Recognising familial hyperlipidaemia in adult patients in primary care

Dorcas Yan 甄多嘉, Kwai-sheung Wong 黃桂嫦, Catherine XR Chen 陳曉瑞

HK Pract 2023;45:97-101

Summary

摘要

The Case

Ms. Chung is still attending our follow-up clinic at the moment. However, she was seen in our General Outpatient Clinic (GOPC) of the Hospital Authority in August, 2021 for skin nodules for 3 months. The skin nodules first appeared on her elbows on both sides, which then extended to her forearms, knees and down to her feet dorsum. The nodules were not associated with pain or itchiness. There was no skin rash, joint pain, or fever, neither history of gout nor rheumatoid arthritis. There was no recent special contact history and she had not taken any herbal medicine or drugs from over the counter. Her blood pressure had been satisfactorily controlled all along with good drug compliance. Up till now, she has no chest pain or shortness of breath, and has maintained a healthy diet and lifestyle. She has never smoked nor consumed alcohol.

In 2021, her general condition had been good. Physical examination was satisfactory. Her clinic blood pressure (BP) was 128 / 76 mmHg, pulse 76 beats per minute, and she was not obese clinically.

There were crops of erythematous papules over the extensor surfaces of both her forearms and knuckles, sparing the palmar crease (Figure 2). There was no arcus cornealis or xanthelasmas. At the time of her visit, clinically she was euthyroid.

Figure 1:

Figure 2:

Lipid profile done in June, 2018 when she was first diagnosed with hyperlipidaemia was: total cholesterol (TC) 8.5 mmol/L, high-density lipoprotein (HDL) 1.5 mmol/L, low-density lipoprotein (LDL) 6.2 mmol/L, and triglycerides (TG) was 1.7 mmol/L. Her liver, renal, thyroid function tests and fasting sugar level were all normal. She was advised to have lifestyle modifications and Rosuvastatin 20 mg was prescribed for the lipid control. Blood tests in July, 2021 showed that TC was down to 6.6 mmol/L, HDL was 1.6 mmol/L, LDL was 4.5 mmol/L, and TG was 1.1 mmol/L. Annual ECG examination showed normal sinus rhythm without ischemic changes.

In light of the strong family history of CVD, the typical physical examination findings and the very high LDL level, the most likely diagnosis of the skin nodules for this lady was cutaneous xanthomas due to her underlying disease of familial hyperlipidaemia (FH). Hence, Rosuvastatin dose was stepped up to 40 mg daily, and the patient was reinforced on lifestyle modifications.

Year 2021

Her lipid profile in November, 2021 showed that TC was 5.0 mmol/L, HDL was 1.6 mmol/L, LDL was 3.0 mmol/L, and TG was 1.1 mmol/L. As the LDL level remained suboptimal, self-financed Ezetimibe (FDAapproved in 2002) 10 mg daily was added on top of Rosuvastatin to intensify the LDL control. Her latest blood tests in March, 2022 showed a satisfactory lipid control with TC 3.6 mmol/L, HDL 1.7 mmol/L, LDL 1.4 mmol/L, and TG 0.9 mmol/L. Ms. Chung was arranged to have continued follow up (FU) with regular monitoring of the lipid profile.

Discussion

Heterozygous familial hyperlipidaemia (HeFH) is one of the most common genetic disorders in the general population across the world, with a prevalence ranging from 1: 200 to 1:311.^1,2 The prevalence of HeFH in Hong Kong remains unknown, but large population studies from mainland China using the Chinese modified Dutch Lipid Clinic Network (DLCN) definition revealed that the crude prevalence of HeFH was 0.28% to 0.35%^3,4, which is slightly lower than that of the western population. HeFH is an autosomal dominant condition caused by genetic mutations related to the LDL receptor pathway, with high levels of LDL leading to the premature development of atherosclerotic cardiovascular disease. If left untreated, men and women with HeFH typically develop coronary heart disease before the ages of 55 and 60 years, respectively; 50% of men and 15% of women die before these ages.^5,6 Despite its prevalence and potential severe consequences, FH remains underdiagnosed and undertreated globally.^6,7 Therefore, concerted efforts among all health care workers, particularly in primary care, should be made to enhance the awareness of FH.

A number of diagnostic criteria for FH have been reported in the literature, such as the Simon Broome Register Diagnostic Criteria and the DLCN Diagnostic Criteria (Table 1 & 2).^8,9 There is no consensus on which set of criteria is superior than the other. The diagnosis of FH mainly takes into account the patient's personal history, family history, clinical signs such as tendon xanthomas and arcus cornealis, as well as the much elevated LDL levels.¹⁰

Tendon xanthomas are white or yellow cholesterol deposits over the extensor tendons, typically the Achilles, subpatellar and hand extensor tendons. They are considered pathognomonic and specific for the diagnosis of FH.^10,11 Secondary causes of hyperlipidaemia including hypothyroidism, nephrotic syndrome, obstructive liver diseases, steroid use, and excessive alcohol intake should be ruled out before the diagnosis of FH is established.¹²

In general, physicians should consider the possibility of FH in patients with premature coronary events and whose TC is over 7.5 mmol/L, or LDL is over 4.9 mmol/L.^2,9,12

Local guideline recommend a lower LDL threshold- the possibility of FH should be considered in patients with family or personal history of premature coronary events and LDL > 4.5 mmol/L.¹¹ Our patient Ms. Chung fulfilled the Simon Broome Register Diagnostic Criteria of definite FH based on her strong family history of CVD, in particular two of her siblings dying of myocardial infarction at 60 years old, the presence of tendon xanthomas over her forearms, as well as her sky-high TC and LDL level (8.5 mmol/ L and 6.2 mmol/L respectively) before treatment. She also fulfilled the DLCN Diagnostic Criteria of definite FH with a total score of 10. The otherwise normal laboratory findings excluded the possibility of a secondary cause accountable for her hyperlipidaemia.

Diagnosis of FH is often made based on the clinical information and the laboratory findings. Although genetic testing is usually not needed, a positive genetic test with FH gene mutation is associated with a significantly higher cardiac risk.¹⁰ Locally, genetic testing is available at Clinical Genetic Service of the Department of Health¹¹ or in advanced private diagnostic centers. CVD risk assessment tools such as those based on the Framingham algorithm should not be used for people with FH. This is particularly important to note for healthcare professionals in the primary care setting as patients with FH are already considered as having a high risk of developing CVD.

Multiple factors modify the risk of HeFH, such as male sex, smoking, presence of diabetes mellitus, hypertension, subclinical coronary atherosclerosis, lower HDL and higher lipoprotein(a) levels.¹³ Our patient Ms. Chung has not been diagnosed to have HeFH until she is 75 years old and fortunately she has not suffered from a CVD attack until this moment. Female gender, well controlled BP, her healthy lifestyle and lack of other CVD risk factors such as smoking or diabetes mellitus might have helped to reduce her overall CVD risk. Indeed, HeFH is easily missed or underdiagnosed in primary care. All family physicians are advised to enlist HeFH as one of the differential diagnoses whenever a dyslipidaemia patient is encountered.

Timely and effective lipid control improves the life expectancy of patients with FH. The management of FH consists of counselling, family screening, lifestyle advice, treatment of CVD risk factors and intensive lipid-lowering therapy starting early in life. Physicians could counsel patients regarding the implications and mode of inheritance of FH. Family screening should be offered as half of the patient’s first-degree relatives could be affected.⁵ Screening can be done by measuring the LDL levels, carrying out genetic analyses, or both.^7,8 Apart from counselling and family screening, physicians should promote positive lifestyle changes, advocating for healthy diet, regular exercises, weight reduction, and

Table 1:

Table 2:

smoking cessation if the patient smokes.⁹ High-intensity lipid-lowering therapy, such as maximum tolerable dose of statin, is the cornerstone of FH management. Ezetimibe is considered as second line treatment if LDL fails to be adequately controlled by statin alone^9,11, and bile acid sequestrants or niacin are considered as third line choices.⁷ If these agents are exhausted, patients could be referred to specialists for considering proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors treatment.^11,12

With regard to the target of LDL control, most guidelines recommend a LDL target of below 2.6 mmol/ L, or at least a 50 % reduction in LDL cholesterol for the primary prevention of CVD.⁷ A LDL target of below 1.8 mmol/L is used for secondary prevention in patients with established CVD.¹¹ Australian and European Society of Cardiology guidelines suggest a stricter target of LDL < 1.4 mmol/L for patients with clinical evidence of atherosclerotic CVD.^7,12

For our patient Ms. Chung, her LDL level of 4.5 mmol/L in July, 2021 was apparently not adequately controlled and therefore Rosuvastatin dose was stepped up. After the dose augmentation, her LDL level had improved, though remained suboptimal. To further reduce her CVD risk, Ezetimibe was added on top of the statin treatment, which successfully brought her LDL level down to target. Ms Chung’s clinical condition will be regularly reviewed and her lipid profile will be closely monitored in future FUs.

Referencess

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