Familial hypercholesterolemia (FH) is one of the most common genetic disorders characterized by a predominant elevation in plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentration and higher incidence of premature atherosclerotic cardiovascular disease (ASCVD). It has been reported that the long-term coronary artery disease (CAD) and ASCVD risk in the US adults with the FH phenotype are up to approximately five-fold higher than that in the general population. It has also been estimated that there is an important long-term burden of ASCVD in phenotypic but undiagnosed FH patients in the US, with the acceleration of CAD risk by 20–30 years. In recent years, the features of under-diagnosis and under-treatment of FH patients has attained an intensive attention worldwide. This increased risk is age dependent, with the highest relative risk in younger index ages. Notably, several atherosclerosis-related international academic organizations or societies have issued statements or guidelines consequently, which call for the actions to improve the diagnosis and treatment of this unique, treatable disease globally.[3–6] In the Asia Pacific region, FH is estimated to affect at least 15 million people. Among them, China alone may account for more than half of the FH patients as it is the world's most populous country.
The general knowledge regarding FH is not very unfamiliar for medical professionals. Premature ASCVD is a great concern in FH patients due to the extremely high plasma LDL-C concentration. If homozygous FH (HoFH) is left untreated, tendon xanthomas may usually be detected. Since the 1950s, FH patients have been divided into heterozygous FH (HeFH) and HoFH, and diagnosing HeFH and HoFH based on the phenotypic features of ASCVD or xanthomas has frequently been difficult without the DNA analysis of FH genes. With the development of genetic testing technology, multiple studies revealed that a severe defect in the ability to bind and internalize LDL particles was caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR). Recent genetic insights indicate that besides LDLR (approximately 75%–95%), mutations in alleles of other genes including apolipoprotein B (ApoB), proprotein convertase subtilin/kexin9 (PCSK9), and LDLR adapter protein 1 (LDLRAP1) may also be a cause in few FH patients, which can result in impaired LDL metabolism, leading to life-long elevations in LDL-C and increased risk for premature ASCVD.[8–10] Currently, it is estimated that this unique disease of abnormal cholesterol metabolism presents in all racial and ethnic groups affecting 1 of 200–500 individuals worldwide and is now increasingly recognized as a global health issue.[5,6] From the perspectives of theory and clinical practice, FH as a major global public health challenge is even more serious in China.
First, China is the largest country in the world and accounts for nearly one-fifth (18.84%) of the total 6.7 billion of the world's population. A commonly cited estimation of the frequency of HeFH is 1/500 (0.2%), which was calculated from the FH frequency in survivors of myocardial infarction (MI), of <60 years of age in a single study with some assumptive frequencies, including the prevalence of CAD in the population of the US. However, contemporary data have suggested a higher frequency, highlighting that the burden of the disease is increasing including in the Chinese population.[9,10] According to the recently published 2016 Chinese guidelines for the management of dyslipidemia in adults (2016 revised version), the prevalence of dyslipidemia in Chinese adults reaches as high as 40.4% and covered approximately 160 million individuals. This implies that at least seven millions of Chinese individuals may be classified as HeFH according to the commonly cited overall frequency estimation. Furthermore, a Chinese FH patients’ study with a large sample size from Beijing Fuwai hospital has recently reported that 3.5% of the patients were identified with definite/probable FH phenotype (definite, 1.0% and probable, 2.5%). This study enrolled 8,050 consecutive patients undergoing coronary angiography (CAG) due to angina-like chest pain, and FH was diagnosed made using Dutch Lipid Clinic Network (DLCN) criteria and target exome sequencing in LDLR, ApoB, and PCSK9 genes. Simultaneously, another study by the same researchers showed that in 1843 consecutive patients with myocardial infraction (MI), the prevalence of definite/probable FH was 3.9% (7.1% in patients with premature MI and 0.9% in those with non-premature MI). The authors concluded that the prevalence of FH among Chinese patients with MI or undergoing CAG appeared to be common, particularly among those with premature MI. These data strongly emphasize that FH is not uncommon in China. Therefore, FH should be considered as a condition of high concern, and more efforts are needed for its management.
Another challenge is the change in the pattern of lipids during the past several years in China. Although the serum LDL-C concentration and the frequency of CAD may be slightly lower in the Chinese population than those before. With rapid economic growth and lifestyle changes, Chinese populations are experiencing increased cardiovascular risk and cardiovascular disease has become the leading cause of death. A national prospective cohort study performed between 1991 and 2000 reported that 43.8% of deaths in Chinese adults of ≥ 40 years of age were attributable to CAD and stroke. A report from the China National Diabetes and Metabolic Disorders Study (CNDMDS) comprising 46,232 Chinese adults suggests an alarm that levels of total cholesterol (TC) and LDL-C are considerably higher than those previously reported in the general Chinese population. Accordingly, the increasing cholesterol levels have changed the FH phenotype in China, which may be another challenge in its diagnosis.
Moreover, early diagnosis as well as effective treatment strategies in affected children with FH are challenges among experts, especially in China due to the single-child policy. Single-child policy which lasted for more than half of a century, resulted in many single-child families. This phenomenon has a high impact on the family in terms of economics burden, psychological stress, healthcare issues, and domestic happiness. Hence, earlier screening of FH individuals including parent-mediated early diagnosis and intervention is important for single-child families. Hence, parent-mediated early diagnosis and treatment for young children are the best strategies for prevention of premature ASCVD and improvement of survival in FH, especially in HoFH patients in the single-child society setting.
Furthermore, improving public and healthcare professionals’ awareness of FH is another way for early diagnosis of FH. It is worth emphasizing that Chinese medical professionals should be obliged to actively take part in a global call for FH management. In China, many people are unaware of FH, even among medical professionals who are working in well-known hospitals located in the first line cities. To improve the awareness, knowledge, and perception of FH among practitioners and hospitalized patients, a FH survey was recently performed in multiple cardiovascular centers including Beijing, Shanghai, Guangzhou, Wuhan, and Changchun (unpublished data). Surprisingly, among 345 cardiologists and 1,083 hospitalized patients with CAD, <10% of doctors recognized that an individual with plasma LDL-C >6.5 mmol/L might be considered as a diagnosis of FH (probable), and 3% of them answered that a person whose plasma LDL-C levels are > 8.5 mmol/L should be diagnosed as FH. Although as high as 82% of hospitalized patients vaguely considered that lipid disorders could be genetically inherited, only 0.7% of them learned about FH through consultation of a health website before hospitalization. More importantly, <50% of the investigated patients did not recognize that consistent elevated plasma LDL-C level was a risk factor of CAD. Therefore, a program of FH course for professionals and more propaganda for the population are urgently needed to improve the management of FH in China.
Besides early diagnosis, early intervention of FH is crucial for the prevention of CAD. FH represents a major gap in preventive medicine and is clearly a public health problem. Considering the public health challenges that FH poses, gaps in care are currently being addressed by clinicians and researchers worldwide. Treatment of elevated LDL-C concentration in FH involves dietary and lifestyle management and pharmacotherapy. Statins are the mainstay pharmacotherapy and are supported by new evidence. A proportion of patients may need additional therapy with ezetimibe or bile-acid sequestrants. Furthermore, PCSK9 inhibitors are also recommended to treat FH. Without treatment, approximately 50% of men and 30% of women experience an ASCVD-related event by age 50 and 60 years, respectively. Evidence has shown that young adults with 20 years of statin therapy started in childhood had lower rates of both ASCVD-related events (1%) and death (0%) than their affected parent at a comparable age (26% and 7%, respectively), who started statin therapy later in life. According to previous studies,[17,18] 750,000 cases of CAD onset and 10,500 CAD deaths could be prevented if early intervention be employed based on the estimated seven million HeFH patients in China. Hence, early and appropriate intervention is of high importance.
In addition, although China has already developed its own diagnostic criteria for FH, which is simpler and more convenient for clinically early diagnosis, more efforts are needed for its popularization and application. During the past several decades, there were scarce studies focusing on FH in China, which were mainly presented as case reports. More recently, a novel modified system of simplified Chinese criteria for FH has been developed. In this criteria, definite FH could be diagnosed in patients who meet any two out of the three items: LDL-C > 4.8 mmol/L, tendon xanthomas, and DNA mutation, which has similar sensitivity and specificity with the Simon Broome (SB) criteria and the Dutch Lipid Clinic Network (DLCN) criteria demonstrated by a large Chinese cohort. However, these novel criteria need to be generalized in Chinese population. Studies in Chinese general population are required to test and confirm these novel FH criteria.
Finally, China needs more joint efforts to respond to FH-related global call to arms due to the basic features of developing countries and imbalance in economics. As well-known, there is a great difference of health insurance system and economic growth between urban and rural areas in China, which may influence the early-diagnosis of FH in children and adolescents. Early detection of FH is difficult due to lack of conventional physical examination, especially in vast rural areas of rural China. Universal lipid screening is not conventionally used in some parts of rural area. More efforts are needed for FH screening, early diagnosis, and early treatment, such as establishing a special network and foundation, performing a registry study, and strengthening the publicity. The professionals, society, and even government should pay attention to this issue. Universal lipid screening FH in children between the ages of 9 and 11 years and common genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies to improve the efficacy of early identification and management of FH in China.[1,2] China may bear a heavy health burden as the most populous country in the world.[22,23]
FH is a common genetic disease characterized by premature ASCVD, which is associated with higher cardiovascular events but is preventable and treatable. With one-sixth of the world's population of individuals who are living with FH residing in China, the time has come to action for FH individuals. The phenotype of FH in China and other Chinese populations is now comparable to that in Western countries and the prevalence of FH in the general population is also similar. However, only a very small proportion of cases has been identified and treated. Although intensive statin treatment or statin plus ezetimibe or PCSK9 inhibitor is recommended for Chinese FH patients, the LDL-C target is often not achieved. Despite a high progress in FH management in China during the last decade, more efforts are needed to improve the current situation of our patients with FH, including engaging healthcare professionals, developing public awareness campaigns, and establishing national FH alliances. Universal lipid screening in children and common or expanded genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies. Finally, optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of FH patients. In summary, although the progress in FH management has been made in China during the past years, greater efforts are still needed in the future.
This work was partially supported by the Capital Health Development Fund (201614035), and CAMS Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr Jianjun Li, MD, PhD.
Conflict of interest statement
The author has no conflict of interest with regard to the content of this manuscript.
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