Calcium and Phosphate Disorders Flashcards
1
Q
Calcium Disorders
A
- Hypercalcemia
- Hypocalcemia
- Vitamin D Disorders
2
Q
Hypercalcemia
A
- 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
3
Q
The Main Players
A
- 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
4
Q
Hypercalcemia Effects
A
•Central nervous system:
- Lethargy and depression
- Ataxia
•Neuromuscular:
- Hypertonia
- Weakness, proximal myopathy
•Cardiovascular:
- Hypertension
- Bradycardia
•Renal:
- Polyuria and decreased glomerular filtration
- Nephrolithiasis
5
Q
Hyperparathyroidism
A
•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
6
Q
A
7
Q
7 Associated Clinical Findings in Hyperparathyroidism
A
- 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.
8
Q
Pathology of Hyperparathyroidism
A
• ademonas > hyperplasia >>> carcinoma
9
Q
Hyperparathyroidism - Adenomas
A
- 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.
10
Q
Hyperparathyroidism - Adenomas - Gross
A
- 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.
11
Q
Brown Tumor - Gross
A
- 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
12
Q
Brown Tumor - Microscopic
A
- 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
13
Q
Hyperparathyroidism - Adenoma - Microscopic
A
- 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.
14
Q
Hyperparathyroidism - Adenoma - Microscopic
A
•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
15
Q
Hyperparathyroidism - Adenoma - Microscopic
A
•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
16
Q
Hyperparathyroidism - Hyperplasia
A
- 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.
17
Q
Hyperparathyroidism - Hyperplasia
A
18
Q
Hyperparathyroidism - Hyperplasia
A
19
Q
Endocrine Atypia
A
- 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
20
Q
Hyperparathyroidism - Carcinoma
A
- 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).
21
Q
Hyperparathyroidism - Carcinoma
A
22
Q
Hyperparathyroidism - Carcinoma - Biochemistry and Physiology
A
- In primary hyperparathyroidism, secretion of PTH is no longer under the feedback control of calcium.
- This leads to hypercalcemia, hypercalciuria, hypophosphatemia, and often renal stones.
- Although PTH normally elicits calcium reabsorption from the glomerular filtrate, consistently elevated calcium exceeds the renal threshold for reabsorption so that calcium leaks into the urine.
- A hallmark of primary hyperparathyroidism is abnormally increased resorption of the subperiosteal bone, which if untreated, causes severe bone pain.
23
Q
Hyperparathyroidism - Carcinoma - Treatment
A
- Treatment consists of parathyroidectomy, with resection of one or more abnormal glands.
- Prior to surgical exploration of neck, patients undergo preoperative technetium-99-m sestamibi nuclear scanning to locate the abnormal glands.
- Due to increased metabolic activity, there is preferential uptake of the radiotracer dye into the pathologic glands.
- Intraoperative PTH blood levels before and after resection provides immediate feedback to the surgeon, ensuring that the pathologic tissue has been removed.
- In addition, intraoperative frozen section examination of the excised tissue by the pathologist is often used to confirm that the excised tissue contains parathyroid tissue.
- If all four parathyroid glands are removed, a small amount of parathyroid tissue may be implanted in the patient’s forearm to conserve some parathyroid gland function.
24
Q
Familial Benign Hypocalciuric Hypercalcemia
A
- FBHH is characterized by a defect of the calcium receptor, leading to decreased sensitivity to extracellular calcium.
- Most cases are caused by an inactivating mutation of the calcium sensing receptor (CASR) gene on chromosome 3q.
- The disease is inherited as autosomal dominant and leads to lifelong asymptomatic hypercalcemia.
- FBHH is generally a mild disorder, with normal or slightly elevated PTH, caused by lack of feedback control by the hypercalcemia.
- Most patients are asymptomatic, and clinical symptoms of hypercalcemia such as bone disease and urinary stones are uncommon. The most notable lab finding is hypocalciuria.
- Due to the loss of feedback inhibition, calcium continues to be reabsorbed in the kidney despite high blood calcium concentration, resulting in unexpectedly low urine calcium concentrations.
- Because the disease has a benign clinical course, it is important to distinguish this disorder from primary hyperparathyroidism to avoid unnecessary surgical removal of the parathyroid glands.
25
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.
26
Secondary Hyperparathyroidism
* This condition is usually characterized by chronically decreased calcium and increased phosphate serum concentrations, leading to compensatory overactivity of the parathyroid glands.
* The most common cause of secondary hyperparathyroidism is renal failure.
* Various gastrointestinal-related problems (e.g., vitamin D deficiency, malabsorption syndromes, biliary obstruction) may also cause decreased serum calcium levels, leading to secondary hyperparathyroidism.
* In renal failure, decreased urinary excretion of phosphate leads to hyperphosphatemia, which directly depresses serum calcium concentration.
* This leads to parathyroid gland overactivity and secretion of PTH. In addition, loss of renal parenchyma results in decreased formation of active 1,25(OH)2D3, which reduces intestinal calcium absorption and contributes to the chronic hypocalcemia.
* Usually, all four parathyroid glands are enlarged to varying degrees, although the enlargement may be asymmetric (similar to primary hyperplasia).
* The histological changes of primary and secondary hyperplasia are identical and afford no clues as to etiology.
27
Tertiary Hyperthyroidism
* In some patients, the PTH secretion of secondary hyperparathyroidism becomes excessive and autonomous, resulting in hypercalcemia that is no longer under feedback regulation.
* This condition is referred to as “tertiary hyperparathyroidism”. At this point, patients often become symptomatic and parathyroidectomy may be necessary.
* Bone changes and metastatic calcification may be present. “Renal osteodystrophy” is a general term used to describe the skeletal changes associated with chronic renal disease.
28
Hypoparathyroidism
* surgical ablation of parathyroid glands during thyroidectomy or radical neck surgery for other malignant disease
* Congenital absence - Associated with thymic aplasia and cardiac defects as a component of the 22q11.2 syndrome.
* Autoimmune hypoparathyroidism (autoimmune polyendocrine syndrome type 1) - Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency.
* Autosomal dominant hypoparathyroidism – Caused by gain of function mutations in the calcium sensing receptor (CASR) gene.
* Familial isolated hypoparathyroidism – Caused by a very rare mutation in the gene that encodes the PTH precursor peptide.
29
Effects of Hypoparathyroidism
* Deficient PTH secretion results in hypocalcemia, hyperphosphatemia and a densely calcified skeleton.
* The clinical presentation is related to the degree of hypocalcemia.
* One of the major clinical manifestations of this disorder is tetany (increased neuromuscular excitability), which can range from circumoral numbness and mild paresthesias (tingling) of the distal extremities to life threatening laryngospasm and generalized seizures.
* Other clinical complications include abnormal cardiac conduction, increased intracranial pressure, dental abnormalities, cataracts, and mental status changes ranging from anxiety and depression to frank psychosis.
* Effective treatment includes 1,25(OH)2D3 to raise calcium levels by promoting intestinal calcium absorption.
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Pseudoparahypothyroidism
* Pseudohypoparathyroidism is a particularly instructive congenital abnormality.
* Fuller Albright first described the syndrome as PsHP caused by target tissue resistance to PTH.
* PTH injection fails to correct hypocalcemia and hyperphosphatemia in these patients, or to elicit an increase in urinary cAMP.
* The classic phenotype is short stature, round face, brachydactylia (abnormally short fingers and toes), subcutaneous calcification and mental deficiency.
* Note that not all patients with PsHP express these features, which are referred to as Albright's hereditary osteodystrophy (AHO).
* The molecular defect in PsHP is a defect in the Gs-protein that couples receptors to adenylyl cyclase.
* Erythrocyte Gs activity is only about 50% of normal in PsHP patients that express features of AHO.
* Since Gs couples many other hormone receptors (besides those for PTH) to adenylyl cyclase (e.g., TSH, glucagon, gonadotrophins, etc.), severely affected patients display resistance to these hormones as well.
* For example, most PsHP/AHO cases exhibit abnormal thyroid function -- low T4, increased TSH, and exaggerated responsiveness to TRH.
* These patients will not have goiter because the thyroid follicular cells are resistant to the effects of TSH.
31
Hypocalcemia
* Hypoparathyroidism
* Resistance to PTH action:
- Pseudohypoparathyroidism
- Renal insufficiency
•Decreased production of 1,25(OH)2D3 : (Vitamin D Disorders)
- Vitamin D deficiency
- Hereditary vitamin D-resistant rickets type I- (renal 1-alphahydroxylase defect)
•Resistance to 1,25(OH)2D3 action:
-Hereditary vitamin D-resistant rickets type II-(vitamin D receptor defect)
32
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.
33
Vitamin D Deficiency
•In children (before epiphyseal closure) causes nutritional rickets
- Bone pain and deformities
- Muscle weakness
- Widening of wrists (metaphyseal hyperplasia)
- Permanent deformities if not treated
•Similar disease in adults is known as osteomalacia
34
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
35
Hereditary Hypocalcemic Vitamin D-Resistant Rickets (HVDRR)
* HVDRR is caused either by a familial autosomal recessive defect in the kidney 1-hydroxylase that produces 1,25(OH)2D3 (type I), or by hereditary (autosomal recessive) end organ resistance to 1,25(OH)2D3 because of a genetically altered receptor (type II).
* Importantly, patients with the type I disorder can respond to superphysiologic doses of 1,25(OH)2D3.
* However, patients with mutations in the DNA-binding domain of the vitamin D receptor cannot respond to any dose of 1,25(OH)2D3.
* In contrast, if the mutation is instead in the hormone binding domain so that it only lowers the affinity of ligand binding, patients can be maintained on extremely high doses of 1,25(OH)2D3.
36
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.
37
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.
38
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!
39
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)
