It has two clinical types--heterozygous and homozygous. Heterozygous FH involves a defective gene coming from one parent. The absence of one functional gene, reported the World Health Organization Human Genetics Program (1997), could lead the LDL-cholesterol levels to "rise to approximately twice the normal level early in childhood." It means that these patients have only about half the number of the necessary receptors, which then could lead to the development of symptomatic coronary-artery disease in men at around age 50, and in women at around age 60. It is estimated to be present in one out of every 500 people.

    Homozygous FH, meanwhile, means that the defective genes are inherited from both parents. It deprives a sufferer of practically all the necessary receptors, and could bring cholesterol levels that sometimes go as high as 1,200 mg/dL (a four- or fivefold rise). It could lead to the development of atherosclerosis in children, and may lead to symptomatic CAD in people in their early 20s. The homozygous type is much rarer, estimated to occur in one person out of every million.

    Since FH leads to the development of heart disease in the relatively young--those in their most productive age, or even younger, in many instances even if they adopt a healthy lifestyle--this problem could also have some socioeconomic impact.

"Early diagnosis prevents early death"

    With the growth in the understanding of FH's impact, experts and other health-care professionals established MEDPED (Make Early Diagnosis Prevent Early Deaths), a global collaboration that aims to register, study, and treat people with FH and other inherited cholesterol disorders. Based in the University of Utah, MEDPED estimates that there are close to 10 million FH patients worlwide. Many of these patients are as yet undiagnosed.

    Several countries in Europe, America, and Asia have joined MEDPED to further research, treatment, and education on FH and related conditions. The Philippines is as yet not part of MEDPED.

The first Philippine study

    Although many local doctors suspected that FH is present among Filipinos, nobody really set out to do a formal study of it. Dr. Felix Eduardo Punzalan, assistant chair for research at the Philippine General Hospital (PGH) Department of Medicine, said: "Wala tayong data, walang attempt para tingnan, pero we always talked about it."

    That is, until 2002. With support from the National Institutes of Health (NIH), Punzalan--who was then a member of the NIH research faculty--with Dr. Rody Sy and a team of clinicians, clinical researchers, and geneticists, made the first attempt to know whether FH, indeed, posed a threat to the health of Filipinos.

    The prospective, cross-sectional study examined 60 patients from the participating cardiologists' clinics at the PGH, Manila Doctors Hospital, and Cardinal Santos Medical Center for the presence of the condition and its characteristics, as well as determine what form of mutation in the LDL-receptor genes is present among those who had clinical features of FH.

    Using the Dutch Lipid Clinic Network Criteria in making the diagnosis (see table), the researchers took the participants' clinical history, performed physical examination, and determined their lipid profile. Blood samples were also taken, from which DNA specimens were taken. Using the criteria, a score higher than 8 could mean "certain" FH, a score of 6-8 "probable" FH, and 3-5 "possible" FH.

    This being a genetic study, there were obviously a number of challenges involved. Punzalan recalled that there was a potential "technology problem." However, the Institute of Human Genetics--particularly geneticist Eva Cutiongco, who became coinvestegator--helped in processing the blood and extracting the DNA samples.

    DNA analysis for FH was not offered in any Philippine laboratory at the time. Punzalan said: "We had to for people who had more experience in looking at [this particular genetic abnormality]." The team found Dr. Peter George from the Canterbury Health Laboratories in Christchurch, New Zealand. The 60 genetic samples were sent to George in two batches.

Confirming suspicions--and more

    Thirty-four (57 percent) of the study participants had hypertension, while 25 had coronary-artery disease. They had a mean age of 55 years, to which Punzalan remarked: "Relatively young pa yung 55 years old." The mean level of LDL cholesterol was a staggering 227 mg/dL. Also, a significant percentage of the participants had family history of CAD (60 percent) and dyslipidemia (60 percent).

    The researchers also looked for signs of arcus cornealis (a grayish ring made up of fatty deposits surrounding the cornea) and tendon xanthoma (accumulation of plaques in the tendons).

    As for the genetic part of the study, 12 participants (20 percent) were confirmed to have genetic mutations, all of which are missense or splicing mutations. Eight of those with LDLR mutations had an FH score of 8 and above. Also, it was inferred in the data that those with a strong family history of dyslipidemia had a tenfold chance of having an LDLR gene mutation. Those who had the gene mutation also had higher cholesterol levels (mean = 276 mg/dL).

    The study team was surprised to see that six of those who tested positive for LDLR-gene mutations had novel mutations. Punzalan said they did not expect to see these novel mutations. "Yan yung data na biglang lumabas," he recalled. The researchers, he said, plans on conducting more intensive study on these mutations, which, once they are able to generate more data, they will report to the international community.

Implications

    The study won two awards. At the Philippine Heart Association annual convention last year, it was voted most outstanding research paper. It was also voted one of the outstanding research papers at the University of the Philippines-College of Medicine research forum, held during the third NIH Science Week in February this year. It is also now under consideration for publication in an international journal.

    But word still needs to get out into the rest of the medical community and the rest of country. Punzalan said that they hope the study "can inspire an information campaign." In other words, they hope doctors would be more thoughtful in examining their patients for possible signs of the problem, so that early intervention will be possible, and thus save patients from early death. And since the condition runs in families, careful history taking will help detect those family members who are also at risk.

    They have also started a "limited registry" at the PGH Research Unit, of which Dr. Rody Sy is coordinator. They wish to expand the registry in the near future, and welcome referrals from other physicians in the country.