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65 Cards in this Set

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What are the 2 major causes of hypercalcemia?
Almost all cases are due to either:
1) primary hyperparathyroidism
2) cancer
Causes of hypercalcemia?

Rarer but important causes:
1) Medications:
- ___ supplement: causes what syndrome?
- Vitamin __ and ___
- _____ (used to treat bipolar disorder)
Medications such as calcium carbonate, often taken as an over-the-counter antacid or calcium supplement. In large doses this produces what is called the milk-alkali syndrome: hypercalcemia, metabolic alkalosis and renal failure.

Vitamins A and D (again, in large doses) cause hypercalcemia.

Lithium (which is used to treat bipolar disorder) stimulates PTH secretion and can cause hypercalcemia.
Causes of hypercalcemia?

Rarer but important causes:
2) ____________ in which macrophages in the _________ convert 25-hydroxy Vitamin D to 1,25 dihydroxy Vitamin D.
b. Granulomatous diseases such as sarcoidosis, in which macrophages in the granulomas convert 25-hydroxy Vitamin D to 1,25 dihydroxy Vitamin D.

Unlike renal 1-alpha hydroxylase, this conversion is not regulated by PTH, so hypercalcemia does not suppress it by negative feedback.
Causes of hypercalcemia?

Rarer but important causes:
3) _____ causes mild hypercalcemia (i know, it's vague...)
Hyperthyroidism
Causes of hypercalcemia?

Rarer but important causes:

An autosomal dominant genetic disorder in which the calcium sensing receptor (CaSR) on parathyroid cells is defective, leading to inadequate negative feedback suppression of PTH secretion by normal plasma calcium levels
Familial benign hypercalcemia (FBH),



Thus, this is a form of primary hyperparathyroidism and can look just like it biochemically

important to recognize since, as the name suggests, these patients are asymptomatic and suffer no adverse consequences of their condition as long as no one mistakes them as having the ordinary form of primary hyperparathyroidism and begins surgically removing parathyroid tissue.

They can be distinguished from ordinary hyperparathyroidism by their very low urine calcium excretion (hypocalciuria)—the renal tubules cannot sense calcium normally either and reabsorb calcium very avidly.
List the minor causes of hypercalcemia:
- Medications (CaCO3, Vit A, D, Lithium)
- Granulomatous diseases
- Familial benign hypercalcemia (FBH)
- Thiazide diuretics
Serum levels in primary hyperparathyroidism:

Serum phosphate levels:
Alkaline phosphatase:
Plasma Ionized Calcium
Serum phosphate levels: lowered, although remain within reference range

Alkaline phosphatase: normal (though, may be high in severe cases, especially in those with osteitis fibrosa)

Ionized Ca: elevated
How to differentiate FBH and ordinary primary hyperparathyroidism:
Measure 24 hour urine calcium excretion (renal tubules cannot sense calcium very well in FBH so they absorb ca avidly --> hypocalciuric hypercalcemia)

Don't see this in ordinary hyperparathyroidism
How does PTH raise plasma calcium?
(a) stimulation of bone resorption by osteoclasts;

(b) stimulation of calcium reabsorption (and phosphate excretion) by the renal tubules; and

(c) stimulation of renal 1-alpha hydroxylation of 25-hydroxyVitamin D to form 1,25 dihydroxy Vitamin D (calcitriol). High levels of calcitriol increase absorption of dietary calcium.
What pathologic lesions cause this primary hyperparathyroidism?
80-90% of cases of primary hyperparathyroidism are due to an ADENOMA of a single gland

almost all of the rest are due to an abnormality that affects all four glands including:
- hyperplasia
- multifocal adenoma
How does the nature of the pathologic lesion affect surgical therapy of this disorder?

adenoma vs. hyperplasia
Adenoma:
- Adenomas are removed with a high probability of cure.

- Preoperative localization of the enlarged gland is often possible and permits less extensive surgery.

Hyperplasia:
-Requires extensive resection of parathyroid tissue to cure hypercalcemia.
- Usually, all four parathyroids are removed, and part of one gland is autotransplanted to the forearm, which allows convenient further resection if needed.
Familial forms of parathyroidism:

Most patients with _____________ have a familial form of hyperparathyroidism
Most patients with parathyroid hyperplasia have a familial form of hyperparathyroidism, such as:

multiple endocrine neoplasia (MEN) type 1 (due to an inactivating mutation in a tumor suppressor gene called menin)

or MEN type 2A (due to an activating mutation in the ret proto-oncogene)
T/F

Familial forms of primary hyperparathyroidism tend to be discovered at a younger age
True
6. What are the major ways that primary hyperparathyroidism presents? Which is most common?
- asymptomatic hypercalcemia found incidentally (most)
- kidney stones (calcium oxalate)
- symptoms of bone disease or symptoms of hypercalcemia
What are the indications for surgery in primary hyperparathyroidism?
(a) symptoms of hypercalcemia,
(b) nephrolithiasis,
(c) reduced bone mass (a t-score below -2.5 SD),
(d) plasma calcium more than 1 mg/dl above the reference range, or
(e) is younger than 50 years
primary hyperparathyroidism

What additional test could be done if it was still unclear whether surgery should be done?
measurement of bone density with DEXA (dual energy x-ray absorptiometry) could be done to determine if low bone mass was present, which would be an indication for parathyroidectomy
Treatments for hyperparathyroidism:
1) surgery
2) calcimimetics (used more for 2ndary hyperparathyroidism)
2a) bisphosphonates (to treat low bone mass in patients that are poor surgery candidates)
2ndary hyperparathyroidism:

Definition:
In secondary hyperparathyroidism, the parathyroid glands are responding appropriately to disorders that lower plasma calcium by increasing PTH secretion to try to keep plasma calcium levels normal.

By definition, secondary hyperparathyroidism does NOT cause hypercalcemia - plasma calcium levels are normal or low.

The stimulus of hypocalcemia leads to hyperplasia of the parathyroid glands.
2ndary hyperparathyroidism:

Causes:
1) Chronic renal failure
2) Vitamin D deficiency

In renal failure, other factors such as deficiency of 1,25 dihydroxy Vitamin D also contribute to increased PTH secretion
What symptoms and signs can be caused by hypercalcemia?
"stones, bones, abdominal groans, and psychic moans"

o Renal effects include:
- kidney stones
- polyuria
- decreased GFR

o Skeletal manifestations include:
- bone pain and fractures

o Gastrointestinal effects: anorexia, nausea, constipation, and abdominal pain.

o Neurological effects: lethargy, confusion, and even coma
What cells are resorbing bone and causing hypercalcemia?
Osteoclasts stimulated by tumor-derived factors resorb bone excessively and cause hypercalcemia.
What are some hallmarks of hypercalcemiea due to cancer (malignant hypercalcemia)?
- Severe, symptomatic hypercalcemia
- a mass,
- spine tenderness + elevation of alkaline phosphatase suggesting the presence of bone metastases (case 2 specific)

Malignant hypercalcemia is the most common cause of hypercalcemia in patients [sick enough to be admitted to the hospital]!

Malignant hypercalcemia progresses quickly to severe hypercalcemia that is recognized because of the symptoms it causes, which explains why it does NOT cause kidney stones.
Malignant hypercalcemia

How can this patient's hypercalcemia be treated?
Emergency treatment of severe hypercalcemia includes:

- IV saline (volume repletion)
- parenteral bisphosphonate (osteoclast inhibitor)
Malignant hypercalcemia

What is the mechanism of action of the drugs that are used to treat it?

IV saline:
IV saline:
- corrects ECF volume depletion and promote urinary calcium excretion.

(Patients are almost always quite dehydrated, due to the combination of polyuria, nausea, and vomiting)
Malignant hypercalcemia

What is the mechanism of action of the drugs that are used to treat it?

Bisphosphonates:
Parenteral bisphosphonate (zoledronic acid or pamidronate):

- Temporarily lowers calcium

- Analogues of pyrophosphate that inhibit osteoclastic bone resorption

- Their full effect on plasma calcium takes several days, and persists for 2 weeks or more with pamidronate, and even longer with zoledronic acid

- They are effective because malignant hypercalcemia is caused by excessive activation of osteoclasts by factors produced by the cancer.
What cancers are most likely to cause hypercalcemia?

What hormones or factors are responsible for hypercalcemia due to cancer/tumors? (in parenthesis)
Breast cancer - very high incidence of bone metastasis- (PTH-rP)

Humoral hypercalcemia of non-metastatic malignancy: (PTH-rP)
- Squamous carcinoma of the lung (the most common cause of malignant hypercalcemia in men)
- Squamous carcinoma of the head and neck or esophagus
- Renal carcinoma

- Myeloma (cytokines)
Major causes of hypocalcemia include:
- Acute or chronic renal failure

- Hypoparathyroidism; post-surgical, idiopathic (autoimmune), or magnesium deficiency

- Pseudohypoparathyroidism (PTH resistance) --> short stature, obesity and short metacarpals, especially the 4th and 5th.

- Vitamin D deficiency or resistance.

- Pancreatitis
What happens to plasma phosphorus levels in the various causes of hypocalcemia?
High plasma phosphorus
1. Hypoparathyroidism,
2. PTH resistance,
3. renal failure

Low plasma phosphorous
4. Vitamin D deficiency or resistance
T/F

PTH resistance is a congenital disorder
True
___________ is elicited by inflating a blood pressure cuff on the arm above systolic blood pressure.

What is a positive response for this sign
Trousseau's sign

A positive response is the development of carpal spasm.

All these signs are manifestations of a decreased threshold for neuromuscular excitation in hypocalcemia. This leads nerves and muscles to fire spontaneously or in response to minimal stimuli.
__________ is elicited by tapping the facial nerve where it crosses the zygomatic arch.

What is a positive response for this sign?
Chvostek's sign

A positive response is contraction (twitch) of the ipsilateral facial muscles.


All these signs are manifestations of a decreased threshold for neuromuscular excitation in hypocalcemia. This leads nerves and muscles to fire spontaneously or in response to minimal stimuli.
________ is the spontaneous presence of carpopedal spasm.
Tetany (not the same as tetanus)

All these signs are manifestations of a decreased threshold for neuromuscular excitation in hypocalcemia. This leads nerves and muscles to fire spontaneously or in response to minimal stimuli.
Aside from Trousseau's sign, Chvostek's sign, and tetany, what are some other effects can hypocalcemia cause?
- paresthesias (numbness and tingling)
- laryngeal spasm or seizures (severe hypocalcemia)
- cataracts and calcification of the basal ganglia in the brain (chronic hypocalcemia)
What tests should be ordered to confirm the diagnosis (in the setting of hypocalcemia)?
- Plasma PTH (low to low-normal levels will rule IN hypoparathyroidism and rule out other causes that show high PTH levels)

- Plasma Magnesium (mg deficiency can cause reversible hypoparathyroidism and resistance to PTH action)
What effect does an abnormal plasma albumin level have on the plasma calcium level?
Since ~ 1/2 of circulating plasma calcium is reversibly bound to albumin, hypoalbuminemia can cause mild decreases in total plasma calcium.

Total plasma calcium changes about 0.8 mg/dl for every 1 gm/dl change in serum albumin above or below 4.0 gm/dl. This does not affect the levels of biologically active ionized (or free) calcium.

In patients with mild hypocalcemia, or hypoalbuminemia, plasma ionized calcium can be measured to tell whether there is a disorder of calcium metabolism or not
What is osteoporosis?

Is the amount of unmineralized osteoid increased as in osteomalacia?
Bone fragility leading to fractures with minimal trauma (fragility fractures). Bone mass is decreased, and the microscopic architecture of trabecular bone is abnormal—there is thinning and loss of trabeculae.

There are no other histological abnormalites (e.g., the amount of unmineralized osteoid is NOT increased as in osteomalacia).q
What are the risk factors for osteoporosis?
- Female sex
- Early menopause,
- Therapy with glucocorticoids
- Family history
- Low calcium intake
- Smoking
- Thin body habitus
- Lack of exercise
- Ethnic background: (Caucasian or Asian women)
- Posture/Balance affecting drugs
- Previous fractures
What cells resorb bone? Where do they come from and what receptor controls their development?
Osteoclasts resorb bone.

They are multinucleated cells derived from the same bone marrow precursors as monocytes and macrophages.

Key factors in the development of osteoclasts are monocyte CSF and RANK-ligand.

The latter binds to RANK (receptor activator of nuclear factor kB). Despite the cumbersome name, this pathway is critical to bone resorption, and there is considerable interest in drugs that disrupt this pathway as treatments for osteoporosis.
What cells form bone, and where do they come from?

What role do they play in controlling bone turnover?
Osteoblasts form bone.

They are derived from mesenchymal cells within bone.

Osteoblasts and their precursors have receptors for PTH, calcitriol, and many other systemic factors that regulate bone turnover, and much of the control of osteoclasts and bone turnover is probably regulated by them through production of locally acting factors like RANK-ligand.
How does estrogen deficiency affect bone?
Estrogen's major action on bone is to diminish resorption by inhibiting the formation of osteoclasts from their monocyte precursors.

Estrogen deficiency at menopause leads to a phase of accelerated osteoclastic bone resorption and decline in bone mass.
What are the benefits and side effects of estrogen replacement therapy in the context of osteoporosis and menopause?
BENEFITS:
- prevents symptoms of estrogen deficiency (hot flashes, dyspareunia - vaginal pain due to dry sex,

- prevents the rapid loss of bone mass in the first 5 years after menopause

- reduces the risk of vertebral and hip fractures

RISKS:
- increased risk of CAD, stroke, and pulmonary embolism
- increased risk of breast cancer

Risks outweigh benefits, so this is no longer recommended
Aside from estrogen replacement therapy, what other options are available for prevention of osteoporosis and how do they work? What are their side effects?
Alternative Options:
- calcium supplement
- Vitamin D supplement
- Selective estrogen receptor modulators (SERMs) -reduce the risk of vertebral fractures (SE: inc. hot flashes, venous thromboembolism)
- Bisphosphonates - inhibit bone resorption (SE: esophagitis)
-

SIDE EFFECTS:
- increase in hot flashes
- inc. risk of venous thromboembolism
-
What test is helpful in assessing a patient's risk for osteoporosis?
Bone mass measurement (dual energy x-ray absorptiometry (DEXA)
What is the meaning of the T-score (DEXA scan)?

How is low bone mineral density classified?
The T-score measures how far an individual's bone mass is from the mean peak bone mass for their sex.

Its unit is the standard deviation (SD) of the mean peak bone mass.

-1 to -2.5 SD = osteopenia
< - 2.5 SD = osteoporosis

development of a fragility fracture = osteoporosis
Other measures to reduce fracture risk are included in the mnemonic "DEMAND":
Densitometry (DEXA)
Evaluation for underlying disorders (Vitamin D def., Cushing's - excess cortisol, hyperthyroidism, myeloma, etc.)
Mobilization (weight bearing = inc. bone mass)
Aminobisphosphonates (dec. bone resorption)
Nutrition (Vit D + Ca)
Defend against falls
What are the major causes of osteoporosis other than estrogen deficiency?
Osteoporosis can also be caused by disorders such as Cushing's syndrome (including that resullting from use of glucocorticoid drugs), hyperthyroidism, and hypogonadism in men. Even though they account for only a minority of cases, it is important to be aware of them since they have to be specifically tested for if they are to be diagnosed.
Do patients with osteoporosis have abnormal levels of plasma calcium? Phosphorus? Alkaline phosphatase?
Plasma calcium, phosphorus, and alkaline phosphatase are all normal in osteoporosis.

The only exception is that alkaline phosphatase may be temporarily increased during bone healing after a fracture. Abnormal levels of any of these are an important clue that something other than osteoporosis is causing low bone mass.
What are the common fractures in patients with osteoporosis? What are their consequences?
The most common sites of fracture in osteoporosis are vertebrae, hip (femoral neck), and wrist (Colles' fracture).
What are the consequences of the common fractures in patients with osteoporosis?
Vertebral fractures:
- pain, loss of height, and if severe enough can cause kyphosis bad enough to cause respiratory problems.

Hip fractures( are most important)
- major cause of disability and death in the elderly, both from their direct effects on patients' mobility and ability to care for themselves and from indirect effects - immobilization increases the risk of venous thromboembolism and pneumonia, for example.

Wrist fractures usually cause only temporary disability.
What is the role of measuring plasma 25-OH vitamin D in the evaluation of bone health?
Plasma 25-OH vitamin D is the best measue of body vitamin D stores, which are primarily located in adipose tissue.

Population studies suggest that the optimal 25-OH D level is at least 30 ng/ml, since plasma PTH levels are often elevated when plasma 25-OH D is lower than this, and secondary hyperparathyroidism contributes to loss of bone mass. Note that the laboratory reference range goes down to 10 ng/ml. Like the situation with cholesterol levels, we are concerned less with "normal" levels (ie the 95 percent confidence interval for the general population) than we are with what is best for an individual.

Suboptimal vitamin D nutrition is very common, especially in people who don't drink milk and don't get much sun exposure.
What treatments are available for osteoporosis? What are their side effects?
- Calcium + Vitamin D
- Bisphosphonates
- SERMs
- PTH 1-34 injection (daily)
What are some characteristic findings in Vitamin D deficiency:
- malabsorption of fat: low phosphate and elevated alkaline phosphatase levels

- Proximal muscle weakness and pain in the back and hips
What tests can confirm VitD deficiency?
- plasma levels of 25-OH Vitamin D,
- radiographic findings of osteomalacia (pseudofractures)
Vitamin D deficiency in children causes 1)_______

Children with this disease have expanded 2)__________ and develop deformity of weight-bearing bones, most often 3)___________
1) rickets

2) epiphyseal growth plates

3) bowing of the legs
What is rickets?
Rickets is a disorder characterized by deficient calcification of bone matrix (osteoid) and cartilage at the growing end of bones in children.
What are the most common causes of rickets?
- nutritional rickets due to Vitamin D deficiency

- Malabsorption of vitamin D due to intestinal disease

- Familial disorders: X-linked hypophosphatemia, Genetic defects in 1-alpha hydroxylase, Genetic defects in the vitamin D receptor, Hypophosphatasia (deficiency of alkaline phosphatase).

- Drugs that affect vitamin D metabolism (primarily certain anticonvulsants).

- Severe liver disease (impaired conversion to 25-OH D).

- Renal failure (but renal osteodystrophy includes components due to abnormalities besides 1,25-OH D deficiency).
Nutritional Rickets:

occurs in:
- breast feeding infants
- most often seen in dark skinned children
- northern latitudes,
Radiographic findings for rickets:
- widening of the growth plate
- unmineralized osteoid and cartilage
- widening (flaring), irregularity, fraying of the metaphysis
- seen most in most rapidly growing bones
- knee and wrist films are commonly ordered
-
Physical findings in rickets:
- bowing of the legs (most important) - seen after child begins to bear weight
- flaring of the metaphysis (associated with widening of the affected bone) - most easily seen at the wrist/ankle
- flaring at the costochondral junction (Rachitic rosary)

- Harrison's groove
- Skull findings: Frontal bossing, parietal flattening, delayed closure of the fontenelle, craniotabes (softening of the skull)

- Growth failure, muscle weakness, hypotonia, motor delay, delayed tooth eruption

- severe rickets: irritability, Chvostek's sign, tetany, and seizures
Lab tests to confirm rickets and determine therapy
- Plasma 25-OH Vitamin D (best)
- Plasma Ca (usually low normal)
- Plasma Phosphorous (low normal or low)
- Alk phosphatase ELEVATED in ALL forms of rickets (except hypophosphotasia)
Milk-Alkali Syndrome
due to excessive intake of calcium carbonate (Tums or Rolaids). Patients who can't afford prescription acid suppressants sometimes take large amounts of cheap over-the-counter antacids instead. It could also be malignant hypercalcemia or some other non-parathyroid cause, but a good medication history that includes OTC and "nutritional supplements" is essential for diagnosis.
Idiopathic Autoimmune Hypoparathyroidism
part of autoimmune polyglandular syndrome type 1 (Addison's, hypoparathyroidism and mucocutaneous candidiasis). The high phosphorus indicates that it is due to either PTH deficiency or resistance, or to renal failure.
Familial Benign (hypocalciuric) hypercalcemia
Primary hyperparathyroidism is rare in young people, and a familial disorder should be suspected. MEN 1 or MEN 2A might cause primary hyperparathyroidism in a child or young adult, but the low urine calciun suggests FBH instead.
PSEUDOHYPOPARATHYROIDISM
due to PTH resistance. She has characteristic findings of Albright's hereditary osteodystrophy (short stature, obesity and short metacarpals) that often accompany this disorder, which is most often due to a mutation in the Gsa protein that couples the PTH receptor to adenylate cyclase.
SECONDARY HYPERPARATHYROIDISM
PROBABLY DUE TO SUBOPTIMAL VITAMIN D STORES. She does not have renal failure, the other common cause of secondary hyperparathyroidism.