## Humoral Hypercalcemia of Malignancy (HHM) ### Mechanisms of Malignancy-Induced Hypercalcemia | Mechanism | Hormone/Mediator | Cancers | Effect on Phosphate | |-----------|------------------|---------|--------------------| | **PTHrP secretion (HHM)** | PTHrP | SCC lung, kidney, breast | **Phosphate wasting** (↓ reabsorption) | | **Calcitriol production** | 1,25-(OH)~2~D~3~ | Lymphomas (Hodgkin, NHL) | Phosphate reabsorption variable | | **Osteolytic metastases** | IL-6, TNF-α, RANKL | Breast, myeloma | Local bone destruction | ### PTHrP Mechanism in HHM **Key Point:** PTHrP mimics PTH by binding to the **PTH1 receptor** on osteoblasts and kidney tubules, but the renal phosphate handling differs: 1. **Bone:** Increases osteoclast activation → bone resorption → ↑ serum calcium 2. **Kidney (Proximal Tubule):** Decreases phosphate reabsorption → **phosphate wasting** → ↓ serum phosphate 3. **Kidney (Distal Tubule):** Increases calcium reabsorption → ↑ serum calcium 4. **Kidney (1α-hydroxylase):** PTHrP does NOT reliably stimulate 1,25-(OH)~2~D~3~ production (unlike PTH) ### Why the Distractor is Wrong **High-Yield:** PTHrP causes **hyperphosphaturia** (phosphate wasting), NOT hyperphosphatemia. The serum phosphate is typically **low or normal** in HHM, not elevated. - PTHrP ↓ proximal tubular phosphate reabsorption - Result: ↓ serum phosphate, ↑ urinary phosphate - This contrasts with primary hyperparathyroidism (PTH also causes phosphate wasting, so phosphate is low there too) ### Cancer Associations with PTHrP **Clinical Pearl:** The most common PTHrP-secreting malignancies are: 1. **Squamous cell carcinoma** (lung, skin, esophagus) 2. **Renal cell carcinoma** 3. Breast cancer (especially with bone metastases) 4. Ovarian cancer ### Calcitriol-Mediated Hypercalcemia (Lymphomas) **Mnemonic: CAL-L** — Calcitriol production, Associated with Lymphomas (Hodgkin and non-Hodgkin) - Tumor-associated macrophages express 1α-hydroxylase - Produce 1,25-(OH)~2~D~3~ → ↑ intestinal calcium absorption - Serum phosphate is typically **normal or elevated** (due to calcitriol's phosphate-reabsorbing effect) ### Laboratory Differentiation | Feature | PTHrP-HHM | Calcitriol-Lymphoma | Primary HPT | |---------|-----------|-------------------|-------------| | PTH | ↓ (suppressed) | ↓ (suppressed) | ↑ | | PTHrP | ↑ | Normal | Normal | | 1,25-(OH)~2~D~3~ | Normal/↓ | ↑↑ | Normal/↑ | | Phosphate | ↓ (wasting) | Normal/↑ | ↓ (wasting) | | Urine cAMP | ↑ | Normal | ↑ |
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