International Journal of Cardiology 176 (2014) e15–e19
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Early development of xanthoma and coronary disease in a young female with homozygous familial hypercholesterolemia Xin Zhao 1,2, Liping Bu 1,2, Shengmei Qin 1, Dehong Kong 1, Bing Fan ⁎,1, Junbo Ge ⁎,1 Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
a r t i c l e
i n f o
Article history: Received 1 May 2014 Accepted 29 June 2014 Available online 6 July 2014 Keywords: Homozygous familial hypercholesterolemia Low-density lipoprotein receptor gene mutation Atherosclerotic coronary disease Xanthoma
Familial hypercholesterolemia (FH) has dramatically and extremely high level of low-density lipoprotein cholesterol (LDL-C), which due to mutations in the LDL receptor (LDLR) gene. Patients with homozygous FH (HoFH), whose incidence is 1/1,000,000 [1], are at high risk of premature aortic valvular stenosis and coronary atherosclerosis, so that require intensive multidrug therapy at an early age. In addition, remarkable skin and tendon xanthomas begin to develop early in life. In the current case, a 17-year-old woman with a history of hypercholesterolemia was admitted to the emergency department with repeated chest pain or discomfort, palpitation for 4 years, which worsened and became cough for 1 week. In 2009, she developed chest tightness, palpitation and syncope after activities. Although echocardiograph indicated aortic stenosis and mitral regurgitation, the patient didn't receive any treatment. In August, 2013, because of recurrent symptoms, she underwent a coronary angiogram in another hospital which showed triple vessel lesion and coarctation of ascending aorta (Fig. 1). Under 4-month-
⁎ Corresponding authors at: Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel.: +86 21 6404 1990x2745; fax: +86 21 6443 7078. E-mail addresses: [email protected] (B. Fan), [email protected] (J. Ge). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 2 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2014.06.083 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
medication of rosuvastatin, ezetimibe and clopidogrel, her symptoms still fluctuated. One week ago, she had cough, fever and the inability to lie flat. Hypercholesterolemia was found when she was 2 years old and without management of dyslipidemias. Around 2005, xanthoma arose. She was hypersensitive to aspirin. Her family history cannot be traced since the girl was adopted and no one knew about her biological parents. Physical examination: T: 38.1 °C; P: 118 beats per minute; R: 22 times per minute; BP: 80/50 mm Hg. Skin and tendon xanthomas which are striking in hip, elbows, wrists, knees and ankles (Fig. 2). Increased breath sounds with obvious rhonchi and moist rales. Mild edema in lower limbs. A 3/6 systolic ejection murmur at the apex region and aortic region. Lipid profile is shown in Table 1. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (at the time of admission. January, 2014.) was 21233.0 pg/mL. ECG (at the time of admission. January, 2014.) was V1–4 ST segment 2 mV horizontal elevation. Echocardiograph is shown in Fig. 3. Gene Capture and High Throughput Sequencing of genes related to hyperlipidemia (MyGenostics Co. Beijing, China) showed a homozygous c.541TNC mutation of exon 3, LDLR gene, which was proven by method of Sanger sequence (Fig. 4). It is a novel LDLR gene mutation based on LOVD system at www.ucl.ac.uk/ldlr/ LOVDv.1.1.0/. For HoFH, early high-dose statins may be effective, but the majority will require LDL apheresis, because statins are often relatively ineffective in the treatment of HoFH because their efficacy largely depends on the upregulation of functional LDL receptors in the liver [2]. Lomitapide [3] and mipomersen [4] were specifically approved in 2013 for adults with homozygous FH, if LDL-C level is not controlled with other therapies. In this case, her parents gave up active treatment, so that we cannot follow up the efficacy. Potential conflict of interest None. Acknowledgement of grant support None.
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X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 1. Coronary angiogram. Equipollent type of coronary artery. Irregularity but no stenosis in LM. Diffuse stenosis in proximal and middle segments of LAD, with the uttermost of 80% stenosis. Diffuse stenosis in proximal and middle segments of LCX, with the uttermost of 95% stenosis. Due to coarctation of ascending aorta, a nonselective angiograph by double J catheter showed 90% stenosis at the RCA opening and proximal segment. Plaque and ulcer in ascending aorta. Stenosis at both carotid arteries: 80% at left and 70% at right. Massive diastolic regurgitation of contrast medium to apex region of left ventricle. Normal bilateral renal arteries.
References [1] Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478a–90a.
[2] Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5:S9–S17. [3] Cuchel M, Meagher EA, du Toit TH, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40–6. [4] Hair P, Cameron F, McKeage K. Mipomersen sodium: first global approval. Drugs 2013;73:487–93.
X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 2. Tendon xanthoma (A) and skin xanthoma (B).
Table 1 Lipid profile before and after pharmacological therapy. Date
TC (mmol/L)
TG (mmol/L)
LDL-C (mmol/L)
HDL-C (mmol/L)
August, 2013 (before therapy) January, 2014 (after therapy of rosuvastatin 10 mg q.d. and ezetimibe 10 mg q.d.)
21.48 12.90
1.60 1.93
19.44 11.67
0.88 0.35
TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
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X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 3. Echocardiograph. Left ventricle was dilated with multiple segmental abnormal activity. LVEF: 32%. Left atrium was significantly dilated. Calcification and moderate regurgitation of mitral valve. Coarctation at the root of aorta. Calcification, stenosis and mild regurgitation of mitral valve. Slight pericardial and pleural effusion.
X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 4. FH-related gene detection: Gene Capture and High Throughput Sequencing of genes related to hyperlipidemia (a); Sanger sequence of the LDLR mutation (b).
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Early development of xanthoma and coronary disease in a young female with homozygous familial hypercholesterolemia Xin Zhao 1,2, Liping Bu 1,2, Shengmei Qin 1, Dehong Kong 1, Bing Fan ⁎,1, Junbo Ge ⁎,1 Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
a r t i c l e
i n f o
Article history: Received 1 May 2014 Accepted 29 June 2014 Available online 6 July 2014 Keywords: Homozygous familial hypercholesterolemia Low-density lipoprotein receptor gene mutation Atherosclerotic coronary disease Xanthoma
Familial hypercholesterolemia (FH) has dramatically and extremely high level of low-density lipoprotein cholesterol (LDL-C), which due to mutations in the LDL receptor (LDLR) gene. Patients with homozygous FH (HoFH), whose incidence is 1/1,000,000 [1], are at high risk of premature aortic valvular stenosis and coronary atherosclerosis, so that require intensive multidrug therapy at an early age. In addition, remarkable skin and tendon xanthomas begin to develop early in life. In the current case, a 17-year-old woman with a history of hypercholesterolemia was admitted to the emergency department with repeated chest pain or discomfort, palpitation for 4 years, which worsened and became cough for 1 week. In 2009, she developed chest tightness, palpitation and syncope after activities. Although echocardiograph indicated aortic stenosis and mitral regurgitation, the patient didn't receive any treatment. In August, 2013, because of recurrent symptoms, she underwent a coronary angiogram in another hospital which showed triple vessel lesion and coarctation of ascending aorta (Fig. 1). Under 4-month-
⁎ Corresponding authors at: Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel.: +86 21 6404 1990x2745; fax: +86 21 6443 7078. E-mail addresses: [email protected] (B. Fan), [email protected] (J. Ge). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 2 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2014.06.083 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
medication of rosuvastatin, ezetimibe and clopidogrel, her symptoms still fluctuated. One week ago, she had cough, fever and the inability to lie flat. Hypercholesterolemia was found when she was 2 years old and without management of dyslipidemias. Around 2005, xanthoma arose. She was hypersensitive to aspirin. Her family history cannot be traced since the girl was adopted and no one knew about her biological parents. Physical examination: T: 38.1 °C; P: 118 beats per minute; R: 22 times per minute; BP: 80/50 mm Hg. Skin and tendon xanthomas which are striking in hip, elbows, wrists, knees and ankles (Fig. 2). Increased breath sounds with obvious rhonchi and moist rales. Mild edema in lower limbs. A 3/6 systolic ejection murmur at the apex region and aortic region. Lipid profile is shown in Table 1. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (at the time of admission. January, 2014.) was 21233.0 pg/mL. ECG (at the time of admission. January, 2014.) was V1–4 ST segment 2 mV horizontal elevation. Echocardiograph is shown in Fig. 3. Gene Capture and High Throughput Sequencing of genes related to hyperlipidemia (MyGenostics Co. Beijing, China) showed a homozygous c.541TNC mutation of exon 3, LDLR gene, which was proven by method of Sanger sequence (Fig. 4). It is a novel LDLR gene mutation based on LOVD system at www.ucl.ac.uk/ldlr/ LOVDv.1.1.0/. For HoFH, early high-dose statins may be effective, but the majority will require LDL apheresis, because statins are often relatively ineffective in the treatment of HoFH because their efficacy largely depends on the upregulation of functional LDL receptors in the liver [2]. Lomitapide [3] and mipomersen [4] were specifically approved in 2013 for adults with homozygous FH, if LDL-C level is not controlled with other therapies. In this case, her parents gave up active treatment, so that we cannot follow up the efficacy. Potential conflict of interest None. Acknowledgement of grant support None.
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X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 1. Coronary angiogram. Equipollent type of coronary artery. Irregularity but no stenosis in LM. Diffuse stenosis in proximal and middle segments of LAD, with the uttermost of 80% stenosis. Diffuse stenosis in proximal and middle segments of LCX, with the uttermost of 95% stenosis. Due to coarctation of ascending aorta, a nonselective angiograph by double J catheter showed 90% stenosis at the RCA opening and proximal segment. Plaque and ulcer in ascending aorta. Stenosis at both carotid arteries: 80% at left and 70% at right. Massive diastolic regurgitation of contrast medium to apex region of left ventricle. Normal bilateral renal arteries.
References [1] Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478a–90a.
[2] Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5:S9–S17. [3] Cuchel M, Meagher EA, du Toit TH, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40–6. [4] Hair P, Cameron F, McKeage K. Mipomersen sodium: first global approval. Drugs 2013;73:487–93.
X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 2. Tendon xanthoma (A) and skin xanthoma (B).
Table 1 Lipid profile before and after pharmacological therapy. Date
TC (mmol/L)
TG (mmol/L)
LDL-C (mmol/L)
HDL-C (mmol/L)
August, 2013 (before therapy) January, 2014 (after therapy of rosuvastatin 10 mg q.d. and ezetimibe 10 mg q.d.)
21.48 12.90
1.60 1.93
19.44 11.67
0.88 0.35
TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.
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X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 3. Echocardiograph. Left ventricle was dilated with multiple segmental abnormal activity. LVEF: 32%. Left atrium was significantly dilated. Calcification and moderate regurgitation of mitral valve. Coarctation at the root of aorta. Calcification, stenosis and mild regurgitation of mitral valve. Slight pericardial and pleural effusion.
X. Zhao et al. / International Journal of Cardiology 176 (2014) e15–e19
Fig. 4. FH-related gene detection: Gene Capture and High Throughput Sequencing of genes related to hyperlipidemia (a); Sanger sequence of the LDLR mutation (b).
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