I. What every physician needs to know.
Primary Hyperparathyroidism (PHPT) results from overproduction of parathyroid hormone, usually secondary to parathyroid adenoma or hyperplasia. It is most often diagnosed in asymptomatic outpatients when routine labs demonstrate hypercalcemia. In the inpatient setting, diagnosis may similarly occur in the evaluation of asymptomatic or symptomatic hypercalcemia. Excess secretion of parathyroid hormone by the parathyroid gland(s) results in an elevated serum calcium levels via increased turnover of bone, increased renal reabsorption of calcium and increased production of calcitriol.
In 85% of cases, PHPT is from a single overfunctioning parathyroid adenoma. Fifteen percent of cases are from parathyroid hyperplasia, and less than 1% of cases are secondary to parathyroid carcinoma. Familial cases of hyperparathyroidism may be part of Multiple Endocrine Neoplasia type 1 or 2a and typically involve multiple parathyroid glands. Parathyroid surgery is recommended for treatment of symptomatic PHPT as well as some individuals without overt symptoms as well.
II. Diagnostic Confirmation: Are you sure your patient has Primary Hyperparathyroidism?
Elevated or normal serum calcium levels in the presence of severe osteoporosis or recurrent nephrolithiasis with calcium stones warrant evaluation of PHPT by checking an intact PTH. In 80-90% of patients with PHPT, the parathyroid hormone is elevated. Diagnosis is usually based on an elevated serum calcium level with an inappropriately normal or elevated serum PTH with normal renal function.
A. History Part I: Pattern Recognition:
Patients with PHPT can be symptomatic or asymptomatic. Those who are symptomatic experience bone and renal effects or symptoms from hypercalcemia itself. Excess parathyroid hormone increases osteoclastic activity and bone turnover which causes osteopenia and osteoporosis. Increasing urine calcium reabsorption with subsequent hypercalciuria can produce nephrocalcinosis and nephrolithiasis, the latter being the most common overt complication of PHPT.
Hypercalcemia produces a constellation of non specific symptoms which may correlate more with the rate of rise of the calcium than the absolute value of the calcium itself. Expression of those symptoms can vary by age, gender and individual susceptibility. Patients may have neurocognitive effects such as anxiety, depression or memory impairment or gastrointestinal disturbances such as abdominal pain or constipation. Neuromuscular weakness may ensue. Given deposition of calcium on cardiac vessels and heart valves, patients may develop hypertension, valvular heart disease and coronary artery disease.
Osteitis fibrosa cystica (demineralized skeleton), a late manifestation of PHPT, is infrequently seen. It occurs with severe hyperparathyroidism and manifests as increased subperiosteal bone resorption, salt and pepper appearance of the skull imaging, and the formation of brown tumors secondary to osteoclasts mixed with poorly mineralized bone.
Only 1-2% of patients with PHPT will experience parathyroid crisis which is defined as severe hypercalcemia (serum calcium greater than 15 mg/dl) and severe symptoms of hypercalcemia.
B. History Part 2: Prevalence:
The age-adjusted incidence of PHPT from a racially mixed database from a single center fluctuated from 34 to 120 per 100,000 person-years (mean 66) among women and from 13 to 36 (mean 25) among men. With advancing age, incidence increases and sex differences become more pronounced. Peak incidence is in women aged between 50-60 years with a 2-3:1 female to male ratio. In the United States, there are nearly 100,000 new cases every year. PHPT is the number one cause of hypercalcemia detected in outpatients. It is the second most common cause of hypercalcemia in inpatients, with malignancy being the first. Hyperparathyroidism may be due to familial syndromes. More than 10% of patients with primary hyperparathyroidism will have a mutation in one of 11 genes.
C. History Part 3: Competing diagnoses that can mimic Primary Hyperparathyroidism.
Hypercalcemia from various causes may mimic PHPT. Those with hypercalcemia of malignancy (humoral or that associated with bone destruction) typically have higher levels of calcium on presentation than those with PHPT but PTH is low or undetectable (PTH-independent hypercalcemia). In addition, symptoms of the malignancy are often present by the time the hypercalcemia is detected. Familial hypocalciuric hypercalcemia is a rare familial condition with autosomal dominant inheritance with normal or slightly elevated PTH levels but low urine excretion of calcium and is not treated by parathyroidectomy. Secondary hyperparathyroidism is the appropriate increase in parathyroid hormone levels to a low calcium level, a state that can be seen in those with decreased vitamin D levels, whether it be from renal failure, malabsorption or decreased dietary intake.
Thiazide diuretics increase proximal tubular reabsorption of calcium, but do not cause hypercalcemia in those with normally functioning parathyroid glands; the increased urine calcium reabsorption causes a mildly elevated serum calcium level which in turn decreases parathyroid hormone levels to ultimately normalize serum calcium levels. However, those with PHPT have autonomously elevated PTH levels (that do not respond to negative feedback), and serum calcium levels remain elevated. Patients on thiazide diuretics with hypercalcemia who are found to have elevated intact PTH levels on evaluation should have measurements of calcium and parathyroid hormone repeated 3 months after the discontinuation of the thiazide diuretic.
Long term lithium use can result in both elevated parathyroid hormone and calcium levels. Unlike thiazide diuretics, lithium directly acts on the parathyroid gland(s) to increase production of parathyroid hormone. Ultrasound may show enlargement of the parathyroid glands. Patients who are on lithium and have mild elevations in PTH and calcium with mild symptoms may continue the medication with close monitoring. However, those with significant symptoms and/or increases in calcium levels should stop the medication. In some cases, the hyperparathyroidism persists after discontinuation of lithium, and these patients may need referral for parathyroid surgery for near total parathyroidectomy.
D. Physical Examination Findings.
Physical exam is typically non-contributory in PHPT. When a neck mass is appreciated it may be a thyroid nodule, or, rarely, a parathyroid carcinoma. Rarely, band keratopathy, or the deposition of calcium on the cornea can be seen. However, this physical exam finding can be seen in all those with chronic hypercalcemia and is not unique to PHPT.
E. What diagnostic tests should be performed?
Primary hyperparathyroidism is a biochemical diagnosis.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
If the PTH is elevated, a creatinine should be checked to ensure that there is no renal impairment from the hypercalcemia itself, and to ensure that elevated parathyroid level does not stem from renal failure (secondary hyperparathyroidism). There are two generations of PTH assays that can be used to measure the intact PTH level. Either second or third generation can be used as studies have not shown a difference in sensitivities in detecting PTH levels. A 24-hour urine test should be done if there is concern for familial hypocalciuric hypercalcemia (FHH), which also typically results in elevated serum calcium and parathyroid hormone levels. Those with FHH have less than 200 mg of urine calcium in a 24-hour urine collection (about 75% have less than 100 mg of urine calcium/24-hour collection), whereas those with PHPT have greater than 200 mg of urine calcium in a 24-hour sample.
Vitamin D levels should also be checked given the role of vitamin D in calcium homeostasis, and the high prevalence of vitamin D deficiency. PHPT and concomitant calcium and vitamin D deficiency can also result in less than 100 mg of urine calcium in a 24-hour sample. In addition, those with PHPT and vitamin D deficiency may have normal levels of serum calcium and ionized calcium. Vitamin D deficiency can cause secondary hyperparathyroidism and needs to be excluded. The values that should be used to define vitamin D deficiency are 50 nmol/L (20 ng/dl) for insufficiency and 25 nmol/L (10 ng/dl) for deficiency. Measuring the 1,25 (OH)2D levels is not recommended unless PTH independent causes of hypercalcemia are being worked up. There is evidence that primary hyperparathyroidism disease manifestations are more active in settings of vitamin D deficiency.
There is an increasingly identified entity called normocalcemic primary hyperparathyroidism (NPHPT), which occurs when there is normal total calcium with elevated PTH levels. This could be due to a few different reasons. It could be due to vitamin D deficiency masking the PHPT. Another possibility is that it could be from developing chronic kidney disease as the PTH starts increasing once GFR < 60. Certain drugs can cause these lab findings such as thiazides, bisphosphonates, denosumab, and lithium. Finally, it has been suggested that elevated PTH with normal serum total and ionized calcium could be the preceding phase to overt PHPT and part of the continuum of this disorder. It is recommended that these patients have regular serum calcium levels evaluated to monitor for progression to hypercalcemic hyperparathyroidism.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
No imaging studies are needed to establish the diagnosis. However, Endocrinologists and endocrine surgeons will order imaging for surgical candidates to guide their surgical approach. Results of sestamibi, parathyroid ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scan of the parathyroids are used to help determine if the patient is a candidate for a minimally invasive parathyroidectomy or needs a four-gland exploration.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
Ionized calcium is unnecessary to make the diagnosis unless there is significant hypo or hyperalbuminemia that may be affecting serum calcium levels.
III. Default Management.
Inpatient treatment of primary hyperparathyroidism focuses on treating hypercalcemia itself or bone or renal effects such as osteoporotic fractures or nephrolithiasis. Those on a thiazide diuretic who have elevated parathyroid levels should have the thiazide diuretic discontinued. PTH levels should be measured after three months of discontinuation of the thiazide. Consideration of parathyroidectomy can occur as an outpatient after consultation with an endocrinologist and endocrine surgeon.
A. Immediate management.
While inpatient, goal is to stabilize significant symptoms of hypercalcemia and order workup to establish diagnosis of PHPT, which can subsequently be completed in the outpatient setting. Those with symptomatic hypercalcemia should be managed as others with IV fluids and possibly bisphosphonates to keep their serum calcium level between 12-14 mg/dl, and, as with those with fractures or kidney stones, can have evaluation for and consideration of parathyroid surgery as an outpatient.
B. Physical Examination Tips to Guide Management.
Thorough neck exam should be performed for evaluation of possible concurrent thyroid goiter as well as lymphadenopathy.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Calcium level should be monitored in order to tailor management. Renal function panel, iPTH, 25 hydroxy vitamin D, 24-hour urine calcium and creatinine, 1,25 dihydroxyvitamin D, SPEP/UPEP, PTHrP should be ordered to workup hypercalcemia and establish clear diagnosis of PHPT. If there is concern for genetic involvement, screening is recommended for MEN1, MEN2, FHH, and HPT-JT syndrome. Patients to consider this in include young patients, those with family histories of endocrinopathies, and if they have multiglandular disease.
D. Long-term management.
Parathyroid surgery is the only definitive curative treatment and is indicated for those with symptomatic hypercalcemia. About 1/3 of asymptomatic hyperparathyroid patients have been shown to develop features of the disease (kidney stones, worsening hypercalcemia, reduced bone mineral density), within 15 years of follow-up. The NIH Consensus Task force on asymptomatic PHPT established that the following patients should have parathyroid surgery for asymptomatic disease:
Serum calcium greater than 1 mg/dl above the upper limit of normal;
Creatinine clearance less than 60 mg/min;
Age less than 50 years;
Bone Density less than 2.5 standard deviations below peak bone mass (T<-2.5);
Renal stone evaluation via x-ray, ultrasound, or CT. If stones or nephrocalcinosis are present, surgery is recommended;
Patients with a fragility fracture.
Given that some patients may have subclinical symptoms and that others may be lost to followup, some authorities advocate greater use of parathyroid surgery for PHPT. Work up recommended for these asymptomatic patients includes biochemistry panel, 25 hydroxy vitamin D, iPTH levels, BMD by DXA (to include lumbar spine hip, and distal 1/3 radius), vertebral spine assessment with lateral spine X rays or VFA, 24-hour urine for (calcium, creatinine, creatinine clearance, stone risk profile), and abdominal imaging by x-ray, ultrasound or CT scan.
Those asymptomatic patients who do not meet the criteria for surgery need to be monitored. This is done to detect changes in serum calcium levels, significant reductions in BMD, occurrence of fragility fractures or changes in renal endpoint. Once a patient meets any of the criteria from above they should be evaluated for surgery. Finally, their vitamin D levels must be kept repleted and monitored.
In terms of long-term management for patients with asymptomatic normocalcemic PHPT, a calcium and PTH should be done yearly along with DXA every 1-2 years. If there is progression to hypercalcemic PHPT, treat as indicated. If there is progression of disease with worsening BMD or fracture, or kidney stone/nephrocalcinosis, the patient should be evaluated for surgery.
Pharmacological agents may be considered in patients who meet surgical criteria, but cannot or will not undergo surgery. Among the bisphosphonates, alendronate has the best evidence for improving BMD. If the goal is to lower serum calcium levels, cinacalcet can be used but this will not affect the BMD. If there is no intention to improve the BMD or to lower serum calcium levels, pharmacological agents are generally not used.
E. Common Pitfalls and Side-Effects of Management.
Patients who do have parathyroid surgery should be seen by endocrinologists post operatively to be monitored for hungry bone syndrome and the hypocalcemia that may ensue. About 10-30% patients experience transient hypocalcemia. Hungry bone syndrome is more common in patients with elevated alkaline phosphatase levels and low 25 hydroxy vitamin D preoperatively.
IV. Management with Co-Morbidities.
PHPT is a biochemical diagnosis and surgical treatment can be undertaken.
A. Renal Insufficiency.
No change in standard management.
B. Liver Insufficiency.
No change in standard management.
C. Systolic and Diastolic Heart Failure.
Those with impaired systolic and diastolic function should be very closely monitored while receiving IV fluids for correction of hypercalcemia. If diagnosis of PHPT is established and patient meets criteria for surgery, they would require cardiac clearance before surgery. If they are deemed poor surgical candidates, medical management of PHPT with bisphosphonate and/or cinacalcet would be more appropriate.
D. Coronary Artery Disease or Peripheral Vascular Disease.
Underlying CAD should be included in peri-operative risk assessment.
E. Diabetes or other Endocrine issues.
No change in standard management.
No change in standard management.
G. Immunosuppression (HIV, chronic steroids, etc.)
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD).
No change in standard management.
I. Gastrointestinal or Nutrition Issues.
Those with gastrointestinal problems may not be able to take a bisphosphonate by mouth, which would be part of the medical treatment of osteoporosis induced by PHPT.
J. Hematologic or Coagulation Issues.
No change in standard management.
K. Dementia or Psychiatric Illness/Treatment.
Those who are on long term lithium use should have calcium levels monitored routinely. If both calcium and PTH levels are elevated significantly and/or patient is symptomatic, hospitalist should work with the psychiatry team to discontinue lithium and use another agent. Irreversible parathyroid hyperplasia caused from long term lithium therapy may require surgical resection.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
B. Anticipated Length of Stay.
Patients with PHPT require treatment of the reason for admission (hypercalcemia, renal stones or osteoporotic fracture). Ongoing monitoring and decisions regarding surgical cure can be made as an outpatient.
C. When is the Patient Ready for Discharge?
Patient can be discharged when symptomatic hypercalcemia is treated.
D. Arranging for Clinic Follow-up.
1. When should clinic follow up be arranged and with whom?
Those discharged with symptomatic PHPT should follow up for recheck of calcium levels within 1 week of discharge. Patients should also see an endocrinologist within 1-2 weeks of discharge that can arrange for surgical consultation.
2. What tests should be conducted prior to discharge to enable best clinic first visit?
Calcium, phosphorous, magnesium, albumin, creatinine, iPTH, 24-hour urine calcium and creatinine and 25 hydroxy vitamin D levels.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?
Calcium level should be followed closely for those following up for treatment of hypercalcemia.
E. Placement Considerations.
F. Prognosis and Patient Counseling.
Patients who are asymptomatic will need their primary care doctor to follow their calcium levels annually and to perform bone density testing every 1-2 years to evaluate for osteoporosis. Those with clear symptoms or associated conditions such as osteoporosis or nephrolithiasis should have parathyroidectomy, which is definitive treatment. Surgery is likely to benefit patients due to high cure rates, low complication rates, and the increased chances of reversing skeletal effects.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
VII. What’s the Evidence?
Silverberg, SJ, Clarke, BL, Peacock, M, Bandeira, F, Boutroy, S, Cusano, NE, Dempster, D, Lewiecki, EM, Liu, JM, Minisola, S, Rejnmark, L, Silva, BC, Walker, MD, Bilezikian, JP. “Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Fourth International Worksop”. J Clin Endocrinol Metab.. vol. 99. 2014 Oct. pp. 3580-94.
Udelsman, R, Åkerström, G, Biagini, C, Duh, QY, Miccoli, P, Niederle, B, Tonelli, F. “The Surgical Management of Asymptomatic Primary Hyperparathyroidism”. J Clin Endocrinol Metab.. vol. 99. 2014 Oct. pp. 3595-606.
Bilezikian, JP, Brandi, ML, Eastell, R, Silverberg, SJ, Udelsman, R, Marcocci, C, Potts, JT. “Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism”. J Clin Endocrinol Metab.. vol. 99. 2014 Oct. pp. 3561-9.
Silverberg, SJ, Clarke, BL, Peacock, M, Bandeira, F, Boutroy, S, Cusano, NE, Dempster, D, Lewiecki, EM, Liu, JM, Minisola, S, Rejnmark, L, Silva, BC, Walker, MD, Bilezikian, JP. “Current issues in the Presentation of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Fourth International Workshop”. J Clin Endocrinol Metab.. vol. 99. 2014 Oct. pp. 3580-94.
Marcocci, C, Bollerslev, J, Khan, AA, Shoback, DM. “Medical Management of Primary Hyperparathyroidism: Proceedings of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism”. J Clin Endocrinol Metab.. vol. 99. 2014 Oct. pp. 3607-18.
“Incidence and turbulence of primary hyperparathyroidism in a racially mixed population”. JCEM. vol. 98. 2013 march. pp. 1122-1129.
Fraser, WD. “Hyperparathyroidism”. Lancet. vol. 364. 2009. pp. 145-58.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Primary Hyperparathyroidism?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Primary Hyperparathyroidism.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management.
- IV. Management with Co-Morbidities.
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure.
- D. Coronary Artery Disease or Peripheral Vascular Disease.
- E. Diabetes or other Endocrine issues.
- F. Malignancy.
- G. Immunosuppression (HIV, chronic steroids, etc.)
- H. Primary Lung Disease (COPD, Asthma, ILD).
- I. Gastrointestinal or Nutrition Issues.
- J. Hematologic or Coagulation Issues.
- K. Dementia or Psychiatric Illness/Treatment.
- V. Transitions of Care.
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge?
- D. Arranging for Clinic Follow-up.
- 1. When should clinic follow up be arranged and with whom?
- 2. What tests should be conducted prior to discharge to enable best clinic first visit?
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures.
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.