Persistent phosphaturic mesenchymal tumor causing tumor-induced osteomalacia treated with image-guided ablation.

Phosphaturic mesenchymal tumors (PMTs) can present with vague symptoms of diffuse bone pain with pathologic fractures that often lead to a delayed diagnosis. We present a 60-year-old patient with a PMT that was persistently hypophosphatemic after resection, who was then successfully treated with cryoablation of the tumor. Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia characterized by vague symptoms of gradual muscle weakness and diffuse bone pain with pathologic fractures that often lead to a delayed diagnosis. This condition is usually caused by benign phosphaturic mesenchymal tumors (PMTs). Here, we present a case of persistent PMT after surgical resection treated with image-guided ablation. We present the patient's clinical examinations and laboratory findings (phosphorus, 1,25 (OH)2D, FGF-23, Intact PTH). Representative histologic images of a PMT are also presented. A 61-year-old male was evaluated for persistent hypophosphatemia and presumed osteomalacia. Six years earlier, he underwent surgical excision of a left ischial mass after presenting with TIO. The pathology was consistent with a PMT; however, hypophosphatemia persisted suggesting incomplete resection. He was treated with calcitriol and phosphate salts. A PET Ga68 dotatate scan of the patient revealed an avid left ischial mixed lytic and sclerotic lesions with marked amount of radiotracer uptake, suggesting persistent tumor. The patient was resistant to re-excision of the tumor due to the extended recovery period from his prior surgery and was treated instead with cryoablation of the tumor. His biochemical findings of hypophosphatemia and elevated FGF23 resolved after the ablation and have remained normal for 5 months after surgery. In patients with TIO, wide surgical excision is the treatment of choice. When this is not possible, image-guided ablation is an alternative therapeutic option.

Diffuse osteosclerosis as a presentation of recurrent breast cancer: role of endothelin 1.

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. INTRODUCTION: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. METHODS: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. RESULTS: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. CONCLUSIONS: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.

Lower extremity insufficiency fractures: an underappreciated manifestation of endogenous Cushing's syndrome.

This report describes the presence of lower extremity insufficiency fractures in 10 women prior to the clinical and biochemical diagnosis of endogenous Cushing's syndrome (CS). Osteoporosis is a well-recognized complication of overt CS resulting in a high rate of vertebral and other fractures. After institutional review board (IRB) approval, we did a retrospective chart review of patients with lower extremity (LE) insufficiency fractures (IF) and CS. This chart review found 10 women in whom LE-IF preceded the diagnosis of endogenous CS. Low bone density was found in all but one patient. The CS was considered to be mild (or subclinical) in five patients. LE-IF should be considered part of the skeletal spectrum of CS. Physicians caring for patients with LE-IF should have a low threshold for the consideration of CS even in patients without overt physical evidence of cortisol excess.

Hypoglycemic coma in anorexia nervosa. Case report and review of the literature.

Clinically significant hypoglycemia is an unusual complication of anorexia nervosa. We describe a 44-year-old woman with a 5-year history of anorexia nervosa who presented with hypoglycemic coma and eventually experienced sudden death. Biochemical studies showed suppressed levels of insulin, C peptide, and proinsulin during hypoglycemia; appropriate elevations of growth hormone and cortisol levels were observed, suggesting that the hypoglycemia was related to severe malnutrition. Nine previously reported cases of severe hypoglycemia in anorexia nervosa are reviewed (six of the patients involved also died). The presence of severe hypoglycemia in anorexia nervosa implies a grave prognosis and mandates aggressive medical and nutritional therapy to improve the chance of survival.

Hypocalcemia and skeletal disease as presenting features of celiac disease.

OBJECTIVE: To describe 15 patients examined for hypocalcemia, skeletal disease, or both in whom the diagnosis of celiac disease was subsequently made. DESIGN: Observational case series. PATIENTS: Fifteen patients (7 women and 8 men) were examined for hypocalcemia (n = 11), skeletal disease (n = 3), or both (n = 1). The diagnosis of celiac disease was subsequently made. The mean age of the patients was 62 years, and 11 patients were 60 years of age or older. RESULTS: Four patients had no gastrointestinal symptoms, 7 patients had mild or intermittent gastrointestinal symptoms, and 4 patients had persistent diarrhea. Ten patients had experienced weight loss. The serum total alkaline phosphatase level was elevated in 10 of 15 patients, the parathyroid hormone level was elevated in all patients, and the urinary calcium level was low in all 6 of the patients tested. The level of 25-hydroxyvitamin D was frankly low in 4 patients, marginal in 8 patients, and normal in 3 patients. Bone mineral density was reduced in all 8 patients in whom it was measured. CONCLUSIONS: Celiac disease should be considered in patients with unexplained metabolic bone disease or hypocalcemia, especially because gastrointestinal symptoms may be absent or mild. Advanced age does not exclude the diagnosis of celiac disease.

WR-2721 reduces bone loss after hindlimb tenotomy in rats.

WR-2721 is a thiophosphate analog of cysteamine that produces hypocalcemia in vivo. Previous studies suggest that WR-2721 produces hypocalcemia by independent inhibitory effects on parathyroid hormone (PTH) secretion, osteoclastic bone resorption, and tubular reabsorption of calcium. We sought to determine if WR-2721 would decrease bone loss in an animal model of disuse osteoporosis produced by unilateral knee tenotomy in the rat. Tenotomy significantly increased osteoclast number in tibias on the side of the procedure compared with tibias on the opposite side which had not undergone the procedure at 3 and 14 days. Femoral weight of tenotomized limbs were also reduced significantly compared with the contralateral limb at 3 and 14 days. WR-2721 treatment (240 mg/kg daily) prevented 26% of the loss of femoral dry weight and 29% of the loss of femoral ashed weight produced 14 days after tenotomy. In addition, WR-2721 treated (240 mg/kg daily) animals had fewer osteoclasts in tenotomized tibias than control animals at 3 days (6.6 +/- 0.7/mm versus 10.3 +/- 0.9/mm, p less than 0.02) and at 14 days (5.8 +/- 0.3/mm versus 8.7 +/- 0.4/mm, p less than 0.02). These data suggest that WR-2721 decreases bone loss in this model by decreasing osteoclastic bone resorption.

Mutation analysis of coding sequences for type I procollagen in individuals with low bone density.

Mutations in one of the two genes encoding type I procollagen (COL1A1 and COL1A2) are frequently the cause of osteogenesis imperfecta (OI), a disorder characterized by brittle bones. Here we tested whether patients with low bone density also have mutations in these genes. The 26 patients studied had no apparent metabolic bone disease, but most had a positive family history of osteopenia or osteoporosis. Although a diagnosis of OI was considered by the clinician in some cases, the clinical criteria for OI were not satisfied. Our strategy for mutation analysis consisted of PCR amplification of cDNA made to fibroblast mRNA using primers specific for the coding regions of COL1A1 and COL1A2. The PCR products were then sequenced directly with primers located within each PCR product. We found that 3 of 26 patients had mutations that altered the encoded amino acid. One mutation, at position alpha 2(I)-661 has been reported (Spotila et al. 1991 Proc Natl Acad Sci USA PNAS 88:5423). The other 2 patients, who were not related to each other, had a mutation that altered the proline codon at alpha 1(I)-27 to alanine. This mutation was not found in 81 normal individuals or in 37 additional osteopenic individuals. However, its effect on the biologic function of type I collagen, as well as its role in osteopenia, is uncertain. In addition to the two mutations, we found a polymorphism in codon alpha 2(I)-459. Although this polymorphism involved an amino acid substitution, it was present with equal frequency in the patient and the normal population. By analyzing this and previously reported neutral sequence variants in the COL1A2 gene, we determined that all patients expressed both alleles of the COL1A2 gene. The 12 patients who were heterozygous for a COL1A1 neutral sequence variant also expressed both alleles. Here we present all PCR primer and sequencing primer information. The results suggest that surveying a larger group of similarly selected individuals may reveal additional mutations in the COL1A1 or COL1A2 genes.

Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome: early recognition of the occult ectopic ACTH syndrome.

The clinical, biochemical, and radiographic features of ectopic ACTH-dependent Cushing's syndrome are often indistinguishable from those of pituitary ACTH-dependent hypercortisolism (Cushing's disease). We prospectively evaluated 29 patients with ACTH-dependent hypercortisolism by means of bilateral inferior petrosal sinus ACTH sampling with ovine CRH (oCRH) stimulation. Patients with Cushing's disease (n = 20), had a maximal basal inferior petrosal sinus to peripheral ACTH ratio (IPS:P-ACTH) of 11.7 +/- 4.4 (+/- SE) from the dominant IPS, which increased to 50.8 +/- 18.3 after oCRH administration. Bilateral IPS sampling was necessary to correctly identify patients with Cushing's disease, since the maximal basal nondominant IPS:P-ACTH was less than 2.0 in over 50% of the patients and remained less than 2.0 after oCRH administration in one third. In contrast, patients with occult ectopic ACTH-secreting neoplasms (n = 9) had maximal basal IPS:P-ACTH of 1.2 +/- 0.1 that did not change after oCRH administration. Occult ectopic ACTH-secreting neoplasms were found in 7 of 9 patients from 0.4-14 yr after the recognition of Cushing's syndrome, and 4 of these patients had intermittent hypercortisolism with prolonged periods of remission. Selective endobronchial lavage for ACTH correctly localized a radiologically occult ACTH-secreting bronchial carcinoid in 1 patient, and magnetic resonance imaging identified a similar neoplasm in a patient with a normal chest computed tomographic scan. Basal ACTH and urinary free cortisol excretion were significantly higher in patients with ectopic ACTH than in those with Cushing's disease, but overlap existed between groups. High dose dexamethasone suppression testing inaccurately classified 24% of patients, and radiological imaging of the pituitary and adrenal glands was misleading. The occult ectopic ACTH syndrome is a common form of ACTH-dependent hypercortisolism that cannot be distinguished from Cushing's disease with routine clinical studies. The accurate differential diagnosis of ACTH-dependent Cushing's syndrome requires bilateral inferior petrosal sinus ACTH sampling with oCRH stimulation.

Primary hyperparathyroidism and severe hypercalcemia with low circulating 1,25-dihydroxyvitamin D.

We report a postmenopausal woman with primary hyperparathyroidism (PHPT) and severe hypercalcemia while her total calcium intake was more than 2 g daily. Despite a markedly elevated intact PTH level, her serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was low (17 pmol/L; 7 pg/mL). With reduced calcium intake, her serum calcium normalized, and 1,25-(OH)2D increased to 122 pmol/L (51 pg/mL). At the same time, intact PTH decreased to 32% of the initial value. PHPT may be associated with low circulating 1,25-(OH)2D levels. Furthermore, low 1,25-(OH)2D levels in PHPT may be due to a direct effect of severe hypercalcemia and be reversible with correction of hypercalcemia.

Hepatitis C-associated osteosclerosis: late onset after blood transfusion in an elderly woman.

A 69-yr-old woman with hepatitis C virus (HCV) infection from blood transfusion 14 yr earlier was evaluated in 1997 for increasing appendicular skeletal pain. Diffusely elevated radioisotope uptake on bone scanning had appeared during the past 15 months. Radiographs spanning 1978-1997 showed remarkable restoration of bone mass and a skeleton like that of a young woman. Bone mineral densities of the femoral neck and lumbar spine were above the mean peak bone mass of young women (T scores, +1.8 and +1.3, respectively) and 160% and 147% of mean values for age-matched female controls (Z-score, +3.7 and +3.6, respectively). Biochemical markers of skeletal remodeling were substantially increased. Bone marrow biopsy showed normal lamellar bone. Serum alkaline phosphatase activity assays suggested that accelerated skeletal turnover began 6-12 months before symptoms. HC-associated osteosclerosis has been reported in nine individuals 27-73 yr of age, most with a history of i.v. drug abuse. Our patient demonstrates that parenteral exposure to blood rather than illicit drugs is the feature common to all affected subjects. Furthermore, we document that there can be a long latency between HCV infection and the development of skeletal abnormalities. We also find that bone mass can be restored by this disorder in a postmenopausal woman. Routine radiographs, however, may not show overt osteosclerosis in the elderly. The precise pathogenesis of this disorder is unknown. Understanding and control of the mechanism of HC-associated osteosclerosis could potentially lead to correction of low bone mass from osteoporosis with good quality skeletal tissue.

Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism.

Determination of the etiology of primary aldosteronism remains a diagnostic challenge. The most common types of primary aldosteronism are bilateral adrenal hyperplasia (BAH), aldosterone-producing adenomas (APA), and primary adrenal hyperplasia. Computed tomography (CT) and adrenal vein sampling (AVS) are the primary modalities used to differentiate these subtypes. The purpose of this study was to compare AVS and CT imaging of the adrenal glands in patients with hyperaldosteronism in whom CT imaging was normal or in whom focal unilateral or bilateral adrenal abnormalities were detected. The diagnosis of primary aldosteronism was made in 62 patients based on an elevated plasma aldosterone to PRA ratio and an elevated urinary aldosterone excretion rate. Thirty-eight patients had CT imaging and successful bilateral adrenal vein sampling and were included in the final analysis. AVS was considered the gold standard in determining the specific subtype of primary aldosteronism. There were 15 patients with APA, 21 patients with BAH, and 2 patients with primary adrenal hyperplasia. Plasma aldosterone was significantly higher in patients with APA (46.3 +/- 8.5 ng/dL; 1284 +/- 235 pmol/L) than in those with BAH (29.3 +/- 2.4 ng/dL; 813 +/- 11 pmol/L; P < 0.05). Plasma potassium was significantly lower in patients with APA (3.1 +/- 0.1 mmol/L) than in patients with BAH (3.5 +/- 0.1 mmol/L; P < 0.02). There was considerable overlap in the other biochemical indices (e.g. PRA and urinary aldosterone) in patients with the different subtypes. In patients with APA proven by AVS, eight had concordant findings with CT imaging, four had discordant findings, and three had normal CT imaging. In patients with BAH proven by AVS, four had concordant findings with CT imaging, eight had discordant findings, and nine had normal CT imaging. Compared with AVS, CT imaging was either inaccurate or provided no additional information in 68% of the patients with primary aldosteronism. We conclude that adrenal CT imaging is not a reliable method to differentiate primary aldosteronism. Adrenal vein sampling is essential to establish the correct diagnosis of primary aldosteronism.

Intraoperative measurement of adrenocorticotropin (ACTH) during removal of ACTH-secreting bronchial carcinoid tumors.

The optimal treatment for ectopic ACTH syndrome is the complete removal of the tumor secreting ACTH. These tumors are often occult, with their location suggested but not proven with imaging techniques. The intraoperative measurement of ACTH by immunoradiometric assay in five patients with the occult ectopic ACTH syndrome during removal of suspicious intrapulmonary lesions is reported. A significant ACTH gradient was detected in the pulmonary veins of the affected lobes in two patients. ACTH had decreased significantly in all five patients by 10 and 15 min after tumor removal. All five patients had histologically proven ACTH-secreting bronchial carcinoid tumors, suppressed plasma ACTH by 24 h after tumor removal, and subsequent secondary adrenal insufficiency indicating successful surgical therapy (five of five true-positive). In one patient, previous surgery was not curative and did not result in a decrease in intraoperative measurement of ACTH (one of one true-negative). It was demonstrated that a rapid ACTH immunochemiluminescence assay with a 15-min incubation time has sufficient sensitivity and precision to detect decreases in ACTH described above. These results demonstrate that complete removal of ACTH-secreting bronchial carcinoid tumors can be detected intraoperatively by a decrease in arterial ACTH by 15 min. The modification of the ACTH immunochemiluminescence assay to 15 min incubation allows the documentation of a successful tumor removal in the operating room. It may also be used to locate the tumor intraoperatively by selective pulmonary vein sampling. This protocol may be applicable to the intraoperative measurement of ACTH during pituitary microadenomectomy for Cushing's disease.

Acute extracapsular parathyroid hemorrhage: case report and review of the literature.

OBJECTIVE: To describe a patient with extracapsular parathyroid hemorrhage and review the signs and symptoms of this condition. METHODS: We report a case of extracapsular parathyroid hemorrhage in a patient with primary hyperparathyroidism and present an overview of previously reported cases. RESULTS: A 48-year-old woman with documented primary hyperparathyroidism, who was awaiting surgical intervention, had acute onset of a neck mass, neck pain, and dysphagia. She was found to have sustained a spontaneous extracapsular hemorrhage of a parathyroid adenoma. Hypercalcemia persisted, and she subsequently underwent curative parathyroidectomy for the primary hyperparathyroidism. We also identified 15 previously reported cases of extracapsular parathyroid hemorrhage and summarized the most common manifestations-most notably, a neck mass or swelling, ecchymoses of the neck and chest, dysphagia, neck pain, hoarseness, and dyspnea. CONCLUSION: Clinicians should be aware of the potential for occurrence of extracapsular parathyroid hemorrhage in patients with primary hyperparathyroidism. When this condition occurs, severe hypercalcemia or acute hypocalcemia may be present. Hypercalcemia is often persistent; however, autoinfarction of the parathyroid adenoma is possible.

Pseudohypercalcemia in an elderly patient with multiple myeloma: report of a case and review of literature.

Hypercalcemia, a common complication of multiple myeloma, is primarily caused by increased bone resorption. The increase in total calcium is usually associated with an increase in the ionized calcium (Ca(I)), and the hypercalcemia is frequently symptomatic. Rarely, pseudohypercalcemia in multiple myeloma is caused by binding of calcium to the abnormal immunoglobulin. In this setting, the Ca(I) is normal. We describe a 90-year-old woman with an IgA-k myeloma who had substantial increases in the total calcium but normal levels of Ca(I). Clinicians should recognize this unusual phenomenon to avoid unnecessary and potentially toxic therapy.

Autoimmune Addison's disease after treatment with interleukin-2 and tumor-infiltrating lymphocytes.

Autoimmune thyroiditis with hypothyroidism is a well-known complication of immunotherapy with interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. To date, however, no cases of IL-2/LAK-induced autoimmune adrenalitis with adrenal insufficiency have been reported. We describe a patient who developed primary adrenal insufficiency following IL-2/tumor-infiltrating lymphocytes (TIL) immunotherapy for renal cell carcinoma. A 64-year-old male with renal cell carcinoma metastatic to bone, skin, lung, and the central nervous system presented for IL-2/TIL treatment. Nine months earlier, he had undergone a right nephrectomy and adrenalectomy. He had already received two courses of IL-2 and one course of IL-4 following surgery. Dynamic studies of adrenal function performed prior to IL-2/TIL immunotherapy demonstrated intact cortisol and aldosterone responses to ACTH as well as negative adrenal antibodies. One week after IL-2/TIL therapy, the patient developed a nonanion gap metabolic acidosis, hypotension and hypoglycemia. Adrenocortical function was re-evaluated demonstrating blunted cortisol and aldosterone responses to ACTH with an elevated plasma ACTH confirming the presence of primary adrenal insufficiency. Adrenal antibodies were now positive. Hydrocortisone and fludrocortisone were given with a good clinical response. We suggest immunotherapy with IL-2/TIL may cause adrenal insufficiency by activating autoimmune adrenalitis.

Case report: hypercalcemia with inappropriate 1,25-dihydroxyvitamin D in Wegener's granulomatosis.

Hypercalcemia associated with the extrarenal production of 1,25-dihydroxyvitamin D (1,25(OH)2D) has been reported in several disorders, most notably granulomatous diseases such as sarcoidosis. The authors describe a woman with hypercalcemia, renal insufficiency, microscopic hematuria, and anemia. The circulating 1,25(OH)2D level was higher than appropriate for the ambient conditions (renal insufficiency, suppressed intact parathyroid hormone, and hypercalcemia). A kidney biopsy was consistent with Wegener's granulomatosis, and treatment with prednisone and cyclophosphamide was associated with normalization of serum calcium levels, improved renal function, a marked decrease in serum 1,25(OH)2D levels, and increased serum intact parathyroid hormone levels. These findings are consistent with the unregulated production of 1,25(OH)2D by inflammatory cells associated with Wegener's granulomatosis.

Case report: renal phosphate wasting, syndrome of inappropriate antidiuretic hormone, and ectopic corticotropin production in small cell carcinoma.

Renal phosphate wasting related to a tumor (oncogenous osteomalacia) is a rare disorder usually associated with benign mesenchymal tumors. In this article, the authors describe a man with renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone associated with small cell carcinoma. Chemotherapy markedly reduced tumor burden and was associated with normalization of renal phosphate handling and serum sodium. With recurrence, renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone developed again, with the additional complication of hypercortisolism secondary to ectopic corticotropin production. The authors report the rare occurrence of renal phosphate wasting with small cell carcinoma (5 previously reported cases) and the unique co-existence of this paraneoplastic syndrome with the syndrome of inappropriate antidiuretic hormone and ectopic corticotropin production.

Thyroid needle aspiration in a community hospital.

Fine needle aspiration of the thyroid has achieved increasing acceptance as a valuable diagnostic aid in the evaluation of nodular thyroid disease. It has been suggested, however, that this procedure should be performed only in major medical centers. We report our experience with thyroid needle aspiration in 400 consecutive patients seen in the ambulatory setting of a community hospital. Benign cytology was found in 80% of patients. Surgery was recommended in 51 patients (12.8%) with either suspicious or malignant cytology, and cancer was found in 31 (61%) of these patients. Non-diagnostic aspirates accounted for 7.2% of patients. Thyroid imaging failed to add anything to the diagnostic evaluation. Our results compare favorably to those from university centers and show that thyroid needle aspiration can be performed well in a community hospital setting. We believe that it should be the initial study in patients with nodular goiter.