Typically, when we see elevated TRIGLYCERIDES in a person’s bloodwork, this is due to their cellular “mailboxes being full.” The Lipoprotein Mailmen are attempting to deliver the mail (triglycerides), and there just isn’t any more room in the Fat Cell and Muscle Cell mailboxes (seen in conditions of INSULIN RESISTANCE). And then in conditions of SEVERE hypertriglyceridemia, there is likely a problem with the Mail Workforce and/or the Mailboxes themselves (which I discuss in the 2nd Edition of “The Home Security System and the Lipid Neighborhood” using a different set of metaphors).
But the topic for today is an unusual situation in which there is a FALSE ELEVATION in triglycerides (pseudohypertriglyceridemia) due to a deficiency in GLYCEROL KINASE. A friend of mine actually requested a discussion about this topic…because LIPIDS FOSTER FRIENDSHIPS!
Ok, so a standard Cholesterol Panel reporting triglycerides is actually reporting the GLYCEROL in your blood. And this almost always works out just fine, since all but roughly 1.8 mg/dL of the glycerol in your blood is part of a triacylglycerol molecule…UNLESS you have glycerol kinase deficiency.
People with glycerol kinase deficiency are unable to convert glycerol to glycerol-3-phosphate, and glycerol-3-phosphate is a key contributor to glycolysis, gluconeogenesis, and triglyceride synthesis. Instead of glycerol being utilized for normal metabolic processes, it accumulates in your bloodstream (and ends up getting peed out in the urine as well). And this is reported as a significant elevation in triglycerides, since the lab doesn’t differentiate between free glycerol and the glycerol that’s part of a triacylglycerol molecule.
Glycerol kinase deficiency is an X-LINKED RECESSIVE condition, so it’s far more common in guys. And occasionally, it can be part of the Xp21 Syndrome. This sounds like a cool “Leveling Up” of one of the characters in my daughter’s Pokemon games, but it’s actually pretty devastating. Not only do these kids end up having glycerol kinase deficiency, they also can have congenital adrenal hypoplasia (underdeveloped and non-functional adrenal glands) and Duchenne’s Muscular Dystrophy (terrible disease where kids end up wheelchair-bound early in life). My Med School mnemonic is that you’ll see GOWER due to no POWER in the legs to remember the characteristic sign where toddlers with weirdly big calves push themselves up using their arms. Super sad.
Thankfully, most people end up with an isolated glycerol kinase deficiency without the other horrific Xp21 components. And although there is some variability in the patient presentation, you could see the following:
–Sometimes these folks with glycerol kinase deficiency actually get hypoglycemic episodes during extended fasting periods. Recall, glycerol contributes to gluconeogenesis. When you haven’t been fasting, glycerol typically has a very minor role in the process of creating your own blood sugar. But with extended fasts, glycerol contributes much more to the gluconeogenic process…and if you can’t phosphorylate glycerol, you might end up getting hypoglycemically hangry.
–But most of the time, you’ll just end up seeing a patient on a bunch of unnecessary lipid-lowering medications with bloodwork that says they have persistently high triglycerides…except it’s just HIGH GLYCEROL! The patient’s only symptoms are angst that his triglycerides won’t go down, frustration that his doctor keeps berating him for assumed non-compliance, and potentially some side effects from all the meds he’s taking!
So how can we determine if this is pseudohypertriglyceridemia without a free glycerol assay, a urine glycerol measurement, and genetic testing? Do we need a Special Friend at a Special Lab?
Well, the more straightforward solution is to LOOK AT THE SERUM SAMPLE. Usually, the blood of folks with super high triglycerides has a layer that looks like Coconut Milk…but folks with glycerol kinase deficiency will have a blood sample that looks like, well, blood. And this can help you keep your fibrates and fish oils on the shelf and save some of your medications for folks who may actually need them😊
BONUS ROUND: If you’re one of the few people actually reading this, you might be wondering, “How do these folks actually synthesize triglycerides without glycerol kinase to make glycerol-3-phosphate?” Well, the majority of triglyceride synthesis comes from the glycolytic intermediate DHAP…DHAP is acted upon by cytosolic glycerol-3-phosphate dehydrogenase (GPD1) to form glycerol-3-phosphate, and then triglyceride synthesis can proceed from there. If glycolysis is D-HAPPENING as usual, you don’t need to worry about glycerol kinase deficiency impeding triglyceride synthesis😊
