygous FH (HoFH) is rare with an estimated global prevalence of 1/160,000–300,000.5 In communities with founder effects, higher disease prevalence is observed. The majority of FH cases are caused by mutations in the LDLR gene, resulting in defective synthesis, assembly, transport, recycling or vesicle formation. Mutations in the LDLR gene cause FH in 79% of cases. Apolipoprotein B (ApoB) helps the LDL-receptor to bind LDL and mutations in ApoB accounts for ∼5% of FH cases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the LDL-receptor and gain of function mutations in PCSK9 account for <1% of FH cases.6 A very rare recessive form of FH is caused by mutations in low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). The remaining 15% of FH cases are either polygenic or are driven by monogenic mutations whose prevalence is not yet determined.6 Diagnosis of FH is based on lipid levels, family history, physical findings (if present), and if available, genetic analy-

Table 1 Clinical approach to diagnosis of familial hypercholesterolemia. Consider FH in the following 1. Presence of premature atherosclerotic cardiovascular disease 2. Fasting LDL-C levels greater than 190 mg/dL in adults after exclusion of secondary causes of elevated LDL-C (hypothyroidism, nephritic syndrome) 3. Fasting untrea ted LDL-C levels that have an 80% probability of FH in the general population: >250 mg/dL in adults >30 years, >220 mg/dL in adults aged 20 to 29, 190 mg/dL in patients under the age of 20 4. Presence of full corneal arcus under the age of 40 5. Presence of tendon xanthomas 6. Family history of premature atherosclerotic cardiovascular disease 7. Family history of high cholesterol levels

sis (Tables 1 and 2). Physical examination findings of tendon xanthomas, arcus corneae (under the age of 45), and tuberous xanthomas or xanthelasma (under the age of 25) when present at an early age should also prompt suspicion for FH. However, physical findings are not present in all patients with FH. There are different clinical criteria to diagnose FH like Simon Broome diagnostic criteria, Dutch Criteria, MEDPED criteria. These criteria are based on family history, LDL levels, physical screening and genetic analysis.7 According to Nice guidelines 2008, cascade screening should be done in first and second degree relatives of index case by either genetic testing or lipid screening. Genetic testing should be done in 1st degree relatives only if genetic mutations were found in index

Fig. 2. Echocardiogram showing thickened and calcified aortic valve and aortic root (a), mild aortic regurgitation (b), plaque (arrow) causing significant obstruction (c, d).

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Fig. 4. Note aortic root calcification (a), on coronary angiography, left main around 40% ostial stenosis (b), Proximal LAD diffuse disease with maximum of 70% stenosis (c, vertical arrow) and LCX discrete around 50% stenosis (c, horizontal arrow), Distal RCA around 90% stenosis (d).

Fig. 5. On brachiocephalic trunk angiography shows around 50% stenosis of distal trunk and around 70% stenosis of right common carotid artery (a), left common carotid shows only mild stenosis, and arch angio shows atherosclerotic narrowing of aorta distal to left subclavian artery with gradient of 40 mmHg.

Table 2 Diagnosis of homozygous familial hypercholesterolemia. Genetic analysis showing mutations in 2 alleles at gene locus for LDLR, APOB, PCKS9, LDLRAP1 OR Presence of untreated LDL greater than 500 mg/dL or treated LDL greater than 300 mg/dL plus: Presence of cutaneous or tendon xanthomas before the age of 10 years OR Both parents with evidence of heterozygous FH (except for the rare LDLRAP1 mutations

case, otherwise lipid screening is adequate.8 The genetic testing is not always required for diagnosis as 15% of FH cases are either polygenic or are driven by monogenic mutations whose prevalence is not yet determined.6 So mutation is not always found in patients with clinical FH, and lack of a mutation should not change treatment. National Lipid Association guidelines recommend a target LDL level of <130 mg/dl or >50% reduction from baseline values. Life style modifications, High dose statins should be used. According to the American Heart Association and American Academy of

Table 3 Low-density lipoprotein apheresis recommendations (National Lipid Association and American College of Cardiology/American Heart Association cholesterol guideline).11,12 LDL apheresis is recommended for the following patients 1. LDL goal reduction has not been achieved despite diet and maximum drug therapy (after 6 months). 2. Adequate drug therapy is not tolerated or contraindicated. 3. Functional homozygous FH patients with LDL-C 300 mg/DL or higher (or non-HDL cholesterol 330 mg/dL). 4. Functional heterozygous FH patients with LDL-C 300 mg/dL or higher (or non-HDL 330 mg/dL) and 0–1 risk factors. 5. Functional heterozygous FH patients with LDL-C 200 mg/dL or higher (or non-HDL cholesterol 230 mg/dL) and with risk characteristics such as 2 or more risk factors or high lipoprotein (a) 50 mg/dL or higher. 6. Functional heterozygotes with LDL-C 160 mg/dL or higher (or non-HDL cholesterol 190 mg/dL) and very high-risk characteristics (established CHD, other cardiovascular disease, or diabetes).

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Table 4 Earlier case reports from India compared with our case. Author

Age

Skin involvement

Family history

Kumar et al.14

18

Yes

Yes

Otikunta et al.15

30

Yes

Yes

Samir G et al.16 Mahajan et al.17

16 19

Yes Yes

Yes Yes

Our Case

36

Yes

Yes

Genetic analysis done

Coronary artery involvement

Arch vessels involvement

Atherosclerotic narrowing of aorta

Acute anterior wall MI, coronary angiography not done Acute anterior wall MI, Double vessel disease (LAD, OM) TVD + Left main disease Aortic root calcification with severe valvular with supravalvular stenosis, coronaries were normal Aortic root calcification, Thickened aortic valve, left main with TVD

No

No

No

No

No

No

Left subclavian artery No

No Supravalvular narrowing of Aorta

Yes No

Yes Brachiocephlic trunk with right common carotid artery

Narrowing of aorta distal to left subclavian artery

No

Paediatrics, statins were proposed as first-line drugs and the age of initiation of therapy was lowered to 8 years. No major side effects with regard to growth, sexual development, muscle, and liver toxicity are documented in children. If desired lipid levels are not attained then drugs from other classes like intestinal cholesterol absorption inhibitors (ezetimibe), bile acid sequesterants and niacin can be used. Low-Density Lipoprotein apheresis is a FDA approved therapy for FH patients. Apheresis is generally done every 1–2 weeks, with each session taking about 3 h and removing greater than 60% of Apo-B-containing lipoproteins. The decline in LDL-cholesterol levels by apheresis is a transitory event and is associated with a rebound escalation of lipid levels after the procedure. Regular apheresis therapy along with medications in patients of HoFH has improved the average life expectancy to over 50 years of age compared to the formerly bleak prognosis of death in the 2nd or 3rd decade.9 ,10 Indications for apheresis are given in Table 3. The FDA has approved 2 novel treatments for homozygous FH individuals older than 18 years of age: lomitapide and mipomersen. Lomitapide is a microsomal triglyceride transfer (MTP) protein inhibitor and mipomersan, an antisense oligonucleotide that causes a reduction in LDL by binding to messenger RNA and inhibiting apolipoprotein B-100 synthesis. Both of these drugs decrease the VLDL secretion from liver. PCSK9 inhibitors are now available as novel therapy for FH. Evolucumab, the PCSK9 fully humanized monoclonal antibody studied in Rutherford trial for HeFH showed that 140 mg of evolucumab subcutaneous every 2 weekly or 420 mg every monthly lowered the LDL cholesterol up to 60%.13

Earlier Reports from India Very few cases of familial hypercholesterolemia have been reported from India.14–17 This is more likely due to lack of awareness of the disease rather than due to its rarity. The earlier reports from India are described in Table 4. Premature atherosclerosis involving all 3 major coronaries, aortic valve, aortic root, aortic arch branches including carotid arteries and aorta distal to left subclavian artery is not reported from India. Our patient is unique as atherosclerotic involvement of all major coronary arteries, aortic root, aortic valve, carotid arteries and descending aorta is seen in our patient.

Conclusion Early diagnosis and prompt institution of therapy with high dose statins to lower the serum LDL-C level will prevent the patient from

developing premature atherosclerosis. If we encounter patient in our routine clinical practice with markedly raised LDL cholesterol level (Tables 1 and 2), his all family members should be screened for skin lesions and lipid levels.

Consent Written informed consent was obtained from the patient for publication of this case report and accompanying Images.

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