It is also known by the names osteitis fibrosa cystica, von Recklinghausen’s disease and parathyrotoxicosis.
Physiology of Parathyroid Hormone
Parathryoid hormone is secreted parathryroid glands located in vicinity of thyroid gland in the neck. Usually two superior and two inferior glands are present. Some times three glands are present, sometimes more. As many as 12 glands may be present in some persons.
[Read more about parathyroid gland and normal metabolism and control of parathyroid hormone.]
Parathyroid hormone or PTH maintains the serum calcium level.
When the serum calcium level is low, it stimulates secretion of parathyroid hormone. The normal level is restored by extracting calcium stored in the bone. Parathyroid hormone helps in dissolving bone calcium in the blood by promoting actions of osteoclasts.
PTH, along with vitamin D, also causes to decease the calcium excretion in urine by promoting absorption of calcium in renal tubules.
Conversely, when the serum calcium level is high, there occurs a decrease in parathyroid levels and the excess calcium is excreted and deposited in bone.
Parathyroid lowers the serum phosphorus level by increasing excretion of phosphorus by inhibiting renal tubular resorption.
A rise in serum phosphorus levels also causes secretion of parathyroid hormone.
It inhibits the calcifying effect of vitamin D and maintains ionic form of calcium and phosphorus by increasing their solubilities in blood.
Hyperparathyroidim secretion can be primary or secondary.
Secondary hyperplasia develops as a response to serum calcium and phosphorus levels and is discussed separately.
Causes of Primary Hyperparathyroidism
- Adenoma of Parathyroid glands [most common cause]
- Single gland involvement – 85%
- Multiple gland involvement – 15% of cases
- Parathyroid carcinoma
- Multiple endocrine neoplasia syndromes (MEN 1 or MEN 2a)
- Hyperparathyroid jaw tumor syndrome
- familial isolated hyperparathyroidism
- Familial hypocalciuric hypercalcemia
Pathophysiology of Primary Hyperparathyroidism
When PTH is secreted in excess, it causes resorption of the bone by increasing osteoclasts and decreasing osteoblasts. Osteoclasts are the cells that resorb the bone whereas osteoblasts are the cells that participate in bone formations and mineralization.
The parathyroid hormone causes fibrous replacement of marrow too.
Resorption of the bone causes increase of calcium and phospohorus levels in blood. Both of these are excreted by kidneys but phosphorus is excreted more readily. This leads to elevation of blood calcium level and the phosphorus level is lowered.
In order to attempt at the restoration of resorbed bone, alkaline phosphatase level is elevated.
The cause of rise in PTH is usually an adenoma of parathyroid gland.
The rise of PTH and compensatory effects cause the changes in bone and other tissues leading to cysts in the bones, deformities and pathological fractures. Skeletal changes are discussed in detail below.
Side by side, during active stage of hyperparathyroidism, an attempt at replacement is by osteoid formation is especially at sites of stress, fractures, and bending deformities.
Hypercalcemia can cause muscle weakness, fatigue, dehydration, nausea and vomiting, and in severe cases, coma and death. But these manifestations are of hypercalcemia and not restricted to hyperparathyroidism.
Hypercalcemia can increase gastric acid secretion, and persons with hyperparathyroidism may have a higher prevalence of peptic ulcer disease. Rarely pancreatitis have also been attributed to hypercalcemia.
Neuropsychiatric manifestations are may include depression, confusion, or other subtle deficits.
Skeletal Changes in Hyperparathyroidism
Bone Resorption and Bony Deformities
The chronic excessive resorption of calcium from bone caused by excessive parathyroid hormone can result in osteopenia. Parathyroid hormone causes resorption of bones causing thinning of cortices and widening of medullae. Haversian canals are enlarged, and cancellous bones can become papery thin.
In severe cases, this may result in osteitis fibrosa cystica, which is characterized by subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, salt-and-pepper appearance of the skull, and brown tumors of the long bones. This is not commonly seen now.
Thin long bones bend under the stress of weight bearing. Intervertebral disks become ballooned as they indent soft vertebral bodies. This is noted as codfish spine on radiographs.
Because the bones have been thinned and weakened, slight trauma, even under physiological loads can lead to fractures.
Under effect of increased parathyroid hormone, marrow turns fibrous and anemia may result.
These tumors are not actually tumors but are localized accumulations of hemorrhage and blood pigments and reactive masses of osteoclasts in a spindle-cell stroma. This is formed where bone resorption has been thorough. Healing may occur by fibrous tissue replacement, or the center may liquefy, and a bone cyst remains.
Multiple Bone Cysts
These cysts are unilocular or multilocular. They expand the cortex, leaving a paper-thin covering, and are often the site of pathologic fractures. The walls are composed of dense fibrous tissue, and the contents are serous fluid and fibrin. [Note difference from Brown tumors]
[ After parathyroidectomy, osteoclasts reduce and osteoblastic activity increases leading to thickening of cortices. Brown tumors disappear and are replaced by bone or get converted into cysts. The smaller cysts usually go but the large cysts may persist.
Bony deformities generally remain. Marrow elements are slowly restored, and the blood picture improves.]
Symptoms and Signs of Primary Hyperparathyroidism
The classical phrase to remember the clinical picture of primary hyperparathyroidism is s “Bones, stones, abdominal groans, and psychic moans”. But with earlier diagnostic abilities and routine monitoring of calcium levels, most of the primary hyperparathyroidism patients are caught in asymptomatic hypercalcemia now.
- Severe pain and tenderness in lower limbs and back
- Generalized muscle weakness and hypotonia
- Pathologic fractures and delayed union
- Deformity of limbs and spine
- Chondrocalcinosis have also been reported.
- Osteitis fibrosa cystic [described in pathophysiology, almost obsolete now]
- Increase in volume of urine – polyuria [due to hyperphosphaturia]
- Increased thirst in take of water – polydypsia [due to hyperphosphaturia]
- Renal calculi
- Nephrocalcinosis – Calcium deposition in renal parenchyma
- Renal colic
- Urinary infections and uremia in rare cases.
- Loss of appetite
- Abdominal pain
- Peptic ulcer disease
- Acute pancreatitis.
- Proximal myopathy
- Weakness and easy fatigability
- Concentration and Memory problems
- Shortened QT interval on ECG
- and left ventricular hypertrophy
Physical examination findings are usually noncontributory. A palpable neck mass in rare cases may indicate parathyroid cancer.
- Familial Benign Hypocalciuric Hypercalcemia [FHH]
- Lithium-induced hypercalcemia
- Cancer-induced hypercalcemia
- vitamin D intoxication
Diagnosis of Primary Hyperparathyroidism
Diagnosis of primary hyperparahryroidism is established by an elevated intact parathyroid hormone level with an elevated ionized serum calcium level.
- Total serum calcium – to know increased calcium levels
- Albumin levels
- Ionized calcium levels
- Intact parathyroid hormone level
- A 24-hour urine calcium [ to rule out FHH]
- Serum phosphate levels
Imaging studies are not used to make the diagnosis of primary hyperparathyroidism but to make a decision about surgery and its extent.
As the surgical recommendation for majority of the patient remains complete parathyroid exploration with resection of all involved glands, imaging studies may be unnecessary.
In patients with recurrent or persistent hyperparathyroidism after a previous surgical exploration, an imaging to localize involved glands is definitely indicated.
It is a safe and widely used for localization of abnormal parathyroid glands. Its accuracy rates that compare favorably with the accuracy of traditional but is not reliable in detecting multigland disease.
Radiolabeled sestamibi is also a widely used technique. It is uptaken by all thyroid and parathyroid glands but persists in abnormal parathyroid tissue. Therefore, on delayed images, an abnormal parathyroid is seen as a persistent focus of activity. But this investigation is not sensitive in case of multiglandular disease.
SPECT stands for single photon emission computed tomography that uses gamma rays. This scan when combined with radionuclide scanning is highly effective in localization of parathyroid adenomas. It is extremely useful in cases of an ectopic adenoma [in mediastinum] or previously failed surgical exploration.
CT scanning and magnetic resonance imaging are have also been used also to locate abnormal parathyroid glands. While CT is not that sensitive, MRI can be useful, particularly in cases of recurrent or persistent disease and in ectopic locations
Dual-energy radiographic absorptiometry is a useful to demonstrate osteopenia.
Early findings consist only of generalized deossification. The trabeculae become thinned, transverse trabeculae disappear, and cortices are narrowed.
As the disease progresses, cysts appear throughout the skeleton, bending deformities develop
The skull displays a diffuse osteoporosis described a pinhead stippling or salt and pepper degranulation. Vertebrae are osteoprotic and deeply indented by ballooned disks. Collapse of the bodies is frequent.
Dental films reveal demineralization of the mandible and, disappearance of the lamina dura .
Thinning of cortices is seen especially in distal third of radius as hyperparathyroidism preferentially affects the cortical bone at the radius. Subperiosteal bone resorption in the phalanges is also seen.
Xray findings are summarized below-
- Subperiosteal bone resorption [Most consistent and specific skeletal finding of hyperparathyroidism ]
- Subchondral resorption
- Lateral end of the clavicles
- Symphysis pubis
- Sacroiliac joints
- Subligamentous resorption
- Intracortical resorption
- Cigar/oval shaped radiolucency in cortex
- Terminal tuft erosion in phalanges
- Rugger-jersey spine
- Brown tumours
- Salt and pepper sign in skull (pepper pot skull)- Multiple tiny hyperlucent areas in the skull vault caused by resorption of trabecular bone
Treatment of Primary Hyperparathyroidism
Surgical excision of the abnormal parathyroid glands offers the only permanent, curative treatment for primary hyperparathyroidism.
There are two groups of patients with hyperparathyroidism
All symptomatic patients with symptomatic disease should undergo surgery.
Guidelines for surgery in hyperparathyroidism are
- One mg/dL above the upper limit of the reference range for serum calcium
- Twenty-four-hour urinary calcium excretion greater than 400 mg
- A 30% reduction in creatinine clearance
- Bone mineral density T-score below -2.5 at any site
- Age younger than 50 years
For patients with asymptomatic hyperparathyroidism
- Serum calcium and creatinine levels every 6 months
- annual bone mineral density (all 3 sites).
Some authors recommend surgical excision of the gland in all the cases, including asymptomatic patients except for those patients who are not able to tolerate surgery.
It is argued so because
- Surgery is generally well tolerated
- Prevents further complications
- Reverses symptoms like fatigue and depression which patients may not realize they have
- Monitoring is expensive and cumbersome
Management of Acute Severe Hypercalcemia
- Sodium chloride to restore intravascular volume
- Diuretics such as furosemide once the volume is restored.
- IV bisphosphonate
Complete Neck Exploration and Excision of all Abnormal Glands
Classical recommendation is complete neck exploration with identification of all parathyroid glands and removal of all abnormal glands.
But 85% of cases of primary hyperparathyroidism are caused by a single adenoma. So dissecting full neck for a single adenoma is unnecessary.
Directed parathyroidectomy uses imaging localize the abnormal gland [sestamibi scanning or ultrasonography]. Only the involved gland is removed then and other glands are not visualized.
To ensure that no abnormal glands are present after excision intraoperative parathyroid hormone assay is done. [half life of the hormone – 4 minutes]. A fall in the level confirms that no abnormal gland is present, otherwise the procedure is continued with further exploration.
Directed parathyroidectomy should be performed only in centers where intraoperative parathyroid hormone assay can be done.
Total Parathyroidectomy with Autotransplantation
This is done for cases of familial disease, such as MEN 1. After removal of parathyroid, some tissue is cryopreserved whereas other is autotransplanted to forearm.
Monitoring of the patient
- Clinical signs and symptoms of primary hyperparathyroidism on an annual basis.
- Serum creatinine level and a 3-site dual-energy radiographic absorptiometry study should also be obtained on annual basis.
- Serum calcium should be checked every 6 months.
- Daily calcium intake and a vitamin D
- Good hydration and exercise
- Medications – Thiazides, diuretics, and lithium.
- Drug Therapy
- Estrogen therapy in postmenopausal women [risky]
- Raloxifene [Selective estrogen receptor modulators]
- Bisphosphonates [alendronate] – improves bone mineral density
- Cinacalcet – Calcimimetic drug that activates the calcium-sensing receptor and inhibits parathyroid cell function.
Complications of Primary Hyperparathyrodism
Hypocalcemia is a common problem after surgery, especially after full parathyroid exploration. Postoperatively, calcium levels must be monitored every 12 hours until stabilization.
The nadir of serum calcium usually occurs 24-72 hours after surgery. Not all patients become symptomatic.
If hypoarthyroidism persists beyond postoperative period, , oral supplementation with calcium and vitamin D is required.
At 1-2 weeks postoperatively normal calcium levels [irrespective of increased parathyroid levels] indicates absence of persistent disease in most patients.
Further, periodic disease, periodic serum calcium levels are determined to recurrence or persistence.
Here is a summary of Hyperparathyroidism in general
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