Calcium and Phosphate Disorders Flashcards
Calcium Disorders
- Hypercalcemia
- Hypocalcemia
- Vitamin D Disorders
Hypercalcemia
- Cancer – Bone marrow malignancies, osteolytic metastases, humoral hypercalcemia of malignancy
- Hyperparathyroidism
- Intoxication with Vitamin D
- Milk-alkali Syndrome – Excess ingestion of calcium plus alkali such as calcium-carbonate (antacids)
- Paget’s Disease – Accelerated bone turnover
- Sarcoidosis – Increased conversion of Vitamin D to active form by macrophages
- FBHH
- HHM
The Main Players
- Four organs are vital for maintaining serum calcium and phosphate levels:
- Small intestine – absorbs dietary calcium and phosphate from the environment
- Kidney has two roles:
- Excretes serum calcium and phosphate
- Synthesizes calcitriol (1,25-dihydroxy vitamin D)
- Bone – serves as a store for both calcium and phosphate
- Parathyroid – secretes PTH
Hypercalcemia Effects
•Central nervous system:
- Lethargy and depression
- Ataxia
•Neuromuscular:
- Hypertonia
- Weakness, proximal myopathy
•Cardiovascular:
- Hypertension
- Bradycardia
•Renal:
- Polyuria and decreased glomerular filtration
- Nephrolithiasis
Hyperparathyroidism
•Primary Hyperparathyroidism
-Due to overgrowth of parathyroid tissue
•Secondary Hyperparathyroidism
-Due to chronically depressed serum calcium levels (usually due to renal failure or intestinal malabsorption)
•Tertiary Hyperparathyroidism
-Long-standing secondary hyperparathyroidism—> PTH secretion becomes autonomous
7 Associated Clinical Findings in Hyperparathyroidism
- Bone disease – May range from generalized mild decalcification to osteoporosis with increased incidence of fractures
- Renal stones (nephrolithiasis) – This may be the only manifestation in 20% of patients.
- Gastrointestinal abnormalities - Peptic ulcers, pancreatitis and gallstones.
- CNS alterations – Depression, lethargy and seizures.
- Neuromuscular abnormalities.
- Metastatic calcifications – Primarily involving gastric mucosa, kidneys, lungs, heart valves (aortic and mitral), systemic arteries and pulmonary veins. Metastatic calcification in the kidney (nephrocalcinosis) leads to chronic injury of the tubules and interstitium, with subsequent progression to renal failure if untreated.
- Osteitis Fibrosa Cystica - Severe hyperparathyroidism characterized by generalized decalcification of bone, bone cysts and “brown tumors” (not a true neoplasm, brown tumors are caused by influx of multinucleated macrophages and reparative fibrous tissue within decalcified bone, excessive osteoclast activity), multiple fractures, renal stones and increased alkaline phosphatase. This constellation of findings is now rarely seen due to early diagnosis of hyperparathyroidism in current clinical practice.
Pathology of Hyperparathyroidism
• ademonas > hyperplasia >>> carcinoma
Hyperparathyroidism - Adenomas
- present in 85-95% of the patients with primary hyperparathyroidism.
- Most are sporadic adenomas.
- 10-20% of adenomas have an inversion on chromosome 11, relocating the cyclin D1 gene adjacent to the 5’-PTH regulatory sequences and resulting in overexpression of cyclin D1 (a major regulator of the cell cycle), leading to cell proliferation.
- Most adenomas are monoclonal and considered true neoplasms from a single progenitor cell.
Hyperparathyroidism - Adenomas - Gross
- Adenomas are usually solitary, although multiple adenomas have occasionally been described.
- Most adenomas weigh between 0.5 to 5 gm and have a thin, delicate capsule.
- They may be tan, orange-brown, or red-brown, and may have cystic spaces.
- Adenomas are usually found in the central neck, within or adjacent to the thyroid, but may also occur in the anterior mediastinum.
Brown Tumor - Gross
- Not a true neoplasm
- Localized area of bony destruction due to excess osteoclast activity in the setting of hyperparathyroidism
- Loss of bony trabeculae, cyst formation, replacement by brown tissue
Brown Tumor - Microscopic
- Not a true neoplasm
- Localized area of bony destruction due to excess osteoclast activity in the setting of hyperparathyroidism
- Microscopic: Loss of bony trabeculae, proliferation of osteoclasts and fibroblasts, hemorrhage and hemosiderinladen macrophages
Hyperparathyroidism - Adenoma - Microscopic
- The enlarged gland usually contains a marked decrease in fat cell content.
- Often, the parathyroid cell population appears monotonous and homogenous.
- The cells usually have bland nuclear features, although focal atypia may be seen (pleomorphism, nuclear enlargement).
- Note: Foci of atypical cells are often identified in various endocrine neoplasms (so called “endocrine atypia”) but does not imply malignancy or aggressive behavior.
- Classically, a small rim of normal parathyroid tissue (with normal fat content and cellular composition) may be seen compressed to one side of the adenoma.
- In a true adenoma, the uninvolved glands should be normal in size and histologic composition.
Hyperparathyroidism - Adenoma - Microscopic
•The cells usually have bland nuclear features, although focal atypia may be seen (pleomorphism, nuclear enlargement). Note: Foci of atypical cells are often identified in various endocrine neoplasms (so called “endocrine atypia”) but does not imply malignancy or aggressive behavior
Hyperparathyroidism - Adenoma - Microscopic
•Classically, a small rim of normal parathyroid tissue (with normal fat content and cellular composition) may be seen compressed to one side of the adenoma
Hyperparathyroidism - Hyperplasia
- prevalent in about 5-10% of patients with primary hyperparathyroidism.
- Primary parathyroid hyperplasia may be sporadic or occur as a component of MEN syndrome.
- On microscopic examination, hyperplastic glands appear similar to adenomas, but tend to have slightly more fat and appear more heterogenous.
- In contrast to adenomas, several glands are enlarged and hypercellular.
- Classically, all four glands are involved.
-However, the changes may be asymmetric, with relative sparing of one or two glands, which can make the distinction between hyperplasia and adenoma difficult prior to surgery.
•However, nowadays the distinction between adenoma and hyperplasia is not necessary clinically.
- Rapid intraoperative parathyroid hormone levels are performed during surgery, before and after a parathyroid gland is removed.
- If there is a sufficient drop in parathyroid hormone after the largest gland is removed, then the surgery will stop, and no other glands will be removed.
- Otherwise, the surgeon will remove the next parathyroid gland, and so on until the parathyroid hormone drops enough.
Hyperparathyroidism - Hyperplasia
Hyperparathyroidism - Hyperplasia
Endocrine Atypia
- Concept in endocrine pathology (parathyroid, adrenal, thyroid, and other endocrine tissues)
- Benign proliferative lesions such as hyperplasias or adenomas may show significant nuclear atypia, including pleomorphic or bizarre looking nuclei
- However, this means nothing diagnostically: it does not predict malignant versus benign behavior
Hyperparathyroidism - Carcinoma
- a very rare cause of primary hyperparathyroidism (<1%).
- It may be suspected when the surgeon encounters an enlarged, firm mass adherent to the surrounding tissues.
- Some common features of malignancy include trabecular growth pattern, mitotic figures, thick fibrous capsule, and capsular and/or blood-vessel invasion.
- However, the diagnosis is based primarily on tumor behavior (invasion of surrounding tissues and metastasis).
Hyperparathyroidism - Carcinoma
Humoral Hypercalcemia of Malignancy
- HHM occurs in cancer patients without bony metastases, often in association with squamous cell carcinoma of the lung.
- It is a major contributor to morbidity and complicates clinical management.
- The hypercalcemia is caused by tumor secretion of PTH-related protein (PTHrP).
- As the name implies, this hormone is similar to PTH – similar enough to bind to PTH receptors and produce the symptoms of hyperparathyroidism.
- PTH itself is not increased in plasma from HHM subjects.
- Unlike PTH, which is feedback regulated by calcium, the tumor autonomously produces PTHrP to elicit uncontrolled hypercalcemia.
Plot of Intact PTH vs. Calcium
•Figure 1 depicts a plot of intact PTH as a function of serum calcium. This figure contains points for a large number of patients with proven diagnoses (points for patients with calcium levels 16.0 mg/dL or PTH levels >1000 pg/mL do not appear in the figure). The normal range or reference values for calcium and intact PTH are indicated by the rectangle. By comparing the position of your patient’s test values relative to the points for the different groups of patients in the chart, one can obtain an immediate visual picture of how your patient’s PTH and calcium results may be interpreted. The nomogram will probably be helpful about 90% of the time. Therefore, the plot of PTH versus calcium should always be studied carefully and compared to clinical findings derived from the patient’s history, physical examination, and other laboratory results for definitive diagnosis.
Renal Rickets or Renal Osteodystrophy
- Renal rickets is caused by destruction of renal tissue to the point where insufficient 1,25(OH)2D3 can be biosynthesized.
- Patients have osteomalacia due to deficiency of 1,25(OH)2D3, and also exhibit osteitis fibrosa cystica from 2° hyperparathyroidism, caused by the hypocalcemia induced by 1,25(OH)2D3 deficiency.
- This is an acquired disorder in which patients on hemodialysis must be treated with high doses of 1,25(OH)2D3
HVDRR - Type I
- A 3-year old female with severe rickets was refractory to physiologic doses of vitamin D. She exhibited tetany (spasms of voluntary muscles).
- Her serum chemistry showed a low calcium of 6.4 mg% (normal = 8.5 to 10.2), elevated PTH, high 25(OH)D3 of 288 ng/ml (normal = 8 to 55), very low 1,25(OH)2D3 < 2 pg/ml (normal = 25 to 65).
- She was treated successfully for 3 years with 0.1 - 0.2 μg 1,25(OH)2D3 per day.
HVDRR- Type II
- Two sisters, 3 and 7 years old whose parents were first cousins, presented with severe rickets refractory to 1,25(OH)2D3, and alopecia (hair loss).
- Both sisters had hypocalcemia, increased PTH, and very high 1,25(OH)2D3.
- They could not be treated with 1,25(OH)2D3 because their vitamin D receptor mutation was in one of the DNA binding zinc fingers.
Hyperparathyroidism - Hyperplasia
- A 30-year-old white woman in good health presents with acute colicky abdominal pain. Workup revealed a urinary calculus composed of calcium phosphate obstructing the left ureter. Further laboratory tests showed a serum calcium level of 14 mg/dl and serum parathyroid hormone level of 300 pg/ml.
- What is the differential diagnosis?
Parathyroid hyperplasia, adenoma, and (rarely) carcinoma
- A nuclear scan showed increased uptake in multiple glands. Surgical exploration of the neck was performed and three enlarged glands were excised.
- Review the digitized slide of parathyroid hyperplasia.
- Note the increased cellularity and decreased fat content.
- There is regional heterogeneity which creates a somewhat multinodular pattern.
- Some regions are composed of cells with granular, eosinophilic cytoplasm (oxyphils) and other regions are composed of cells with pale pink to clear cytoplasm (chief cells).
- In general, the nuclei are round, centrally located, and without significant atypia.
•the “lumpiness”, heterogeneity and multinodular give it away as being hyperplasia and not adenoma!
Hyperparathyroidism - Adenoma
- A 40-year-old man presents with symptoms of muscle weakness and easy fatigability. Careful questioning reveals recent change in personality, with anxiety and some symptoms of depression. A serum chemistry screen shows normal values with the exception of serum calcium of 13.5 mg/dl and serum phosphorus 2.0 mg/dl. Additional studies reveal a serum alkaline phosphatase of 200 IU/L and a serum parathyroid hormone level of 400 pg/ml. Radiographs of the hands reveal bony reabsorption of the phalangeal tufts and irregular outline of digits.
- What is the differential diagnosis?
Parathyroid hyperplasia, adenoma, and (rarely) carcinoma
- Head and neck CT shows a 3 x 4 cm mass near the right lower pole of the thyroid.
- Review the digitized slide of parathyroid adenoma. The adenoma has been sectioned, with mulitiple cuts of the same gland on the slide.
- Similar to parathyroid hyperplasia, the gland is enlarged, with marked hypercellularity and decreased fat.
- Compared to hyperplasia, the adenoma appears more uniform because it is composed of a single population of cells (oxyphils).
- Should a definitive diagnosis of adenoma or hyperplasia be made based solely on the histological appearance of a single gland?
No. However, in adenoma, the other glands should be normal. In hyperplasia, multiple glands are involved.
•homogenous, one gland, uniform nuclei (not carcinoma)
