Abstract
Two patients with a diagnosis of oncogenic osteomalacia are described. This rare disease, characterized by secretion of fibroblast growth factor-23 by the tumor cells, causes myopathy, extreme debilitation and severe osteopathy because of severe hypophosphatemia. Both patients presented with severe bone pain, pathological fractures and proximal muscle weakness. Multiple diagnostic tools had to be utilized to settle the diagnosis of this rare disease. Although supplemental therapy for hypophosphatemia is usually started preoperatively, surgical excision of the causative tumor is the only definite treatment. Surgery is almost always curative; however, there is a lack of discourse in the literature regarding the anesthetic implications for the disease. The complete pathophysiology of the disease, clinical picture, its diagnostic intricacies as well as the salient points in its anesthetic management are discussed in this report.
Keywords
anesthesia; hypophosphatemia; osteomalacia: oncogenic;
1. Introduction
Oncogenic osteomalacia (OOM) is a rare syndrome characterized by the presence of a mesenchymal tumor that causes hypophosphatemia by producing a phosphaturic substance, which is thought to be fibroblast growth factor (FGF)-23, leading to serious osteopathy and myopathy. FGF-23 also has other ill effects on the kidneys, which hamper the compensatory mechanism for hypophosphatemia in the sufferer. It is a rare disorder that involves a complex diagnostic approach so that by the time the syndrome is diagnosed for sure, the disorder has become well advanced with severe osteoporotic changes and extreme debilitation. Hypophosphatemia may not be completely resolved by supplemental therapy but resection of the tumor is usually curative and is indicated in most patients. Providing anesthesia to these patients poses unique challenges. We present two cases for discussion of the unique pathophysiology of the disease and the anesthetic management for these patients.
2. Case reports
2.1. Case 1
A 35-year-old male patient, weighing 60 kg, showed up at the endocrinology department presenting with a history of progressive proximal muscle weakness and pain in all joints for 2 years. He had been bedridden for the past 6 months due to pain and extreme weakness. There was no history of familial bone disorders, abuse of alcohol, intake of heavy metals or taking of chemotherapeutic agents. On physical examination his vital signs were stable, but the musculoskeletal system showed decrease in power especially in the proximal joints (2-3/5). Tenderness was present in all joints. A mass was seen in the left nostril. Routine blood investigation showed an alkaline phosphatase of 1000 IU/L (normal, 110–350 IU/L), serum calcium of 9.5 mg/dL (normal, 8–11 mg/dL) and serum phosphate of 1.8 mg/dL (normal, 2.5–4.5 mg/dL). His serum 1α25(OH)2 D3 (calcitriol) levels were 7.5 pg/ml (normal, 15–60 pg/ml). The renal function tests were essentially normal except that the tubular reabsorption of phosphate was 45% (normal range, 80–95%). All other biochemical parameters, including the arterial blood gas analysis, were within normal limits. Skeletal survey revealed multiple fractures in left lower ribs and pelvis. The bone scan was suggestive of polyarthritis with metabolic bone disorder. The normal parathyroid hormone (PTH) level and negative ammonium chloride test ruled out hyperparathyroidism and renal tubular acidosis, respectively, and a probable diagnosis of OOM was made. Contrast enhanced computed tomography of the paranasal sinuses revealed a solid heterogeneously enhancing mass lesion in the left nasal cavity which extended into the maxillary sinus, ethmoid sinus and extraconal space of the left orbit. The patient was subsequently referred to the otorhinolaryngology unit, where a biopsy of the mass was performed, and the result was suggestive of hemangioma. Oral phosphate and calcitriol supplementation were started, and removal of the tumor by the craniofacial route was planned. The patient was evaluated by the anesthesia team and was found to have a normal airway and good intravenous access. Preoperative pulmonary function tests revealed mild restriction. The biochemical profile was reviewed to rule out any severe deficiencies. Before the surgery, his serum phosphate had increased to 2.8 mg/dL. His chest radiology and electrocardiogram were unremarkable.
In the operation theatre, he was carefully shifted on to the operation table, and routine monitoring including SpO2, electrocardiogram and noninvasive blood pressure was applied. After attaining intravenous access, anesthesia was induced with sodium thiopentone. Monitoring for neuromuscular blockade was initiated to search for supramaximal stimulus after having been appropriately set. Muscle relaxation was achieved with 40 mg rocuronium, and the trachea was intubated with an 8.5-mm cuffed orotracheal tube. Anesthesia was maintained with nitrous oxide and isoflurane in oxygen. Hyperventilation was avoided. Analgesia was reinforced with adequate doses of morphine, and acceptable muscle relaxation was maintained with boluses of rocuronium so as to keep the train of four (TOF) count ≤1. A central venous catheter was placed via the right basilic vein, and the left radial artery was cannulated for continuous invasive blood pressure monitoring. Additional intravenous access was set in the left foot. Urinary bladder was catheterized. The surgical resection took almost 6 hours, and the estimated 2.5 L of blood loss was replaced with crystalloids, colloids and blood products. Mannitol was administered intraoperatively to lower the intracranial pressure to facilitate surgical exposure. Postoperatively, the patient was transferred to the intensive care unit for mechanical ventilation without reversal of the residual neuromuscular blockade. Serum calcium and phosphate levels were continuously monitored, and the patient was weaned from ventilatory support 24 hours afterwards. He was returned to the ward after spending 2 days in the intensive care unit, and he had an uneventful recovery. His serum phosphate levels increased within 6 days (Fig. 1) and phosphate supplementation was slowly withdrawn. His histopathologic diagnosis of the resected mass suggested a phosphaturic mesenchymal tumor of mixed connective tissue variant without evidence of malignancy. He was discharged from the hospital after a stay of 20 days.
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2.2. Case 2
A 55-year-old female patient presented with pain in both lower limbs for 5 years and total chest pain and symptoms of proximal myopathy for 2 years. There were no renal, gastrointestinal or neurological symptoms. She was known to have diabetes for 2 years, well controlled with oral hypoglycemics. Her family and medical history was not remarkable. On examination she had thoracic and pelvic tenderness along with decreased power in proximal joints. Examination of other organ systems revealed no abnormality. All her laboratory investigations were within normal limits except for serum phosphate of 2.0 mg/dL, serum 1α25(OH)2 D3 of 11 pg/ml and a serum alkaline phosphate of 725 IU/L. Positron emission tomography scan and bone scan did not reveal any abnormality except for fractures of ribs and pelvic bones. DOTATOC (octreotide scan) showed intense uptake in a soft tissue mass in the inferior nasal turbinate, a guided biopsy of which was suggestive of hemangiopericytoma. The diagnosis of OOM was made, and endoscopic removal of the mass was planned for the patient. Anesthesia was induced with fentanyl, sodium thiopentone and vecuronium, and maintained with nitrous oxide and isoflurane in oxygen. Intraoperatively neuromuscular monitoring was applied and TOF count was kept around ≤1. It was observed that the requirement of nondepolarizing muscle relaxant was very less. Surgical removal of the tumor was achieved endoscopically, and blood loss was minimal. After the surgery, recovery of TOF count to 4 was noticeably prolonged. However, endotracheal tube could be removed some time later, and the patient had an uneventful recovery. The histopathology of the tumor was suggestive of spindle cell proliferation with osteoclast like giant cells and flocculent calcification. Phosphate supplementation was slowly withdrawn after serum levels of alkaline phosphate had increased, and patient was sent home after symptomatic improvement was observed within a month (Fig. 2).
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3. Discussion
The first patient with tumor-induced osteomalacia (TIO) was wrongly diagnosed as having osteomalacia due to resistance to vitamin D by McCance in 1947.1 After 17 years, in 1964, Dent and Friedman described spontaneous recovery of symptoms in this patient after surgical resection of a tumor, and the correct diagnosis of OOM was confirmed.2 Meanwhile, Prader et al3 reported the first confirmed case of OOM in 1959. Hitherto, only about 170 cases have been described in the literature. However, because of increased awareness and better investigating tools, more and more cases have recently been diagnosed and the condition is now known to be more common than previously thought. OOM or TIO is a unique paraneoplastic syndrome in which the causative tumor secretes a phosphaturic substance causing severe hypophosphatemia. Numerous recent investigations and research point out that this substance is probably FGF-23 as the levels of this factor have been found to be raised in many (but not all) patients.4 FGF-23 produced by normal body tissue is very low, but biochemically detectable, and plays a major role in phosphate homeostasis. FGF-23 reduces renal phosphate reabsorption by suppressing expression of sodium phosphate cotransporter in brush border membrane of proximal tubules. At the same time, it also decreases the expression of 25-hydroxyvitamin D-1α-hydroxylase in kidney leading to decreased production of 1α25(OH)2 D3 (the active form of vitamin D or calcitriol), which stimulates intestinal phosphate absorption. Thus, FGF-23 reduces serum phosphate by suppressing both proximal tubular phosphate reabsorption and intestinal phosphate absorption.5 The normal body response to hypophosphatemia due to other common causes (e.g., nutritional, chronic alcoholism, heavy metal poisoning and renal tubular defects) is an elevation in calcitriol level which causes a rise in both calcium and phosphorus absorption in the intestine and increased mobilization of these elements from bone. Increased serum calcium and calcitriol, in turn, inhibit PTH (which also functions in the physiological regulation of phosphate levels in the body by increasing its excretion through the kidney) secretion with subsequent increase in urinary calcium excretion and increase in tubular reabsorption of phosphorus, thus normalizing the levels of both phosphorus and calcium.5
Raised levels of FGF-23 will, however, cause increased excretion of phosphate and inhibit the compensatory mechanism of the increase in serum calcitriol levels, thus differentiating it from other causes (Fig. 3). Apart from FGF-23, other humoral elements have also been suggested as the causative element in the pathogenesis of TIO; however, conclusive evidence is yet to come forth in support of any other single factor.6 FGF-23 is also implicated as a causative factor of hypophosphatemia in certain genetic diseases, which is also helpful for the differential diagnosis of this disease. These genetic diseases include X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and autosomal recessive hypophosphatemic rickets/osteomalacia.4, 6 These diseases are hereditary in nature, and the onset of disease usually occurs during childhood with a positive family history being almost always involved. Genetic studies can also be helpful to rule out these diseases if confusion about the diagnosis is present. Serum FGF-23 levels in the whole body7 or in the suspected tumor site can be obtained by venous drainage8 for various novel immunoassays should the localization of the tumor be difficult. The causative tumor was obvious in our patients, thus precluding the need for any other diagnostic studies. The diagnosis of TIO is therapeutically beneficial because clinical manifestations are expected to improve after the removal of the responsible tumor.
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The OOM-induced neoplasms are usually benign arising either from bone or soft tissue with extremities and craniofacial region being the preferred sites, the majority of which are mesenchymal in nature, and almost 40% are vascular tumors, frequently being hemangiopericytomas. However, an extensively wide variety of fibrous, cartilaginous and osseous lesions have been described to be associated with OOM.5
Phosphorus is a critical element for skeletal development, bone mineralization, membrane composition (phospholipids), nucleotide structure (adenosine triphosphate, which provides energy and serves as components of DNA and RNA), and cellular signaling (phosphorylated intermediates). Hypophosphatemia may predispose patients to myopathy and, in severe cases, rhabdomyolysis, encephalopathy and peripheral neuropathy could mimic Guillain–Barré syndrome. Moderate hypophosphatemia can also have consequences on renal function, specifically of mild metabolic acidosis and hypercalciuria. Onset of hypophosphatemia in childhood will lead to rickets with characteristic gait disturbances, skeletal deformities and growth retardation while the onset in adulthood will lead to osteomalacia. Severe osteomalacia may lead to fractures of the long bones as well as the vertebra and ribs, with resultant chest wall deformity and respiratory compromise. Muscle weakness in OOM is multifactorial. Hypophosphatemia, calcitriol deficiency and disuse atrophy due to pain and fractures may all contribute to muscle weakness. Respiratory compromise similarly has a multiple etiology with myopathy, hypophosphatemia, chest wall deformity and fractures of thoracic cage playing a role.
In most patients, musculoskeletal symptoms and signs precede, for several months to many years, discovery of the underlying tumor, by which time the osteomalacia is in a well-advanced stage.8 Our patients presented symptoms 2 and 5 years after the onset of disease, respectively. The biochemical parameters show hypophosphatemia, hyperphosphaturiaa and normo- or hypocalcemia. The serum 1α25(OH)2 D3 levels are inappropriately low for hypophosphatemia. A few patients may show mildly elevated PTH levels. Serum alkaline phosphatase levels are raised in many patients.
Patients may present for anesthesia either for the resection of primary tumor or for fixation of the pathological fractures. The anesthetic challenges encountered in these patients are related to the extreme osteomalacia associated with these tumors. The patients are usually bedridden with extreme pain and myopathy. Preoperative pain control reduces anxiety and is warranted. Another concern is the use of prophylaxis to forestall deep vein thrombosis in patients who have been immobile for a long time. Although phosphate supplementations are started in the preoperative period. it may or may not be enough to normalize the serum phosphate levels.9
Preoperative investigations should include determination of serum calcium and phosphate levels, arterial blood gas analysis, and renal function tests apart from the routine ones. Pulmonary function tests may reveal a restrictive respiratory insufficiency due to extreme myopathy and bone pain involving the chest wall. Preoperatively, patients should be shifted with extreme caution, and meticulous care should be essential to avoid iatrogenic fractures.
Histological diagnosis of hemangioma or hemangiopericytomas (as in our cases) should indicate the use of invasive monitoring depending on the size of the tumor as in our case 1. Neuromuscular monitoring is a must for these patients with myopathy. Another important concern is to avoid hyperventilation, which is known to decrease plasma phosphate levels, thus causing an intracellular shift of the phosphate.10 Although our first patient required control of intracranial pressure in the postoperative period, we avoided hyperventilation and maintained the expired carbon dioxide levels within the normal range. In our second patient, not only was her requirement of nondepolarizing muscle relaxant low, but she also showed a delay in recovery from the effects of muscle relaxants. Irrespective of the extent of surgery and the time of the intraoperative course, the patients may require mechanical ventilation.
Postoperatively, hypercalcemia may manifest in the immediate postoperative period followed by a delayed hypocalcemia.11 Daily monitoring of phosphate and calcium levels is a must, and any abnormality should be corrected appropriately. Features of hyperparathyroidism have also been observed in many patients in the postoperative period.11 It might be necessary to continue phosphate supplementation for a few days until the levels start normalizing.