You are in: eMedicine Specialties > Radiology > MUSCULOSKELETAL Hyperparathyroidism, PrimaryArticle Last Updated: Jan 24, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Bonnie Freitas, MD, Assistant Professor, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland Bonnie Freitas is a member of the following medical societies: Alpha Omega Alpha and American College of Physicians-American Society of Internal Medicine Coauthor(s): Alex Freitas, MD, Assistant Professor, UCLA Department of Radiology, Assistant Chief of Musculoskeletal Radiology, Renaissance Imaging Medical Associates Editors: Leon Lenchik, MD, Director, Densitometry Minifellowship, Assistant Professor, Department of Radiology, Wake Forest University Medical Center; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Wilfred CG Peh, MD, MBBS, FRCP(Glasg), FRCP(Edin), FRCR, MHSM, Clinical Professor, Faculty of Medicine, National University of Singapore; Senior Consultant Radiologist, Programme Office, Singapore Health Services; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Felix S Chew, MD, MBA, EdM, Professor, Department of Radiology, Vice Chairman for Radiology Informatics, Section Head of Musculoskeletal Radiology, University of Washington Author and Editor Disclosure Synonyms and related keywords: von Recklinghausen's disease of bone, von Recklinghausen disease of bone, generalized osteitis fibrosa cystica, PTH, parathyroid glands, multiple endocrine neoplasia syndrome type 1, MEN 1 / MEN-1, brown tumor INTRODUCTIONSection 2 of 11
  BackgroundIn 1891, von Recklinghausen described the classic bone disease termed osteitis fibrosa cystica. In 1925, the Viennese surgeon Mandl performed the first parathyroid exploration and adenoma resection. Mandl noted improvement of the patient's severe skeletal abnormalities postoperatively, thereby linking hyperparathyroidism with bone disease. Albright later described the clinical entity of classic primary hyperparathyroidism in the 1930s on the basis of 17 cases from his clinical practice.1 Historically, the disorder was marked by characteristic skeletal changes, nephrolithiasis, and neuromuscular dysfunction.2 Primary hyperparathyroidism is now a different entity. Since the advent of chemical screening with an autoanalyzer in the 1960s, most cases are discovered in asymptomatic patients with hypercalcemia.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Patients may also present with nonspecific complaints of back pain, or they may have osteopenia, as depicted on radiographic studies.14, 15, 16, 17, 18, 19, 20 Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient population, and it is second only to malignancy as an etiology of hypercalcemia in the inpatient population. The natural progression of disease in asymptomatic patients is unclear.21 PathophysiologyNormal parathyroid glands function to maintain appropriate serum calcium concentrations and to regulate bone metabolism by means of the production of parathyroid hormone (PTH). In the nonpathologic state, PTH secretion increases in response to low serum calcium concentrations and enhances the synthesis of 1,25-dihydroxyvitamin D. PTH and 1,25-dihydroxyvitamin D act together to increase calcium reabsorption in the gut and kidney and to promote osteoclastic resorption and the demineralization of bone. Primary hyperparathyroidism is caused by an overproduction of PTH, in excess of the amount required by the body. In contrast, secondary hyperparathyroidism involves an increase in PTH levels to meet some bodily requirement. In 75-80% of cases of primary hyperparathyroidism, one or more adenomas account for the overproduction, whereas approximately 20% of cases are secondary to diffuse hyperplasia of all glands. Carcinoma accounts for less than 2% of all cases. The effects of hyperparathyroidism on bone are numerous. Excess PTH results in an increase in bone breakdown by means of osteoclastic resorption with subsequent fibrous replacement and reactive osteoblastic activity. The bone may have microfractures, with subsequent hemorrhage and growth of fibrous tissue and an influx of macrophages. The resulting mass is called a brown tumor because of the brown color of the vascular elements and blood in the mass. The process of bone resorption and fibrous replacement results in the characteristic radiologic features of generalized bone demineralization, resorption, cysts, brown tumors, erosion of the dental lamina dura, and pathologic fractures (see Images 13-16). Other effects of hypercalcemia include nephrolithiasis or nephrocalcinosis, neurologic changes, peptic ulcer disease, and pancreatitis. FrequencyUnited StatesThe incidence of primary hyperparathyroidism is approximately 25-30 cases per 100,000 people. In individuals aged 15-65 years, the incidence increases to 70-150 cases per 100,000 people. The disease is rare in children. InternationalIn Europe, the overall incidence of primary hyperparathyroidism is similar to the incidence in the United States. Mortality/MorbidityThere is supportive evidence of an increase in the morbidity and mortality rates in patients with hyperparathyroidism that is primarily related to cardiac disease. This topic is controversial, with the results of some studies refuting the increased risk. Differences in mortality data may reflect the different clinical profiles of classic primary hyperparathyroidism and the modern asymptomatic cohort of patients. (See also Special Concerns.) SexThe incidence of primary hyperparathyroidism in women is 2-3 times the incidence in men. AgeThe average patient age at diagnosis is 55 years.
AnatomyUsually, 4 parathyroid glands develop, although approximately 10% of people may have 2, 3, or 5 parathyroid glands. The superior glands are typically located on the posterior aspect of the upper thyroid, whereas the location of the inferior glands is more variable. The inferior glands may be posterior to the inferior aspect of the thyroid or ectopically located in the thyroid gland, along the carotid sheath, or attached to the thymus. The superior glands may also be ectopic and in a retroesophageal, retrotracheal, or retropharyngeal location. Typical parathyroid glands are approximately 5 X 3 X 1 mm. Clinical DetailsHistorically, in classic primary hyperparathyroidism, nephrolithiasis was noted in 50% of patients, and this condition was the most common clinical presentation of the disease. Currently, stone disease is present in 10-20% of patients and continues to be the most common complication that is clearly attributable to primary hyperparathyroidism. However, patients typically present without symptoms after routine laboratory testing reveals hypercalcemia. Patients may also report nonspecific back pain. Additional manifestations of primary hyperparathyroidism include a wide range of neuromuscular and neuropsychiatric symptoms, pancreatitis, peptic ulcer disease, and cardiovascular abnormalities. Symptomatic bone disease may be present in 10-25% of patients. The diagnosis is based on an elevated PTH level in the setting of elevated calcium levels. Other chemical alterations that support the diagnosis include hypophosphatemia, hyperphosphaturia, elevated uric acid levels resulting from tissue destruction, and increased alkaline phosphatase levels resulting from bone formation. Hereditary hyperparathyroidism is seen in multiple endocrine neoplasia type 1 syndrome (MEN 1) in association with tumors of the anterior pituitary gland and pancreas (see Images 19-22). Hyperparathyroidism develops in 95% of patients with MEN 1, and hypercalcemia occurs in those aged 10-30 years. In multiple endocrine neoplasia type 2a syndrome (MEN-2a), parathyroid disease is infrequent and occurs in conjunction with medullary cancer of the thyroid and pheochromocytoma. Two rare hereditary syndromes include an inherited form of primary hyperparathyroidism that is not associated with other endocrine tumors and a hyperparathyroidism–jaw tumor syndrome. In patients with the latter, fibrous jaw tumors are seen with parathyroid adenomas and potentially with thyroid cancer, renal cysts, and Wilms tumors. Preferred ExaminationParathyroid imaging To image the parathyroid glands before a repeat operation for recurrent or persistent disease, technetium-99m sestamibi (99mTc MIBI) scanning or magnetic resonance imaging (MRI) are the preferred imaging modalities because of their high sensitivities in depicting ectopic or mediastinal glands.22, 23, 24, 25, 26, 27 99mTc MIBI imaging has a sensitivity of 70-95% in depicting parathyroid tumors, and this modality allows 3-dimensional (3-D) imaging with anterior-to-posterior localization of the tumor. Studies reveal equal sensitivities of 99mTc MIBI imaging and MRI in the localization of abnormal glands before a repeat surgery, with sensitivities of 82-85%. By combining the 2 modalities, the sensitivity increases to 94%. Ultrasonography may be preferred for initial preoperative tumor localization, if desired by the surgeon, because of this technique's low risk, low cost, and high sensitivity in depicting parathyroid glands that are not ectopic or in the mediastinum.28, 29 However, many surgeons believe that the initial 4-gland exploration enables a 95% cure rate with little morbidity and that initial preoperative localization provides no improvement in the outcome. Some surgeons advocate initial localization to guide directed dissection, obviating bilateral exploration. Opponents argue that the sensitivities of imaging modalities are not sufficient and that parathyroid glands can be missed in an unacceptable number of patients. Musculoskeletal imaging The diagnosis of primary hyperparathyroidism is made by means of the laboratory confirmation of an elevated PTH level in the setting of hypercalcemia. Radiologically, radiographs may yield the most specific findings that are consistent with the disorder, and radiography is the preferred examination when the clinical findings suggest primary hyperparathyroidism. Radiographs of the hands may yield the diagnostic finding of subperiosteal resorption, which is virtually pathognomonic for the disease (See Images 2-4 and 23). If radiographs of the hands reveal no abnormalities, other sites are unlikely to demonstrate abnormal findings. Dual-energy x-ray absorptiometry (DXA) and quantitative CT (QCT) scanning may provide evidence of osteoporosis that is consistent with the diagnosis; however, the finding is nonspecific for primary hyperparathyroidism. Limitations of TechniquesRadiographs of the hand may yield the pathognomonic finding of subperiosteal resorption, which is consistent with a diagnosis of primary hyperparathyroidism. However, other findings on radiographs are not specific for this disorder. In addition, DXA and QCT scanning are the preferred diagnostic modalities for the evaluation of osteoporosis, which is one of the most common findings in patients with primary hyperparathyroidism. However, osteoporosis may be associated with a host of other diagnoses; therefore, the specificity of this condition may be limited. Currently, the diagnosis of primary hyperparathyroidism is primarily based on the laboratory confirmation of elevated PTH concentrations in the setting of an increased calcium level. DIFFERENTIALSSection 3 of 11
Adamantinoma Ankylosing Spondylitis Bone Metastases Calcium Pyrophosphate Deposition Disease Chondroblastoma Crohn Disease Eosinophilic Granuloma, Skeletal Ewing Sarcoma Fibrous Dysplasia Gout Hyperparathyroidism, Secondary Osteoblastoma Osteomalacia and Renal Osteodystrophy Osteomyelitis, Acute Pyogenic Osteomyelitis, Chronic Osteoporosis, Involutional Psoriatic Arthritis Rheumatoid Arthritis, Hands Rheumatoid Arthritis, Spine Rickets Ulcerative Colitis Other Problems to Be ConsideredOsteoarthritis, Secondary RADIOGRAPHSection 4 of 11
FindingsHyperparathyroidism is a disease of increased bone resorption and bone formation. Subsequently, plain radiographic findings may include resorption and sclerosis of numerous sites in the skeletal system. These days, the most common radiologic finding in primary hyperparathyroidism is osteopenia, which may be generalized or asymmetric (see Image 1). Fine trabeculations are initially lost, with resultant coarse and thickened trabeculae. The disease may progress with further destruction that results in a ground-glass appearance in the trabeculae. About 30-50% of the bone density must be lost to show changes on radiographs. Other methods for the quantification of bone density, such as QCT scanning and DXA, are more sensitive in the evaluation of osteopenia. Additional findings include bone resorption, which may occur at many different anatomic sites. Bone resorption may be classified as subperiosteal, intracortical, trabecular, endosteal, subchondral, subligamentous, or subtendinous. Subperiosteal bone resorption is an early and virtually pathognomonic sign of hyperparathyroidism, and this finding is marked by marginal erosions with adjacent resorption of bone and sclerosis. An unusual lacelike appearance may be seen beneath the periosteum with an occasional spiculated external cortex. The underlying resorptive process may progress to complete cortical disappearance. Although subperiosteal bone resorption can affect many sites, the most common site in hyperparathyroidism is the middle phalanges of the index and middle fingers, primarily on the radial aspect (see Images 2-3). Other sites of subperiosteal resorption include the phalangeal tufts (acro-osteolysis) (see Images 4 and 23), the lamina dura around the teeth, the medial aspect of the tibia, the humerus (see Images 5-6), the femur (see Images 10-11), and the distal clavicle (see Images 7-8). When the resorption extends to the margins of joints, particularly in the hands, wrists, and feet, findings may appear articular. Other areas of resorption, such as cortical or endosteal regions, are usually accompanied by subperiosteal findings. Intracortical bone resorption is an indicator of rapid bone turnover and is described as linearly oriented striations in the cortex. The linear lucencies are produced by resorption of bone in the haversian canals and are best seen on the cortical surface of the second metacarpal. Trabecular bone resorption may occur throughout the skeleton and usually accompanies advanced disease. In the skull, areas of decreased radiopacity are intermingled with sclerotic radiopaque areas, resulting in a classic appearance called the salt-and-pepper skull (see Image 9). In endosteal resorption, the medullary cavity widens, with thinning of the inner cortex (see Images 10-11). Changes are usually best seen in the hands and appear as scalloped lucencies on the inner aspect of the bony cortex. Endosteal changes are usually accompanied by subperiosteal or cortical resorption. Subchondral bone resorption is most common in the joints of the axial skeleton, such as the sacroiliac, acromioclavicular (see Image 12), discovertebral, sternoclavicular, and symphysis pubis, but it may also occur in the joints of the appendicular skeleton. Subchondral bone is resorbed; collapse with subsequent new bone formation and fibrous replacement may result. On radiographs, areas of subchondral lucency are noted with surrounding sclerosis. In the sacroiliac joint, bilateral findings affect the ilium more than the sacrum and may produce an irregular articular margin with the appearance of a widened joint. At the acromioclavicular joint, bilateral erosions affect the clavicle side more than the acromion, whereas the sternum and clavicle are equally affected at the sternoclavicular joint. Subligamentous and subtendinous resorption occurs at insertion sites on bones. Common sites are the plantar aspect of the calcaneus, dorsal aspect of the patella, inferior margin of the distal clavicle, trochanters, and ischial and humeral tuberosities. Brown tumors are well-circumscribed lytic lesions of bone that represent the osteoclastic resorption of a confluent area of bone with subsequent fibrous replacement (see Images 13-16). The lesions may be single or multiple, with expansion of overlying bone, and they may be present in any site, although the lesions usually occur in cortical bone. Common sites include the mandible, clavicle, ribs, pelvis, and femur. After resection of an adenoma, lesions may become sclerotic on radiographs. Once considered a finding that was characteristic of primary hyperparathyroidism, brown tumors are more common in secondary hyperparathyroidism because of the increasing population and life expectancy of patients undergoing dialysis. Calcium pyrophosphate dihydrate crystal deposition disease (CPPD) is more common in association with primary hyperparathyroidism than with secondary hyperparathyroidism. Chondrocalcinosis may affect the menisci of the knee, the triangular cartilage of the wrist, and the symphysis pubis. CPPD arthropathy is less common in these patients than in patients with idiopathic disease. Other radiographic findings in primary hyperparathyroidism include varying degrees of sclerosis, although generalized sclerosis is more common in secondary hyperparathyroidism. Soft-tissue and vascular calcification is more common in secondary disease, as is superior and inferior band sclerosis of the spine, which is called rugger-jersey spine. The laxity of ligaments and tendons primarily affects the sacroiliac and acromioclavicular joints, whereas rupture may be seen at several sites, including the quadriceps, triceps, and patellar tendons. Degree of ConfidenceIn the setting of elevated serum calcium levels and elevated PTH levels, the diagnosis of primary hyperparathyroidism is certain. However, radiographic findings of subperiosteal resorption are most specific for the disease and should prompt consideration of the primary hyperparathyroidism. CT SCANSection 5 of 11
FindingsWith parathyroid imaging, ectopic adenomas can be assessed by using contrast-enhanced CT scan studies. However, sestamibi and MRI are more sensitive, and these are the imaging studies of choice in most patients. In musculoskeletal imaging, QCT scanning is another method of bone densitometry. This modality offers the advantage of selective evaluation of the mineral content in trabecular bone, which makes QCT scanning more sensitive in detecting small changes in bone density. MRISection 6 of 11
FindingsMRI is one diagnostic modality that can be used to evaluate ectopic parathyroid adenomas. On T1-weighted images, adenomas appear as low-signal-intensity masses, whereas intermediate or high signal intensity is seen on T2-weighted images. Gadolinium enhancement with fat suppression results in diffuse enhancement of the adenoma. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. MRI findings of brown tumors are nonspecific. Bony expansion can be visualized, and the extent of the lesion can be determined. The imaging characteristics depend on the amount of fibrous tissue, hemorrhage, and cystic changes that are present in the lesion. Lack of an associated soft-tissue mass is a pertinent negative finding that can be demonstrated on MRIs. ULTRASOUNDSection 7 of 11
FindingsUltrasonography is one of the primary modalities used to localize parathyroid tumors. The size of the adenoma is usually correlated with the degree of parathyroid elevation. Adenomas appear as well-defined hypoechoic lesions with potential cystic or necrotic areas. Ultrasonography offers the advantage of depicting potential concomitant thyroid disease, which is present in approximately 40% of patients with parathyroid disease. In renal imaging, ultrasonography can demonstrate bilateral hyperechoic medullary pyramids that are consistent with medullary nephrocalcinosis; this is a nonspecific finding (see Image 17). Degree of ConfidenceUltrasonography is approximately 75% sensitive in identifying adenomas, but this technique has low sensitivity in identifying ectopic lesions. NUCLEAR MEDICINESection 8 of 11
FindingsIn parathyroid imaging, localization of the parathyroid glands may be accomplished with 99mTc MIBI scanning (see Image 18). Both thyroid and parathyroid tissues demonstrate radionuclide uptake, but sestamibi washes out of thyroid tissue early after its injection, leaving only parathyroid tissue that demonstrates activity at 2-4 hours. In musculoskeletal imaging, bone densitometry is extremely valuable in assessing primary hyperparathyroidism because it can be used to quantify bone loss, and it may help making predictions regarding the fracture risk. DXA helps in evaluating the mineral content of all bone in the path of the beam. Bone mineral density is expressed as either a T score, which is based on the standard deviations from a young-adult mean, or as a Z score, which is compared with an age-matched mean. The T score is used to clinically diagnose osteopenia or osteoporosis and to predict the fracture risk. DXA may also be used after an intervention to document improvements in bone density. The diagnosis of primary hyperparathyroidism is based on biochemical determinations, and bone scanning has a limited role in making the diagnosis. In addition, a few patients with hyperparathyroidism have insufficient disease for its demonstration on bone scans. However, bone scanning may assist in differentiating hyperparathyroidism from metastatic disease in the setting of elevated calcium levels. Because bone turns over significantly in hyperparathyroidism, findings on bone scans include generalized increased radionuclide uptake throughout the skeleton in contrast to soft tissues; this observation is called a superscan. Because the contrast of the skeletal system is increased, renal activity may not be apparent. INTERVENTIONSection 9 of 11
Ultrasonography-guided fine-needle aspiration and biopsy are infrequently performed in the setting of recurrent or persistent disease and equivocal imaging findings. The procedure may be used in conjunction with ethanol ablation as a therapeutic modality, but this is rarely indicated. Medical Legal PitfallsRelated Medscape topic: Special Concerns
Related Medscape topics: MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Hyperparathyroidism, Primary excerpt Article Last Updated: Jan 24, 2008 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
