Despite almost 40 years elapsing since Brown and Goldstein’s 1985 Nobel prize in Physiology or Medicine for their ground-breaking research concerning the regulation of cholesterol metabolism, awareness among the general public and health professionals about hereditary conditions such as familial hypercholesterolaemia (FH) remains low.
With a one in 250 general population prevalence, Australia has 100,000 individuals with inherited FH. Currently less than 10% are ever diagnosed and most remain untreated. The situation is similar worldwide with up to 40 million affected.
The increased cholesterol burden is present from birth, with individuals at increased risk of premature heart attacks and death due to the progressive accumulation of atherosclerotic cardiovascular disease (ASCVD).
Inheritance
Early detection and lifelong management are the keys to successful treatment and normal life expectancy. About 50% of first-degree relatives of newly diagnosed index cases will also inherit FH, mainly due to a defect in receptors on their liver cells responsible for removing the ‘bad’ cholesterol (LDL-c) from the circulation. Diet and exercise alone are insufficient to manage it.
Cascade testing of first- and second-degree relatives in a well-organised, systematic manner offers the best opportunity for diagnosis and treatment. The Consensus Statement of the European Atherosclerosis Society and the International FH Foundation recommends that most FH patients be managed in primary care and preferably in the family context.
Provision for management of more complex cases including pregnant women and children should involve specialist FH clinics. A shared-care approach with the patient’s GP is the ideal.
Early diagnosis in children at toddler immunisation stage, or even newborn screening, offers opportunities for reverse cascade testing to parents. This approach facilitates diagnosis of the transmitting parent, the commencement and maintenance of appropriate treatment for the parent and the future treatment of their child from age 8-10 years.
Diagnosis in the toddler with potential to save the life of the FH-affected parent is a powerful argument for this approach. Such early diagnosis allows time to plan and reduce the cumulative cholesterol burden from a young age while simultaneously adding decades of healthy life and the associated socio-economic and societal benefits.
Treatment & genetics
The mainstay of treatment is with statins (based on clinical trials) capable of reducing LDL-c levels by 25-55% when taken regularly; initiation and adherence remain major challenges.
The risks from myocardial infarction and stroke can be reduced. Patient resistance to statins occurs but evidence from randomised trials shows that major side-effects are rare. Most adverse reactions can be managed by switching statins and employing non-statin therapies (e.g., Ezetimibe).
CSK9 inhibitors facilitate the recycling of LDL receptors to the surface of hepatocytes, thereby clearing 60% LDL-c from the circulation. A downside is their two- to four-weekly injection requirements, expense and limited access on the Australian PBS.
Other novel, emerging treatments for FH include Bempedoic Acid (now FDA approved.). It acts upstream of statins inhibiting cholesterol production with no effects on striated muscle or myalgia. Inclisaran (another injectable medication) reduces hepatic synthesis of PCSK9 utilising small interfering RNA therapeutics.
Results from Orion trials show that inclisaran can achieve over 50% reduction in LDL-c levels when combined with statins and/or ezetimibe. Its twice yearly injection and minimal side-effects has potential for less polypharmacy and greater treatment adherence.
The advent of genetic testing for FH on the Australian MBS in May 2020 marked an important landmark opportunity for more accurate diagnosis of FH. Patients meeting FH phenotypic criteria (score of 6+ on the Dutch Lipid Score) can be referred to specialist who can authorise genetic testing.
If genetic mutation is positive, the GP can initiate subsequent genetic tests among first- and second-degree relatives. Appropriate pre- and post-test counselling should be provided to such relatives.
Genetic testing offers diagnostic precision thus facilitating subsequent cascade testing. It also offers GPs a more defined role in recognising close family relatives likely to benefit from genetic testing while also encouraging greater involvement in ongoing care management at the primary care level.
FH is recognised by the UK National Institute for Health and Clinical Excellence (NICE) as the exemplar for personalised medicine – getting the most appropriate medicine to the right patient at the right time for the best outcome. Implementation requires a seamless and adequately funded model of care between general practice, genetic, and specialty services.
– References available on request
ED: Dr Brett is the Director of General Practice and Primary Health Care Research at the University of Notre Dame.
The author is Lead Investigator on NHMRC Partnership Grant, part sponsored by WA Department of Health, into ‘familial hypercholesterolaemia in Australian general practice.’