The case study

Multiple choice questions

• 1.
  

  In Mrs. TW’s case, the laboratory findings are suggestive of:

  
  
  
  
  • A.
    

    Primary hyperparathyroidism.

    
    
  • B.
    

    Secondary hyperparathyroidism.

    
    
  • C.
    

    Osteoporosis.

    
    
  • D.
    

    A and C.

    
    
  • E.
    

    B and C.

  
  
  
  

  Correct answer: D

  
  

  Comment:

  
  

  The characteristic diagnostic features of Primary Hyperparathyroidism (PHPT) are hypercalcemia and an elevated or “inappropriately normal” serum parathyroid level. Normally an inverse relationship exists between serum calcium and parathyroid hormone levels. In Mrs. TW’s case, however, both the serum calcium and parathyroid hormone (PTH) levels are elevated. The likely diagnosis therefore is primary hyperparathyroidism (PHPT). As she also sustained a fragility fracture, she has osteoporosis regardless of her T-score. The final diagnosis therefore is osteoporosis and primary hyperparathyroidism.

  
  

  PHPT is a very common endocrine disorder and is the leading cause of hypercalcemia in outpatients. In the USA, its prevalence is estimated to be 0.86%. Its epidemiology has changed as the introduction of multichannel serum auto-analyzers leads to the identification of several asymptomatic patients with the biochemical characteristic features of PHPT. The proportion of patients presenting with the classical characteristic features of nephrolithiasis and nephrocalcinosis, originally about two-thirds of the patient population, and osteitis fibrosa cystica (brown tumors and periosteal bone resorption of the long bones), originally about a third of the patient population, is shrinking. Primary hyperparathyroidism is now predominantly diagnosed in asymptomatic Black women, especially within the first 10 years after the menopause. It tends to have a worse prognosis in women than in men. About 70%–80% of patients with primary hyperparathyroidism now present during the asymptomatic stage.

  
  

  A large descriptive epidemiological study performed on about 3.5 million enrollees in the Kaiser Permanente, Southern California, revealed that the incidence of PHPT (as diagnosed by hypercalcemia and elevated PTH or “inappropriately normal” PTH levels) fluctuated in women from 34 to 120 per 100,000 person-years (mean 66), and in men between 13 and 36 (mean 25). The incidence increased with age and the differences between the genders became more pronounced: 12–24 per 100,000 for both sexes under the age of 50 years; 80 and 36 per 100,000 for women and men between the ages of 50 and 59 years, respectively; and 196 and 95 for women and men aged 70–79 years, respectively. The incidence of PHPT was higher among Black (92 women, 46 men) than White women (81 women, 29 men), Asians (52 women, 28 men), and Hispanics (49 women, 17 men). Of interest, the prevalence of PHPT tripled during the study period (1995–2010) increasing from 76 to 233 per 100,000 women and from 30 to 85 per 100,000 men.

  
  

  Patients with parathyroid cancer are usually much younger that those with PHPT: between the ages of 40 and 50 years. Unlike PHPT which affects women more than men, parathyroid cancer affects both genders about equally. Their serum calcium and PTH levels are much higher than those seen in patients with PHPT. Nephrolithiasis, nephrocalcinosis, and bone diseases are more prominent in parathyroid cancer than in PHPT.

  
  

  Brown tumors are rare benign lesions developing during the remodeling process in advanced, long-lasting primary or secondary hyperparathyroidism. They are rarely seen nowadays as in most instances the diagnosis of hyperparathyroidism is made early during the increased remodeling process. They are sometimes misdiagnosed as nontreatable osteosarcomas. Characteristic diagnostic features of brown tumors include elevated serum parathyroid hormone and calcium levels. Bone imaging studies help exclude bone malignancy. Selective parathyroidectomy is the first-line therapy.

  
  

  Rarely, primary hyperparathyroidism is inherited as an autosomal dominant trait including multiple endocrine neoplasia type I (MEN1, MEN2, MEN4) and familial hypocalciuric hypercalcemia (FHH).

  
  
• 2.
  

  Match the following:

  
  
  
  
  • (a)
    

    Hypercalcemia and elevated PTH level.

    
    
  • (b)
    

    Hypercalcemia with suppressed PTH level.

    
    
  • (c)
    

    Both.

    
    
  • (d)
    

    Neither.

    
    
  • A.
    

    Primary hyperparathyroidism.

    
    
  • B.
    

    Secondary hyperparathyroidism.

    
    
  • C.
    

    Familial hypocalciuric hypercalcemia.

    
    
  • D.
    

    Lithium.

    
    
  • E.
    

    Thiazide diuretics.

  
  
  
  

  Correct answers: A (a); B (b); C (a); D (a); E (c)

  
  

  Comment:

  
  

  In patients with hypoalbuminemia, the assayed serum calcium level should be first adjusted to the serum albumin level. Directly assaying the ionized serum calcium level obviates the need to adjust the serum calcium level to the serum albumin level and is routinely done in several laboratories. In secondary hyperparathyroidism (SHPT), the serum calcium level is not elevated; instead, it is usually in the low normal range, but may also be low, depending on the efficacy of parathyroid hormone at maintaining the serum calcium within the normal range.

  
  

  Several factors may contribute to hypercalcemia in patients on long-term thiazide therapy, including reduced renal calcium excretion, increased intestinal calcium absorption, metabolic alkalosis, and hemoconcentration. As the hypercalcemia is sometimes associated with elevated serum parathyroid hormone levels and as the hypercalcemia often persists after the discontinuation of the diuretic, it is possible that, in some patients, long-term thiazide therapy uncovers previously unknown hyperparathyrodism.

  
  

  Lithium induces hypercalcemia and elevated or nonsuppressed PTH levels by interfering with CaSRs. 10%–20% of patients on lithium develop hypercalcemia, a condition sometimes referred to as “lithium-associated hyperparathyroidism.” It is therefore recommended to assay the serum calcium levels at least annually in patients on lithium therapy. Other causes of hypercalcemia with suppressed PTH levels include sarcoidosis, malignancy-associated hypercalcemia, Addison’s disease, vitamin D intoxication, and prolonged immobilization. The chloride/phosphate ratio is sometimes used to differentiate hypercalcemia due to PHPT from hypercalcemia due to other causes: a ratio greater than 33 is suggestive of PHPT.

  
  
• 3.
  

  The main actions of parathyroid hormone include:

  
  
  
  
  • A.
    

    Activation of osteoclastic bone resorption.

    
    
  • B.
    

    Increased renal calcium reabsorption from the distal convoluted tubules.

    
    
  • C.
    

    Stimulating the 1-alpha-hydroxylase enzyme in the kidneys.

    
    
  • D.
    

    A and B.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  The main function of PTH is to maintain the serum calcium level within a narrow range of normality. As soon as the calcium-sensing receptors (CaSRs) in the parathyroid chief cells detect any decrease in ionized serum calcium level they trigger the immediate release of PTH.

  
  

  PTH increases serum calcium level through three main mechanisms. First, activation of osteoclastic bone resorption, thus mobilizing calcium from bone matrix to the circulation; second, increasing renal calcium absorption in distal convoluted tubules, thus saving any calcium that would have otherwise been lost in the urine; and third, stimulation of 1-alpha hydroxylase enzyme in the kidneys to hydroxylate 25-hydroxy-vitamin D at the 1-position to yield 1,25 di-hydroxy-vitamin D, the most active vitamin D metabolite which increases intestinal calcium absorption. When the serum calcium level normalizes, the CaSRs are no longer stimulated and the release of PTH is stemmed. Normally there exists an inverse relationship between serum calcium, especially ionized serum calcium, and the serum PTH level.

  
  
  
  
  • •
    

    In primary hyperparathyroidism (PHPT) , the inverse relationship between serum calcium and PTH levels is not seen and both serum calcium and PTH levels are elevated because in these patients the production and release of PTH is autonomous and independent of the serum calcium level.

    
    
  • •
    

    In normocalcemic hyperparathyroidism , the serum calcium level is within the normal range, but the PTH is elevated in the absence of secondary causes of hyperparathyroidism. Normocalcemic hyperparathyroidism may be the precursor of PHPT.

    
    
  • •
    

    In secondary hyperparathyroidism (SHPT), the parathyroid glands try to maintain the serum calcium level within the range of normality by increasing the production and release of PTH stimulated by a low or decreasing serum calcium level. Therefore, in SHPT, the serum calcium is within or below the normal range, depending on the ability of the parathyroid glands to produce/release sufficient quantities of PTH to prevent hypocalcemia. The serum PTH is elevated.

    
    
  • •
    

    Tertiary hyperparathyroidism is characterized by an excessive/prolonged production of PTH after a long period of secondary hyperparathyroidism when the parathyroid glands were stimulated to produce/release larger quantities of PTH to prevent hypocalcemia from developing. In tertiary hyperparathyroidism, however, the excessive PTH production and release are no longer in response to any stimulus and the serum calcium level is elevated. Tertiary hyperparathyroidism is therefore the end result of prolonged SHPT. It is possible that the calcium-sensing receptors in the parathyroid glands have altered their set point and more PTH is produced/released even in the presence of hypercalcemia. Tertiary hyperparathyroidism is seen in patients with chronic kidney disease and postrenal transplant.

  
  
  
  
• 4.
  

  Classical features of primary hyperparathyroidism include:

  
  
  
  
  • A.
    

    Osteitis fibrosa cystica.

    
    
  • B.
    

    Increased bone turnover rate.

    
    
  • C.
    

    Nephrolithiasis and nephrocalcinosis.

    
    
  • D.
    

    A and C.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  The incidence of primary hyperparathyroidism increases with age in both sexes. Osteitis fibrosa cystica refers to the radiological pathognomonic skeletal radiological features of primary hyperparathyroidism which include “salt-and-pepper” degranulation of the skull, subperiosteal resorption of the distal phalanges, tapering of the distal clavicle, bone cysts and brown tumors, often associated with skeletal deformities and fractures. Bone pain and swelling are often the presenting symptoms and usually affect the ribs, clavicles, pelvis, and mandible. They sometimes are erroneously suspected of being bone metastases.

  
  

  The full spectrum of osteitis fibrosa cystica is rarely seen nowadays as in most instances the diagnosis of PHPT is made after finding an asymptomatic elevated serum calcium level which prompts the patient’s investigation and diagnosis of PHPT, prior to its full-blown manifestation.

  
  

  In Western countries, about 80% of patients with PHPT are diagnosed as a result of a blood profile done for some unrelated medical condition.

  
  

  Common skeletal manifestations include low BMD, low trabecular bone score (an indirect measure of trabecular microarchitecture and strength independent of BMD), and an increased fracture risk especially in cortical bones such as the distal 1/3 radius which are affected to a larger extent than the proximal femoral and lumbar vertebrae. This pattern of bone loss is different from that seen in postmenopausal women which tends to affect trabecular bone earlier and to a larger extent than cortical bone.

  
  

  Successful parathyroidectomy is associated with significant increases in BMD which tend to occur first and to a larger extent in the trabecular bones. Similarly, bisphosphonates and estrogen increase BMD in patients who do not undergo surgery. The administration of Cinacalcet, however, does not improve BMD although it reduces the serum calcium level.

  
  

  Levels of bone turnover markers are elevated in untreated patients with PHPT, and decrease rapidly, usually within hours after successful surgical parathyroidectomy. This decrease is also seen, albeit less rapidly, in patients treated with estrogen, raloxifene, and bisphosphonates, but not cinacalcet. The decrease in levels of bone turnover markers is associated with an increase in BMD and a reduced fracture risk.

  
  

  Nephrocalcinosis and nephrolithiasis are characteristic features of PHPT because the kidneys have such a pivotal role in calcium metabolism regulating the concentration of serum calcium and phosphate and determining the whole body calcium and phosphate. Factors regulating renal tubular calcium reabsorption include parathyroid hormone, calcium-sensing receptors, filtered sodium load, and tubular calcium transporters. The reduction in glomerular filtration rate often seen in patients with PHPT is due to either complications of PHPT or comorbid conditions. Renal imaging for nephrocalcinosis and nephrolithiasis is recommended. Positive imaging is an indication for surgery. The risk of renal calculi formation should be assessed and above average fluid intake should be encouraged in patients who do not undergo surgery.

  
  

  A number of nonspecific manifestations have been reported in patients with PHPT . Often patients are not aware of these and report dramatic improvements in their quality of life after successful parathyroidiectomy. Psychiatric manifestations range from mild depression and anxiety to paranoid delusions, visual and auditory hallucinations. Patients often have shortened attention spans, impaired concentration, impaired memory, and impaired executive functions and complain of intellectual weariness. Sleep and circadian rhythm disturbances are also reported.

  
  

  PHPT is also associated with an increased left ventricular mass; increased risk of coronary artery disease, hypertension, valvular and myocardial calcifications; and dysfunction of the cardiac microcirculation. Arrhythmias and cardiac mortality in patients with PHPT are increased. Abnormalities in the cerebral circulation have been reported. Peptic ulcer disease and pancreatitis are also seen in primary hyperparathyroidism.

  
  

  Normocalcemic hyperparathyroidism is a variant of PHPT. Its diagnosis is established by finding a normal serum total calcium (adjusted for the albumin level) and ionized calcium in the presence of an elevated serum PTH level on at least three occasions over a period of 3–6 months, after causes of secondary hyperparathyroidism have been excluded. It has been postulated that NPHPT is the first phase of a biphasic disorder which eventually manifests itself at a later stage as hypercalcemic PHPT. NPHPT therefore is considered to be part of the diagnostic spectrum of PHPT.

  
  

  Common causes of elevated PTH and normal serum calcium levels include vitamin D insufficiency/deficiency; chronic renal diseases; hypercalciuria; gastrointestinal diseases (including gluten enteropathy) associated with calcium malabsorption; and a number of medications, including thiazides, bisphosphonates, denosumab, and lithium. These should be ruled out before making a diagnosis of normocalcemic PHPT.

  
  
• 5.
  

  Match the following bone loss:

  
  
  
  
  • (a)
    

    Due to postmenopause estrogen deprivation.

    
    
  • (b)
    

    Due to primary hyperparathyroidism.

    
    
  • (c)
    

    Both.

    
    
  • (d)
    

    Neither.

    
    
  • A.
    

    Affects predominantly skeletal sites with high cortical bone content.

    
    
  • B.
    

    Affects predominantly skeletal sites with high trabecular bone content.

    
    
  • C.
    

    Increased fracture risk.

    
    
  • D.
    

    Increased surface area of the distal radius.

    
    
  • E.
    

    Reduced by bisphosphonates.

  
  
  
  

  Correct answers: A (b); B (a); C (c); D (b); E (c)

  
  

  Comment:

  
  

  Both estrogen deprivation and PHPT induce an increased rate of bone turnover, a reduced bone mass, and an increased fracture risk. However, whereas in postmenopausal women the rate of bone resorption is increased primarily through estrogen deficiency and an increased release of RANK-L which stimulates the formation/activation of osteoclasts, and affects initially the more vascular trabecular bone, such as the vertebrae, in PHPT the increased rate of bone turnover is triggered through the stimulation of receptors on the surface of osteoblasts and preosteoblasts down-regulating sclerostin leading to an increased differentiation, activity, and life span of osteoblasts and increased bone formation. A secondary effect is the increased release of RANK-L by osteoblasts, which activates osteoclastic bone resorption, thus increasing bone turnover. PTH also decreases osteoprotegerin release further increasing osteoclastic bone-resorbing activity and hence rate of bone turnover. Initially hyperparathyroidism targets cortical more than trabecular bone, whereas estrogen deficiency targets trabecular more than cortical bone.

  
  
• 6.
  

  Indications for parathyroid surgery include:

  
  
  
  
  • A.
    

    Hypercalcemia.

    
    
  • B.
    

    Creatinine clearance below 60 mL/min.

    
    
  • C.
    

    Asymptomatic patients with PHPT.

    
    
  • D.
    

    A and C.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  A solitary adenoma is the underlying etiology of primary hyperparathyroidism in 85%–90% of cases. Multiglandular hyperplasia affects about 15% of cases. Parathyroid carcinoma is very rare. Parathyroid surgery should be considered in patients with PHPT especially in the following instances:

  
  
  
  
  • •
    

    Age under 50 years

    
    
  • •
    

    Serum calcium level more than 1.0 mg/dL (0.25 nmol/L) above the upper limit of the normal range, or

    
    
  • •
    

    Creatinine clearance less than 60 mL/min, 24-h urinary calcium exceeds 400 mg, presence of nephrolithiasis, nephrocalcinosis (X-ray, ultrasound, or CT), or

    
    
  • •
    

    DXA lowest T-score: −2.5 or lower at lumbar vertebrae, total hip, femoral neck, or distal 1/3 radius or

    
    
  • •
    

    Fragility fracture, including evidence of vertebral fracture by X-ray, CT, MRI, or VFA

    
    
  • •
    

    Medical surveillance is not possible.

  
  
  
  

  Surgical parathyroidectomy is the only option that potentially cures PHPT. The surgery is minimally invasive, usually performed under local anesthesia and conscious sedation. An index of successful surgery is the serum PTH level dropping by more than 50% into the normal range within 10 min of the surgical removal of the abnormal parathyroid gland(s). Cure rates exceed 98%.

  
  

  Several prospective studies have documented the positive effects of surgical parathyroidectomy in patients with primary hyperparathyroidism on BMD, fracture risk, risk of developing renal calculi, and risk of renal impairment even in asymptomatic patients.

  
  

  Recommended monitoring of patients with PHPT who do not undergo surgery includes :

  
  
  
  
  • •
    

    Annual serum calcium assay.

    
    
  • •
    

    Annual or every 2 years DXA (three sites), X-ray, or VFA if clinically indicated (height loss, back pain).

    
    
  • •
    

    Annual eGFR and serum creatinine.

    
    
  • •
    

    If renal calculi suspected: 24-h biochemical stone profile, renal imaging: X-ray, ultrasound, or CT.

  
  
  
  
• 7.
  

  Pharmacologic management of primary hyperparathyroidism includes:

  
  
  
  
  • A.
    

    Bisphosphonates.

    
    
  • B.
    

    Calcium and vitamin D restriction.

    
    
  • C.
    

    Cinacalcet.

    
    
  • D.
    

    A and C.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: D

  
  

  Comment:

  
  

  For patients with PHPT who refuse or cannot undergo surgery, oral bisphosphonates reduce serum calcium levels, increase BMD, reduce fracture risk, and improve survival, but to a lesser extent than surgical parathyroidectomy. Calcium and vitamin D should not be restricted. Among patients with PHPT those who in addition have hypovitaminosis D tend to have higher rates of bone turnover, lower BMD, and an increased fracture risk. Similarly, postsurgical parathyroidectomy, those patients who have low serum 25-hydroxy-vitamin D level tend to have smaller increases in BMD. It is therefore recommended to assay the serum 25-hydroxy-vitamin D in all patients with PHPT and prescribe vitamin D supplementation to those with a serum level below 20 ng/mL. Bisphosphonates, estrogen, and raloxifene are also useful in the management of patients who do not undergo surgical treatment as they induce an increase in BMD and reduce the fracture risk.

  
  

  Cinacalcet, a calcimimetic, activates CaSR by increasing their affinity for ionized calcium. When administered in doses of 30–50 mg twice a day, the serum calcium normalizes in over two-thirds of patients and PTH levels decrease. These changes, however, are associated with neither a significant increase in BMD nor with a reduced fracture risk.

  
  

  It is important to ensure the patient has an adequate fluid intake to avoid volume contraction which may exacerbate the degree of hypercalcemia and may lead to a hypercalcemic crisis.

  
  
• 8.
  

  Cinacalcet:

  
  
  
  
  • A.
    

    Decreases the production of PTH

    
    
  • B.
    

    Increases the sensitivity of calcium receptors

    
    
  • C.
    

    Lowers the serum calcium

    
    
  • D.
    

    Is approved for the treatment of patients with primary and secondary hyperparathyroidism

    
    
  • E.
    

    All of the above

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  Cinacalcet increases the sensitivity of calcium receptors to activation by extracellular calcium, thus decreasing the synthesis and secretion of PTH resulting in a lower serum calcium level. There is a paucity of research studies on Cinacalcet. One multicenter, international, phase 3 RCT enrolled 67 patients with moderate PHPT who could not undergo parathyroidectomy. For the first 6 months, patients were randomly allocated to either cinacalcet or placebo, and for the following 6 months, all subjects were receiving cinacalcet, starting at 30 mg twice a day. The dose (median) of cinacalcet titrated to maintain normocalcemia was 60.2 mg/day. The serum calcium level normalized (<2.575 mmol/L) in 75.8% of patients receiving cinacalcet versus 0% in the placebo group. Similarly, PTH blood levels decreased by 23.8% versus 1.1% in the placebo group. The phosphate level increased from a mean of 0.665 to 0.885 mmol/L.

  
  

  A recent meta-regression study of 28 manuscripts reported that whereas the serum calcium levels normalized in 90% (CI 0.82–0.96) of the enrolled subjects, with a mean reduction of serum calcium levels of 0.412 mmol/L (CI 0.343–0.481 mmol/L), the serum PTH levels normalized in only 10% (CI 0.02–0.23) of the subjects. The main side effects reported included mild to moderate gastrointestinal symptoms (nausea or vomiting 23%) but only 3% hypocalcemia.

  
  
• 9.
  

  Medical management of patients with primary hyperparathyroidism includes:

  
  
  
  
  • A.
    

    Adequate calcium intake.

    
    
  • B.
    

    Adequate vitamin D intake.

    
    
  • C.
    

    Adequate hydration.

    
    
  • D.
    

    Hydrochlorothiazides.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  Optimum calcium intake should be maintained. Whereas calcium inhibits parathyroid proliferation, a low intake of calcium stimulates PTH production. Indeed, the 22-year-long Nurses’ Health Study showed that the relative risk of PHPT was reduced in the group with the highest dietary calcium intake compared to the group with the lowest dietary calcium intake.

  
  

  Optimum vitamin D intake should also be maintained. Vitamin D insufficiency is more prevalent in patients with PHPT than in the general population, and an inverse relationship has been demonstrated between elevated PTH and low vitamin D levels. Vitamin D insufficiency also has been identified as an independent risk factor for postoperative hypocalcemia and the hungry bone syndrome.

  
  

  Adequate hydration should be maintained to avoid hypercalcemic crises. Hydrochlorothiazides also should be avoided because they stimulate calcium reabsorption in the distal renal tubule.

  
  
• 10.
  

  Familial hypocalciuric hypercalcemia (FHH):

  
  
  
  
  • A.
    

    Parathyroid hormone levels are always elevated.

    
    
  • B.
    

    Parathyroidectomy is the treatment of choice.

    
    
  • C.
    

    Hypermagnesemia is a characteristic feature.

    
    
  • D.
    

    A, B, and C.

    
    
  • E.
    

    A and B.

  
  
  
  

  Correct answer: C

  
  

  Comments:

  
  

  Apart from primary hyperparathyroidism (PHPT), the main causes of hypercalcemia and elevated/high normal PTH level include familial hypocalciuric hypercalcemia (FHH), malignancy-associated hypercalcemia, lithium therapy, thiazide therapy, and tertiary hyperparathyroidism associated with chronic renal disease. In patients with primary hyperparathyroidism, the urinary calcium level is elevated and the serum phosphorus concentration is usually at the lower limits of normality.

  
  

  Familial Hypocalciuric Hypercalcemia (FHH), also known as Familial Benign Hypercalcemia, is a benign condition characterized by hypercalcemia, hypocalciuria (24-h urine calcium excretion less than 100 mg), normal to elevated levels of PTH, and hypermagnesemia. It is due to autosomal dominant loss-of-function mutations of the calcium-sensing receptors gene (CaSRs) in the parathyroid glands and kidneys. Apart from multiple myeloma, hypercalcemia associated with malignancy is a relatively rare and late finding in patients with malignancies who are rarely asymptomatic.

  
  

  In the parathyroid glands, CaSRs trigger the feedback inhibition of parathyroid hormone release in response to a rise in the serum calcium concentration. Loss-of-function mutations in CaSRs impair this feedback inhibition of parathyroid hormone secretion in response to a rise in the blood calcium concentration and lead to hypercalcemia with inappropriately normal or mildly elevated levels of parathyroid hormone. The degree of hypercalcemia depends on the degree to which the mutation affects the function of CaSRs.

  
  

  In the kidneys, CaSRs are involved in the feedback inhibition of parathyroid-independent renal tubular calcium reabsorption. Loss-of-function mutations in CaSRs interfere with the feedback inhibition of calcium reabsorption in response to a rise in the serum calcium concentration. Calcium continues to be reabsorbed in the renal tubules resulting in hypercalcemia and hypocalciuria. The renal calcium/creatinine clearance ratio is usually less than 0.01 in patients with FHH, but higher in patients with PHPT.

  
  

  Although usually asymptomatic, some patients with FHH may complain of generalized weakness, fatigue, difficulties concentrating, and polydipsia. Pancreatitis and chondrocalcinosis are rare complications. Often FHH does not require treatment and is accidentally discovered when the patient is having serum biochemical tests done for some unrelated condition. It should be differentiated from PHPT because whereas parathyroidectomy is usually the treatment of choice for primary hyperparathyroidism, parathyroidectomy in FHH is not indicated, and is inappropriate, because it does not affect the FHH-associated hypercalcemia. Genetic testing can assist in the diagnosis of FHH.

Case summary

Follow-up recommendations

• •
  

  Vary whether patient treated surgically or medically.

Key points

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