A Family Affair – Familial Hypercholesterolemia and the Need for Early Detection

Based on a projected prevalence of one in 200 to 300, Singapore has about 22,000 cases of heterozygous familial hypercholesterolemia (FH)1,2,3. However, there is no telling what the real disease frequency is—due to underdiagnosis and undertreatment.

FH is a silent killer. Globally, only about 1% of the approximately 25 million individuals with FH are diagnosed4. Therefore, it is not unusual for someone who appears healthy and at low risk of traditional cardiovascular disease to discover their condition only when a catastrophic cardiovascular event happens.

Truth is, having FH doesn’t necessarily predict a deadly or devastating outcome if detected and treated early—because effective pharmacological therapies are available. They can significantly reduce low density lipoproteins cholesterol (LDL-C) levels and prevent cardiovascular disease development.

The case for genetic testing

“Most doctors are familiar with FH clinical diagnostic criteria such as the Simon Broome Diagnostic Criteria and the Dutch Lipid Clinic Network Criteria. However, the application of these involves taking a number of steps to arrive at a score. The score helps to identify patients with clinical FH which can be confirmed by genetic testing. Those with confirmed diagnosis by genetic testing will then be asked to refer their immediate family members for testing as these family members have a 50% chance of having FH too,” said Associate Professor Tavintharan Subramaniam, Senior Consultant, Department of Medicine, Khoo Teck Puat Hospital (KTPH).

Add to that, genetic testing was not available in Singapore as a clinical standard of care before the rollout of the FHCARE programme at KTPH. A/Prof Tavintharan explained, “We first started offering genetic testing as a means of FH diagnosis in 2015. In the beginning, we focused on referrals with high cholesterol levels from lipid clinics in KTPH. That allowed us to build up capabilities and confidence in genetic testing. Since then, we have gained good traction to garner quite a bit of interest and support among clinicians both within our institution and beyond.”

To date, the FHCARE team has diagnosed over 1,000 FH cases.

Associate Professor Wee Hwee Lin, Saw Swee Hock School of Public Health, National University of Singapore, said, “But let’s not forget that this number is only a fraction of the actual number of persons with FH in Singapore.”

A/Prof Wee continued, “There’s no question about it—if we were to provide support for all FH patients, we’ll need to scale up our existing system in a sustainable and cost efficient manner. This goes beyond the specialists to include FH coordinators and even family physicians in the primary care network. With the clinical implementation pilot under PRECISE, we want to address how we can do that without burdening the healthcare system.”

The push for cascade screening

Familial hypercholesterolemia is a genetic condition that is passed down in families. Hence, identifying and diagnosing the proband—the first person to be diagnosed with FH in a family is just the beginning. Family cascade screening is essential to enable early identification, diagnosis and intervention.

“As important as cascade screening is, only about 40 to 50% of my patients with confirmed FH genetic diagnosis agree to bring their family members for genetic testing. While this is a significant improvement over the less than 10% when we first started, we will need to improve this number further to be effective,” A/Prof Tavintharan shared. Cascade screening is key to avoiding delay in diagnosis—allowing opportunity for early, effective and preventive treatment.

For that to happen, a few challenges need to be addressed first. The lack of a standardised cascade screening programme in the current clinic setup means that probands mostly remain uninitiated about the potential disease risk of their family members. But even when they are aware, family dynamics could pose barriers for communication with their family members. As a result, acceptance rates for cascade screening are impacted.

A/Prof Tavinatharan said, “The good news is we are changing the conversation surrounding cascade screening with a clinical implementation pilot. With the support of PRECISE, we have established partnership with an accredited sequencing partner locally. We hope the faster turnaround of reports, plus the 150-day window for first-degree family members to get free testing, will make family members of probands more receptive to come forward for cascade screening.”

A sustainable effort in navigating FH challenges

“Indeed, we have made some good headway with the pilot. Over the past few months, we have engaged clinicians in meaningful discussions on support needed for scaling up the pilot. We are also very encouraged by the good recruitment rates—which is a good motivation for us to expedite the establishment of data sharing agreements and ramp up manpower, for instance,” A/Prof Wee said.

“Next, we are exploring to leverage technology for scaling up. Can we use an algorithm to screen people in the electronic medical records system but who are not in our clinics and may not have considered that their high lipid levels at a young age is potentially problematic? This widens our reach to more people who are potentially at risk of having FH with minimal manpower. Separately, we are also looking to use technology to facilitate conversations around cascade screening.”

A/Prof Tavintharan said, “Ultimately, FH can be readily treated and is easily detected. But it all starts with better awareness and education around FH, and for probands and cascades to come forward and accept treatment early. Together, we can work towards delaying or even preventing the onset of coronary diseases.”

Read more about PRECISE’s clinical implementation pilots here.

This project is supported by the National Research Foundation, Singapore, through the Singapore Ministry of Health’s National Medical Research Council and the Precision Health Research, Singapore (PRECISE), under PRECISE’s Clinical Implementation Pilot grant scheme.

[1] Benn, M., et al., Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab, 2012. 97(11): p. 3956-64.

[2] Shi, Z., et al., Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population. Int J Cardiol, 2014. 174(3): p. 834-6.

[3] Watts, G.F., et al., Prevalence and treatment of familial hypercholesterolaemia in Australian communities. Int J Cardiol, 2015. 185: p. 69-71.

[4] Hu, P., et al., Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease. APA Journal, 2020. Volume 141 (22): p. 1742-1759. https://doi.org/10.1161/CIRCULATIONAHA.119.044795