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The USMLE is pedantic about how/where in the skin this occurs.
- Vitamin D synthesis is initiated in the stratum basale / basal layer. This specific detail regarding where in the skin is currently being tested on USMLE Step1.
- In the skin, 7-dehydrocholesterol, via UV-B, → cholecalciferol.
- A person who is vitamin D deficient from decreased sun exposure will have ↓ cholecalciferol. There will be normal levels of 7-dehydrocholesterol.
The 25-OH hydroxylation step occurs in the liver.
- Cholecalciferol → 25-hydroxyD3 (calcidiol) in the liver.
- 25-hydroxyD3 is an inactive form.
- If they give you an alcoholic who has vitamin D deficiency, select decreased hepatic hydroxylation as the answer.
- Students frequently get this question wrong because USMLE resources tend to overly fixate on the 1α hydroxylation that occurs in the kidney.
Parathyroid hormone (PTH) induces the 1α (activating) hydroxylation in the PCT of the kidney
- PTH induces the conversion of 25-hydroxyD3 → 1,25-(OH)2-D3 (calcitriol) in the PCT of the kidney.
- 1,25-(OH)2-D3 is the active form of vitamin D3.
- Hypoparathyroidism causes ↓ in 25-OH-D3 and ↓ 1,25-(OH)2-D3.
1,25-(OH)2-D3 causes increased calcium AND phosphate absorption in the small bowel
- BOTH are absorbed more in the small bowel secondary to the effects of vitamin D.
- Vitamin D deficiency therefore causes ↓ calcium AND ↓ phosphate in the serum.
- 1,25-(OH)2-D3 also increases bone resorption.
USMLE wants you to know your arrows for rickets / osteomalacia
| The USMLE likes to turn vitamin D deficiency into an arrow-type question. You need to know:
↓ Ca2+ | ↓ PO43- | ↑ ALP | ↑ PTH ALP levels reflect ↑ osteoblastic activity. PTH binds to and activates osteoblasts (which causes them to express RANK-L in order to activate osteoclasts to break down bone). In rickets/osteomalacia, there is a rise in PTH to compensate for the low Ca2+, so ALP is up. Even if not all patients have ↑ ALP and PTH in real life, this is how the USMLE tests it. |
The rickets / osteomalacia pathologic descriptions are exceedingly HY
- For rickets, classic signs are Harrison sulci (indentations of lower ribs), craniotabes (softening of the skull), and rachitic rosary (bony prominences at the costochondral junctions).
- The USMLE might describe rickets as a child with widened wrists/ankles and marked enlargement of the costochondral junctions.
- Bowing of the tibias (genu varum) is a HY finding in rickets.
- They also want you to know that whereas bone in osteoporosis has a porous, hollowed-out structure, in rickets/osteomalacia, there is disordered bone with ↑ osteoid.
- Osteoid is unmineralized bone.
- Without vitamin D, but the bone cannot mineralize the osteoid because calcium and phosphate levels are insufficient.
- Pseudofractures = a key word / x-ray finding seen in vitamin D deficiency. Just memorize it.
| A 6-year-old boy has genu varum. Calcium, phosphate, ALP, PTH levels?
↓ Ca2+ | ↓ PO43- | ↑ ALP | ↑ PTH |
Chronic renal failure presents a rare exception regarding phosphate
- In chronic renal failure, vitamin D activation via 1α hydroxylation in the PCT may be impaired, leading to ↓ 1,25-(OH)2-D3.
- So you might think, “Well, if we have vitamin D deficiency, then calcium and phosphate are both down.”
- But in renal failure, phosphate is always up no matter what because the kidney can’t filter + secrete it out.
- In other words, despite the vitamin D deficiency, phosphate will be up in renal failure.
- But for vitamin D deficiency in the absence of renal failure, both calcium and phosphate are down.
- In short, renal failure wins when it comes to arrows. Always select high phosphate in renal failure.
| A long-standing diabetic with renal failure has hip pain. X-ray shows a pseudofracture of the femoral head. Calcium and phosphate levels?
Calcium is down; phosphate is UP. |
Hypervitaminosis D is due to granulomatous disease
- High vitamin D levels are not because some girl went to the pharmacy and decided to OD on vitamin D pills. High vitamin D levels are almost always due to sarcoidosis on the USMLE.
- The non-caseating granulomas in the lungs, kidney, etc., in sarcoidosis have epithelioid macrophages that secrete 1α hydroxylase. This increases the active form of vitamin D (1,25-(OH)2-D3) and leads to hypercalcemia +/- hyperphosphatemia.
- Classic hypervitaminosis D presents with high calcium and phosphate, but I’ve seen an occasional question where phosphate is normal. That’s just a heads up so you’re not dumbfounded if/when you encounter that.
- However if you get an arrow question and are forced to choose, always select ↑ calcium AND ↑ phosphate.
Effects of high vs low calcium due to vitamin D levels
- Any time there is vitamin D deficiency and ↓ serum Ca2+, there is the possibility of hypocalcemic tetany.
- In contrast, hypervitaminosis D is associated with hypercalcemia and flaccidity.
24,25-(OH)2-D3 is a storage form of D3 and is asked in a key, HY way
- If a patient has hypoparathyroidism (↓ PTH), there will be ↓ 1,25-(OH)2-D3 and ↑ in 25-OH-D3.
- However, 25-OH-D3 is rapidly converted to a storage form called 24,25-(OH)2-D3.
- For all intents and purposes, memorize 24,25-(OH)2-D3 as being synonymous with 25-OH-D3 if you are confronted with an arrow question.
Miscellaneous
- Breast milk has low vitamin D. If a mother is exclusively breastfeeding and asks about a vitamin that could be optionally supplemented for her child, vitamin D is the answer.
- William syndrome is condition characterized by hypercalcemia 2° to ↑ vitamin D sensitivity. It is AD and on chromosome 7. There are well-developed verbal skills and elfin-like facies. They can be born with supravalvular aortic stenosis. Not a HY condition but shows up once in a blue moon.
- Calcipotriene is a topical vitamin D used in the Tx of plaque psoriasis.
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