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Familial dyslipidemias
There are three that you need to know for the USMLE: type I (hyperchylomicronemia), type II (hypercholesterolemia) and type IV (hypertriglyceridemia). There are plenty of other types but the USMLE won’t assess them. But hey, who’s to say you couldn’t score a 290.
So for the sake of the USMLE, know this concise chart:
| Disorder | Hyperchylomicronemia | Hypercholesterolemia | Hypertriglyceridemia |
| Lab report | ↑ Chylomicrons + TGAs | ↑ LDL | ↑ TGAs |
| Mechanism | Deficiency of Apo-CII or LPL | Deficiency of LDL receptor | ↑ hepatic production of VLDL |
You can remember hyperchylomicronemia is type I because chylomicrons are the 1st out of the intestines. This disorder is due to deficiency of either Apo-CII or LPL (lipoprotein lipase). Apo-CII and LPL are your USMLE buzzwords for type-I familial dyslipidemia.
If you are ever asked about which apolipoprotein allows for delivery of TGAs to tissues, the answer is CII.
Apo-CII is a cofactor for LPL. So both are required for chylomicron release of TGAs into tissues.
The important point about hyperchylomicronemia is that cholesterol and triglycerides (TGAs) are increased. Chylomicrons contain large amounts of cholesterol and TGAs.
When they are absorbed by the gut, they travel to peripheral tissues, where they release TGAs. The release of TGAs into the tissues requires apolipoprotein (Apo) CII and lipoprotein lipase (LPL).
| USMLE lab report shows high TGAs and LDL → answer = Deficiency of Apo-CII or LPL |
If you ever see a question that asks about the location of LPL, and both adipocytes and endothelial surface are answers, endothelial cell surface is correct.
It is at the endothelial surface that LPL converts TGAs into three phospholipids and monoacylglycerol; only these individual components can be absorbed, not the fully assembled TGA itself, so LPL must act at the vascular endothelium before the TGA can enter the adipocyte.
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For familial hypercholesterolemia, one of the highest yield points is that it is autosomal dominant.
The other really high-yield point is that if they give you an LDL level of ~300s mg/dL, the patient is heterozygous, i.e., he or she has a deficiency, rather than absence, of LDL receptors, and generally presents in adulthood; if they give you an LDL level of ~700s mg/dL, the patient is homozygous and has near absence of LDL receptors. The latter will present as a child or adolescent with an MI.
Xanthomas of the Achilles tendon or eyelid are a fairly standard presenting feature of this disorder.
| 300s mg/dL = heterozygous; 700s mg/dL = homozygous |
Treatment is statins (e.g., atorvastatin), which competitively and reversibly inhibit HMG-CoA reductase (the rate-limiting step in cholesterol synthesis).
This leads to increased HMG-CoA reductase mRNA expression (liver increases gene transcription to compensate for inhibited enzyme function). This is an answer on one of the NBME exams.
Statins also indirectly lead to increased synthesis of LDL receptor expression on vascular endothelium. This is because decreased synthesis of cholesterol by the liver leads to more being pulled out of the blood to compensate.
| Statins are competitive and reversible, meaning they increase Km but do not change Vmax. The dose-response curve is shifted to the right, not down. Sounds pedantic, but it’s shown up in a question. |
A side note about statins is that they are the best at reducing morbidity/mortality because they have an antioxidant effect on endothelial cells that transcends the mere LDL-lowering effects.
Ezetemibe, for instance, which directly blocks cholesterol absorption in the small bowel, doesn’t decrease mortality, despite lowering LDL. By all means there are many lipid-lowering agents that could be mentioned, but the USMLE likes you to know the MOA of ezetimibe for whatever reason.
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Familial hypertriglyceridemia presents with an isolated increase in TGAs. They might mention pancreatitis in the vignette, but in general, they’ll drive the fact that only TGAs are up, not cholesterol, and then they’ll ask about the mechanism. LPL or Apo-CII deficiency might be listed, but they’re wrong because deficiency of either would result in elevated cholesterol as well (as we discussed with hyperchylomicronemia). The mechanism of type IV is a simple hepatic overproduction of VLDL, which is composed predominantly of TGAs.
| Fibrates (e.g. fenofibrate, gemfibrozil) are the answer for the best drugs for lowering TGAs. However they can cause myopathy and hepatotoxicity. The risk of myopathy is augmented when combined with statins because of cytochrome (CYP) inhibition. This latter point is an answer on one of the NBMEs. |
| Ezetimibe directly inhibits cholesterol absorption in the gut. |
| ↑ LDL cholesterol = MI ↑ TGAs = pancreatitis |
Another important point is that hypertriglyceridemia is strongly linked to pancreatitis. This means if you get a question that mentions ↑ TGAs but normal cholesterol, and then they ask you what is the most likely symptom, and both chest pain and abdominal pain are answers, abdominal pain is correct over chest pain. Chest pain is the WRONG answer in this scenario. This isn’t to say that clinically a patient couldn’t get chest pain, but PANCREATITIS resulting in abdominal pain is what the USMLE wants you to assume is more likely in isolated triglyceridemia.
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