Familial Hypercholesterolemia Combined With Sitosterolemia

Abstract

Background

Hyperlipidemia is a heterogeneous disorder with genetic and acquired causes, and severe forms may cause vascular calcification and stenosis. Familial hypercholesterolemia (FH) and sitosterolemia are distinct inherited lipid diseases, yet their co-occurrence has not been previously reported.

Case Summary

A patient with combined FH and sitosterolemia was identified via genetic testing. Single hypolipidemic therapies failed, whereas combined treatment targeting both disorders achieved significant lipid reduction.

Discussion

This is to our knowledge the first reported case of concurrent FH and sitosterolemia, expanding the spectrum of inherited hyperlipidemia and highlighting the value of targeted therapy for dual lipid metabolic disorders.

Take-Home Message

Genetic testing is indispensable for patients with refractory hyperlipidemia to guide precise combined hypolipidemic treatment.

Visual Summary

Visual Summary.

Summary of Case Presentation

A 35-year-old man with refractory hyperlipidemia was diagnosed with concurrent familial hypercholesterolemia and sitosterolemia via genetic testing, which identified homozygous mutations in LDLR (c.691T>C) and a novel ABCG5 (c.1798T>C) variant. Monotherapy with statin or statin plus PCSK9 inhibitor was ineffective, whereas combination therapy (statin + PCSK9 inhibitor + ezetimibe + low–plant sterol diet) significantly reduced lipid levels. The key conclusion highlights that genetic testing guides precision therapy for refractory hyperlipidemia.

Hyperlipidemia refers to excessively high blood lipid levels, which can directly cause diseases that endanger human health, such as atherosclerosis and coronary heart disease.¹ Strong evidence indicates that inherited factors contribute to severe and refractory hyperlipidemia.² Here we report a patient with a combined phenotype of familial hypercholesterolemia (FH) and sitosterolemia, with severe calcification and stenosis of the systemic arteries. Two homozygous mutations on ABCG5 (ATP-binding cassette subfamily G member 5) and LDLR (low-density lipoprotein receptor), proven by exon sequencing, were found in this patient; in addition, different from previously reported mutations, a new harmful mutation on the exons of the ABCG5 gene was identified. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.

History of Presentation

A 35-year-old man came to our hospital for chest pain, which was exertional rather than resting. Physical examination showed a regular heart beat with normal blood pressure, and there was a systolic murmur around the aortic valve area. Tuberous xanthomas in the joints of extremities and lipid deposition in the corner of eyes and corneal arcus were apparent.

Past Medical History

No additional medical history was documented other than refractory hyperlipidemia.

Differential Diagnosis

Considerations included severe FH, sitosterolemia, combined inherited lipid disorders, and premature coronary artery disease.

Investigations

Laboratory examination showed that total cholesterol, low-density lipoprotein, apolipoprotein B, and lipoprotein (a) were increased significantly, while high-density lipoprotein cholesterol was 0.51 mmol/L and apolipoprotein A1 were decreased obviously (Table 1). Echocardiography showed calcification of aortic valves, severe aortic valves stenosis, narrowed aortic valve annulus, calcification of the whole aorta, and weakened motion of the inferior wall of the left ventricle. Coronary angiography reported the stenosis of multiple coronary arteries. Computed tomography angiography presented the calcification of the whole aorta, severe stenosis of the left common carotid artery, and occlusion of right common carotid artery. In addition, severe calcification existed in the initial segment of the ascending aorta, and the lumen was narrowed to 1.4 cm in diameter. However, after 3 cm extending, the lumen returned to 2.7 cm (Figure 1).

Table 1.

Changes in Blood Lipid Levels During Treatment

Drug Treatment	Total Cholesterol (mmol/L)	Triglyceride (mmol/L)	HDL-C (mmol/L)	LDL-C (mmol/L)	Sitosterol (μmol/L)	Campesterol (μmol/L)	Stigmasterol (μmol/L)
Statin	16.51	1.91	0.51	16.17	—	—	—
Statin + PCSK9 inhibitor	15.61	1.72	0.61	13.14	69.94	180.46	28.78
Statin + PCSK9 inhibitor + ezetimibe tablets	8.06	1.35	0.62	6.8	34.23	100.36	15.28

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

Figure 1.

Images Reflecting the Lipid Deposition and Severity of Artery Stenosis

(A) Slit-lamp photograph showing bilateral corneal arcus and orbital lipid deposition, characteristic clinical signs of severe hypercholesterolemia. (B) Clinical photograph of the hand demonstrating tuberous xanthomas on the finger joints, indicative of chronic lipid accumulation and severe dyslipidemia. (C and D) Coronary angiography showing severe atherosclerotic lesions in the coronary arteries (C: left coronary system, D: right coronary system), consistent with acute coronary syndrome. (E) Gross pathological examination of resected vascular tissues showing extensive atherosclerotic plaques with yellowish discoloration and luminal stenosis, confirming severe atherosclerosis. (F and G) Three-dimensional volume-rendered computed tomography angiography revealing extensive atherosclerotic calcifications and dilatation/stenosis of the abdominal aorta (F) and significant vascular involvement of the extracranial cerebral arteries (G), consistent with widespread vasculopathy.

Management

Before entering our hospital, the patient had already been taking 10 mg rosuvastatin calcium tables daily to control blood lipids, but the effect was suboptimal. After being admitted, a PCSK9 inhibitor (evolocumab 140 mg every 2 weeks) was added, but no significant improvement was observed. Considering his youth, severe calcification, abnormal lipid metabolism, and history of close relative marriage of his parents, we suspected gene mutations existing. After obtaining the patient's consent, we performed whole-exon sequencing and found 2 pathogenic mutations related to hyperlipidemia. One was a novel homozygous missense mutation in the LDLR gene (c.691T>C, p.Cys231Arg) located in LA module 3 of the ligand-binding domain, which is associated with FH. The other was homozygous mutation in the exon of the ABCG5 gene (c.1798T>C,Cys600Arg), which has a connection with sitosterolemia. Serum plant sterol concentrations were then measured and were very high (Table 1). Based on this result, the patient was prescribed an additional 10 mg ezetimibe tables daily and was placed on a low–plant sterol diet. Four months later, the patient's blood lipids decreased significantly, with total cholesterol falling from 16.51 to 8.06 mmol/L (Table 1). The changes in the patient's blood lipids during drug treatment are shown in Table 1.

After 4 months of drug treatment, the patient's blood lipids were controlled to reduce serum cholesterol and plant sterol concentrations to guideline-recommended levels, and then the patient requested radical surgery to treat his coronary heart disease, aortic valve, and aortic disease. As for cardiac surgery, we performed bilateral common carotid artery replacement, aortic annulus plastic enlargement (Nicks-Nunez), aortic valve replacement, and coronary artery bypass grafting of the anterior descending branch, circumflex branch, and right coronary.

Homozygous mutations in LDLR often lead to resistance to conventional lipid-lowering drugs such as statins and PCSK9 inhibitors, which is consistent with the poor therapeutic effect before genetic testing was performed.

Outcome and Follow-Up

Regrettably, the patient died 2 days after surgery. The cause of death was considered to be acute left heart failure and pulmonary edema caused by perioperative myocardial infarction.

Discussion

Patients with homozygous FH typically demonstrate resistance to statins and PCSK9 inhibitors because of defective low-density lipoprotein receptor function. Severe and refractory hyperlipidemia is often genetically related, which can cause calcification and stenosis of arteries and valves.^1,2 FH is a common inherited disorder of cholesterol metabolism resulting from mutations in LDLR, APOB, and PCSK9.³ Sitosterolemia is a rare inherited disease characterized by abnormal lipids metabolism resulting from ABCG5 or ABCG8 gene mutations.⁴ To our knowledge, it is the first report of a combined phenotype of FH and sitosterolemia. In addition, a new harmful mutation related with FH was detected. Reviewing the patient's treatment, this kind of hyperlipidemia is effective in the lipid-lowering therapy combining of FH and sitosterolemia. This case gives us a hint, for patients with abnormal lipid levels, that gene detection is necessary when regular treatment is ineffective. Gene detection can help in identifying causes and keeping blood lipid level under control earlier.

The LDLR p.Cys231Arg mutation is located in the ligand-binding domain (LA domain) of the LDLR protein, and both LDLR p.Cys231Arg and ABCG5 p.Cys600Arg are cysteine-to-arginine missense mutations. Cysteine is essential for disulfide bond formation and protein folding, while arginine is positively charged and structurally disruptive. Both mutations occur in highly conserved, functionally critical domains: the ligand-binding domain of LDLR and the nucleotide-binding domain of ABCG5. Based on amino acid properties, structural location, and conservation, these 2 variants are predicted to be pathogenic loss-of-function mutations responsible for FH and sitosterolemia, respectively.

Conclusions

This is to our knowledge the first reported case of concurrent FH and sitosterolemia caused by LDLR and ABCG5 homozygous mutations. Combined lipid-lowering therapy provides effective control of lipid profiles. Genetic testing is critical for precise diagnosis and targeted management.

Funding Support and Author Disclosures

This study was supported by the National Natural Science Foundation of China (82370376 and 82200409). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Message

• •Genetic testing is indispensable for patients with refractory hyperlipidemia to guide precise combined hypolipidemic treatment.