High Lp(a)

Hi Lisa,
 
I tried to comment on your interesting Lp(a) family on the NLA web site but was stymied  (I am sure it is e-challenged me – not the site).
 
Your family has good questions.  And of course we all have more questions about Lp(a) than answers – but not for lack of trying to understand.  This follows from the PedAL exchange on Lp(a) back in May last year.  I had sent the link for a very informative ‘Biomarker Bliki’ linked on the Lp(a) Foundation site written by Tom Dayspring and Joe McConnell (HDL Inc). I went back to that and then ran your case by Tom who is always so gracious with his encyclopedic knowledge.
 
The gist of our exchange:
1)     If we extrapolate from the insight measurement of LDL particles has lent to our understanding of LDL-cholesterol risk, the question on the Lp(a) risk curve at the extremes is hard to answer – as we have not yet mastered Lp(a) particle quantification.  So many factors modulate the risk associated with Lp(a) in a given person: specific SNPs, the isoform present, the amount of oxidized phospholipids on the lysine binding domains, total LDL-P and any number of inflammatory cardiometabolic risk factors, that we are a long way from answering this question. In the meantime, Tom Dayspring did not see what exposing such children to a CT angiogram would accomplish and suggested we start with noninvasive imaging tools - such as PWV and CIMT. Especially since (see #3), they each seem to be at ~half as much Lp(a) risk as father.
 
2)     When pediatric patients with elevated Lp(a) are sent to me from hematology where they have presented for a thrombotic event and work up – the Lp(a) is seldom in isolation – ie there is usually Factor V Leiden or other inherited clotting tendencies (or smoking).  I always counsel young women in this category to avoid OCP that contain estrogen for sure.  Data are conflicting for contraceptive patches and Depo-Provera injectable progestin-only preps. In the absence of clear guidelines I am conservative.  Our pedi gynecologist recommends a levonorgestrel-containing Mirena IUD when there is a contraindication to estrogen – especially if there is also menorrhagia.
 
It is a little harder to be OCP-aversive for female patients who have had elevated Lp(a) identified in isolation of symptomatic thrombotic events and/or other thrombotic risk factors.  In these cases Tom Dayspring was very clear to say the effect of estrogen is not known with certainty. Low doses of estrogen in menopausal hormone therapy actually reduce Lp(a) mass and possibly reduce clinical atherothrombotic events but there is no data on what estrogen does to Lp(a)-particles. Very high levels of estrogen during pregnancy raise Lp(a) mass. There is no data on what the Lp(a)-mediated risk is with different forms of OCP. So low-dose estrogen-containing OCP might be OK in presence of isolated Lp(a) elevation but my feeling is- since there are some other alternatives – we might counsel young girls carrying elevated Lp(a) in those alternate directions while we learn more.
 
3)     Lp(a) will increase transiently with inflammation (mostly small movement within its inherited risk stratum- unless there is some major inflammatory insult like nephrosis that can skyrocket Lp(a)).  That said, age is one of the chronic ‘inflammatory’ conditions we can slow down or accelerate but never totally avoid – so levels will likely climb a bit over time – again within the inherited risk category based on the apo(a) phenotype.  These kids each likely care one small MW isoform – their levels may drift up but I would not expect either to ever have a level as high as their dad.
 
It looks from what you have shared like father is homozygous positive for two small apo(a) isoforms.  I would imagine, given the wide range between the two children who are otherwise close in age that mom has large apo(a) isoforms and each child is heterozygous for only one of dad’s alleles (209 vs 278 nmol/L- each only ~one half of dad’s 478 nmol/L – crazy how strictly Mendelian apo(a) inheritance is).  Paternal Grandfather who had later onset of disease than father maybe carried the smaller of the two (Lp(a) ~ 278nmol/L) and paternal grandmother whom you don’t mention was maybe protected longer by having a slightly larger allele and slightly lower Lp(a) (predicted ~209) and by being female – father may have then inherited a small allele from both of his heterozygous parents.
 
The kids should not therefore have the same risk for such brutally early onset of CVD as father - though once in adulthood, they will need something to keep their LDL’s low as their heterozygous levels are still plenty high to avoid a risk trajectory resembling grandfather.  Especially the little girl if that was a fasting lipid profile and she indeed also has a combined hyperlipidemia (with increased TG and lowish HDL-c for a young female).  In adults, statins lower the risk of Lp(a) without reducing Lp(a) mass. There are obviously no pediatric data or treatment guidelines for Lp(a) in kids.
 
Every time one of these Lp(a) cases arise I am reminded we should really put our heads and collective practices together on this issue!
 
Thanks for keeping the conversation going Lisa.  Hope this helps.  Sorry I could not figure out how to post his on the NLA site!
 
Best regards,
 
Michele
 
_______________________________________
Michele Mietus-Snyder, MD
Co-Director, Children's National Obesity Institute
Center for Translational Science
Associate Professor, George Washington University
Children’s National Health System
111 Michigan Ave NW, 2M-2155
Washington DC, 20010
Ph: 202-476-5161
Email: mmsnyder@childrensnational.org