家族性高膽固醇血症的診斷與治療新進展

Updated Guidelines for the Diagnosis and Treatment of Familial Hypercholesterolemia

隨著篩檢技術的普及和遺傳醫學的發展，家族性高膽固醇血症(familial hypercholesterolemia, FH)已逐漸揭開其神秘面紗，如今證據顯示其與心血管和腦血管疾病高度相關，且如果可以早期診斷並及時介入治療，將可大幅改善病人的生活品質和預期壽命。

家族性高膽固醇血症為體染色體顯性遺傳，根據基因型可分為同型合子(HoFH)和異型合子(HeFH)。HeFH的病人，低密度脂蛋白膽固醇(low-density lipoprotein cholesterol, LDL-C)通常在200-400 mg/dL之間，若不治療其心血管風險將是健康人的十倍。HoFH的病人之LDL-C數值更高，通常高於500 mg/dL，且容易出現嚴重的心血管併發症。

有早發性心血管疾病的家族史和高血脂症相關的理學檢查可初步篩檢並幫助家族性高膽固醇血症的診斷，更詳細的診斷標準可參考Dutch Lipid Clinic Network (DLCN)和台灣血脂異常防治共識中的家族性高膽固醇血症篇章。

根據台灣的家族性高膽固醇血症治療指南，成人LDL-C的治療目標是低於100 mg/dL，兒童則是低於135 mg/dL。美國和歐洲方面對危險因子的分析更為細緻，也設定了更嚴格的LDL-C治療目標。在降血脂治療方面，除傳統的史他汀類藥物，膽汁酸結合樹脂，膽固醇吸收抑制劑和菸鹼酸外，新型藥物如evolucumab或alirocumab等PCSK9抑制劑也被證明具有優異的療效。此外一些新興藥物也顯示出令人滿意的療效，但在台灣尚未獲得批准，例如MTP抑制劑(lomitapide)、反義寡核苷酸(mipomersen)、雙苯甲酸(Nexletol)等。在2019年歐洲心臟病學會上提出的inclisiran之有效性和安全性已得到證實，有望在將來成為對抗高膽固醇血症的利器。

總結而言，家族性高膽固醇血症作為一種遺傳性疾病，相對而言並不罕見；可憑藉台大醫院次世代定序的分子基因學工具，並根據台灣FH建議診斷標準，做出診斷。家族性高膽固醇血症治療之黃金標準，為使用高效價之statin，甚或合併使用ezetimibe或PCSK-9抑制劑，積極使血中LDL-C濃度達標：併有冠心病之病人為70 mg/dL，無冠心病之病人為100 mg/dL。早期診斷與積極治療FH病人，在預防心臟病學上堪為一重要標的。

 

Familial hypercholesterolemia (FH) is highly correlated with cardiovascular and cerebrovascular diseases. With the development of advanced screening techniques and genetic medicine, previous mystery surrounding FH has been gradually unveiled to facilitate in-time diagnosis and treatment. Early intervention of the genetic condition has shown to have positive influence on patients’ prognosis and qualify of life.

FH as an autosomal dominant genetic disorder can be divided into homozygous FH (HoFH) and heterozygous FH (HeFH) by genotypes. In patients with HeFH, the low-density lipoprotein cholesterol (LDL-C) can be as high as 200-400 mg/dL, and the cardiovascular risk is ten times higher than that of healthy people if left untreated. For patients with HoFH, the LDL-C is even higher (usually above 500 mg/dL), making them more vulnerable to severe cardiovascular complications.

Family history of early cardiovascular disease and hyperlipidemia-associated physical examination identifying the presence of corneal arcus, tendon xanthoma and eruptive xanthoma are suggestive of the diagnosis of FH. Details of the FH diagnosis can be found in the Dutch Lipid Clinic Network FH criteria and the Taiwan FH diagnostic criteria.

According to the Taiwanese guidelines, the goal of treating FH is to bring LDL-C down to 100 mg/dL or below in adults and 135 mg/dL or below in children, while the practice of risk factor analysis is more delicate and the treatment goals more rigorous in the United States and Europe. In terms of lipid-lowering therapy, in addition to traditional statins, bile acid-binding resins, cholesterol absorption inhibitors, and nicotinic acid, novel agents such as evolucumab or alirocumab and other PCSK9 inhibitors have also reported excellent efficacy. There are several other emerging medications showing satisfactory effectiveness but still in need of approval in Taiwan, such as MTP inhibitors (lomitapide), Antisense oligonucleotide (mipomersen), and bempedoic acid (Nexletol). Meanwhile, with its efficacy and safety confirmed now, inclisiran, first proposed at the 2019 European Society of Cardiology, can be expected to become a promising medication against hyperlipidemia in the future.

In conclusion, FH is not a rare hereditary disease and can be diagnosed by molecular genetic methods based on the National Taiwan University Hospital FH next-generation sequencing platform and the Taiwanese FH criteria. The gold standard treatment of FH should be aggressive with high potency statins alone or combined with ezetimibe or PCSK-9 inhibitor, striving to reduce serum LDL-C to 100 mg/dL or below for those without coronary heart disease, and to 70 mg/dL or below for those with coronary heart disease. Early diagnosis and aggressive treatment of patients with FH is a good example of preventive cardiology.