A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

Palliative care and hospice specialists consult on a variety of patients in the acute care setting that span all diagnoses and specialties. These include patients in the intensive care units, oncology units, as well as patients with end‐stage pulmonary, cardiac, and renal diseases. Discharge of these patients is often complicated by social issues, intensive personal care needs, and decreased functional status, as well as by the patient's insurance. Options for discharge disposition for patients accepting enrollment in hospice are often limited by financial constraints. Medicare pays for a set package of hospice benefits that do not include payment for room and board for hospice residential care and have a limited number of hours for a personal care attendant.[1] Hospice inpatient units are typically covered only for patients with acute care needs. Patients with secondary commercial insurance similarly find that custodial care benefits are often lacking, as most private and managed care plans mimic the Medicare hospice benefit.[2]

Palliative care inpatient consultation and palliative or hospice home care are associated with decreased 30‐day readmission rates.[3, 4, 5, 6] None of these studies, however, evaluated the effect of insurance status on readmission rates. Patients with dual coverage of Medicare and Medicaid are eligible for coverage of room and board (covered by Medicaid) in addition to the standard hospice benefit (covered by Medicare), and therefore have more options for discharge planning, including admission to a hospice residence, nursing home care with hospice services, or increased personal care attendant hours at home. Dual eligible patients (those with both Medicare and Medicaid) represent 20% of the Medicare population. They are generally poorer and with worse health status that those with Medicare alone; they have on average 25% more medical conditions than Medicare‐only patients.[7] Previous studies of readmissions and healthcare costs in the general population have found that dual eligible patients have higher rates of readmissions and higher overall healthcare costs compared with other groups.[7, 8, 9] However, these studies did not specifically look at patients near the end of life receiving hospice services. We hypothesize that dual eligible patients may actually have a lower rate of readmission at end of life compared with other groups, and that this effect may be partially mediated by discharge location (facility or home).

Previous studies have identified risk factors for 30‐day readmission to hospital, including living alone, insurance status, and poor or fair satisfaction with their primary care provider (PCP).[10] This study aims to evaluate, in the cohort of patients who have received a palliative care consultation during their hospital stay and who were discharged with hospice services, whether type of insurance is associated with risk of early readmission.

METHODS

Data were extracted from a replicate of Montefiore's Clinical Information System using healthcare surveillance software (Clinical Looking Glass; Emerging Health Information Technology, Yonkers, NY). We queried this database to find patients who received palliative care consultation from August 2010 to January 2014 at Montefiore Medical Center, an academic medical center in Bronx, NY, consisting of 3 general hospitals with 1491 beds. The medical center provides care to many underserved and minority patients and serves as the University Hospital of the Albert Einstein College of Medicine.

RESULTS

A total of 2755 inpatients were seen by the palliative care consultation service across the Montefiore Medical Center sites and discharged with hospice services. Of those, 1688 were dual eligible for Medicare and Medicaid, and 1067 were not. Specifically, 695 patients had Medicare only, 148 had private insurance only, 126 had Medicaid only, 78 had Medicare and private insurance, and 19 had Medicaid and private insurance. Univariable relationships between patient characteristics, insurance status, and readmission are shown in Table 1.

In this sample, 9.2% of patients in the dual eligible group were readmitted within 30 days compared with 13.1% of others (² = 10.3, P = 0.001). Of the total cohort, 1500 patients, including 862 dual eligible patients, were discharged to a facility, and 1255 patients, including 826 dual eligible patients, were discharged home. Dual eligible patients had a lower readmission rate compared with others in both settings (Figure 1). In univariable analysis, gender, age, hospital length of stay, race/ethnicity, SES, English as a primary language, LAPS, BUN, Charlson score, and comorbid peripheral vascular disease, cerebrovascular disease, heart disease, dementia, cancer, and liver disease were found to be related both to the predictor and the outcome variables and were included in the logistic regression model. While controlling for these variables, dual eligible patients had a lower odds of readmission within 30 days compared with others (odds ratio [OR]: 0.77; P = 0.041; 95% confidence interval [CI]: 0.59‐0.98) (Table 2). The Hosmer‐Lemeshow test was not significant, indicating that the overall model fit was good.

Figure 1

In the secondary analysis, we found that disposition (hospice services in a nursing home or hospice residence vs home hospice) partially mediates the relationship between insurance status and readmission, explaining 30% of the total effect (z = 5.06, P < 0.001). When accounting for disposition as a mediator, dual eligible patients still had a lower odds of readmission within 30 days compared with others, although the difference was no longer statistically significant (OR: 0.86; P = 0.24; 95% CI: 0.66‐ 1.11). Patients discharged with hospice services in a nursing home or hospice residence were less likely to be readmitted within 30 days (OR: 0.41; P < 0.001; 95% CI: 0.31‐0.54) (Table 3).

DISCUSSION

This study showed an association between dual coverage and lower odds of 30‐day readmission for patients discharged to hospice compared to all other insurance categories, excluding uninsured. This is the first study to date looking specifically at the association between insurance and readmission rates of patients discharged with hospice services. This association was attenuated, and no longer statistically significant, when accounting for discharge location.

These findings suggest that the added services available to patients enrolled in Medicare and Medicaid likely provide an enhanced level of postacute care. Patients with Medicaid have access to increased hours of personal care attendants as well as residential care, which often provides 24‐hour trained staff for rapid assessment of a change in clinical status and adjustment to therapeutic management. Combined with the Medicare hospice benefit, which provides better attention to symptom management, better supervision, and improved compliance with medications, as well as education of family and caregivers,[21, 22, 23] additional coverage with Medicaid is associated with a decrease in early readmission to the hospital.

It is often a financial hardship for family members or caregivers to take time off work to care for a dying patient. Without adequate postdischarge resources, the hospital to home transition will be ineffective, which has been shown to increase readmissions.[24] The option of increased attendant hours or residential care can have a positive impact on the financial and psychosocial stressors of caring for a family member at the end of life. Although we did not assess for this in our study, caregiver burnout often plays a role in emergency room visits and admissions of patients at the end of life.[25] The average age of the patients in our cohorts was 81 and 79 years; primary caregivers are often elderly with multiple medical conditions themselves and often struggle to provide the patient's care.[26, 27]

The main limitation of this study is that it is a retrospective observational study rather than a prospective randomized controlled trial. Many patients become dual eligible after requiring institutional custodial care, making the relationship between insurance status, discharge location, and readmissions complex and the causal relationship bidirectional. Patients discharged to hospice residence or to a nursing home with hospice services, who are more often dual eligible patients, are likely to receive more timely management of medical crises or changes in medical status, thus preventing readmission, whereas patients who receive home hospice with family providing the bulk of care may have a lower threshold for emergency room visits, possibly leading to greater incidence of readmission. Therefore, our results may be more a reflection of where the care is provided than what insurance the patient has. However, dual eligible patients discharged home also had a lower readmission rate compared with others, suggesting that insurance status has an independent association with readmission.

Unmeasured variables may explain the relationship between dual eligibility and 30‐day readmission rates. Some variables that we were not able to reliably measure in this study include functional status, number of hospitalizations in last year, patient educational level, patient self‐reported health status, quality of life, cognitive functioning, hearing or vision impairment, income, employment status, number of people in the home, and caregiver availability.[11, 12, 13, 19] However, omitting these variables from this study is more likely to bias our results toward the null, because these variables are likely related to dual eligibility and a higher, rather than lower, rate of readmission. We also did not measure whether participating decision makers were involved in the hospice admission or whether patients and families contacted their PCPs after discharge, variables found to be important in a previous pilot study.[5]

The generalizability of the results may be affected by the relative generosity of the New York State Medicaid benefits compared to many other states. New York State ranks third in the nation for eligibility and first for scope of services, including increased access to home‐ and community‐based services.[28] In addition, this study was a single‐center study in an urban, socioeconomically disadvantaged environment, explaining the higher rate of readmission compared to hospice patients nationally,[29] which is similar to other urban, academic medical centers.[5] For patients in our practice setting, the financial burden of paying privately for home care or residential custodial services is often prohibitive, which may not be the case in other settings.

Further research to identify whether discharge with hospice services mediates the relationship between insurance status and readmission could help confirm these findings. In addition, the relationship between caregiver burden and quality of life, and increased healthcare costs at the end of life should be explored. Overwhelming evidence suggests that being socioeconomically disadvantaged is a significant risk factor for early readmission, and enrolling these patients in Medicaid may modify this risk.[10, 30] Further research should explore whether policies that expand access to Medicaid or otherwise increase access to custodial care services can decrease burdensome hospital readmissions near the end of life.

Palliative care and hospice specialists consult on a variety of patients in the acute care setting that span all diagnoses and specialties. These include patients in the intensive care units, oncology units, as well as patients with end‐stage pulmonary, cardiac, and renal diseases. Discharge of these patients is often complicated by social issues, intensive personal care needs, and decreased functional status, as well as by the patient's insurance. Options for discharge disposition for patients accepting enrollment in hospice are often limited by financial constraints. Medicare pays for a set package of hospice benefits that do not include payment for room and board for hospice residential care and have a limited number of hours for a personal care attendant.[1] Hospice inpatient units are typically covered only for patients with acute care needs. Patients with secondary commercial insurance similarly find that custodial care benefits are often lacking, as most private and managed care plans mimic the Medicare hospice benefit.[2]

Palliative care inpatient consultation and palliative or hospice home care are associated with decreased 30‐day readmission rates.[3, 4, 5, 6] None of these studies, however, evaluated the effect of insurance status on readmission rates. Patients with dual coverage of Medicare and Medicaid are eligible for coverage of room and board (covered by Medicaid) in addition to the standard hospice benefit (covered by Medicare), and therefore have more options for discharge planning, including admission to a hospice residence, nursing home care with hospice services, or increased personal care attendant hours at home. Dual eligible patients (those with both Medicare and Medicaid) represent 20% of the Medicare population. They are generally poorer and with worse health status that those with Medicare alone; they have on average 25% more medical conditions than Medicare‐only patients.[7] Previous studies of readmissions and healthcare costs in the general population have found that dual eligible patients have higher rates of readmissions and higher overall healthcare costs compared with other groups.[7, 8, 9] However, these studies did not specifically look at patients near the end of life receiving hospice services. We hypothesize that dual eligible patients may actually have a lower rate of readmission at end of life compared with other groups, and that this effect may be partially mediated by discharge location (facility or home).

Previous studies have identified risk factors for 30‐day readmission to hospital, including living alone, insurance status, and poor or fair satisfaction with their primary care provider (PCP).[10] This study aims to evaluate, in the cohort of patients who have received a palliative care consultation during their hospital stay and who were discharged with hospice services, whether type of insurance is associated with risk of early readmission.

METHODS

Data were extracted from a replicate of Montefiore's Clinical Information System using healthcare surveillance software (Clinical Looking Glass; Emerging Health Information Technology, Yonkers, NY). We queried this database to find patients who received palliative care consultation from August 2010 to January 2014 at Montefiore Medical Center, an academic medical center in Bronx, NY, consisting of 3 general hospitals with 1491 beds. The medical center provides care to many underserved and minority patients and serves as the University Hospital of the Albert Einstein College of Medicine.

RESULTS

A total of 2755 inpatients were seen by the palliative care consultation service across the Montefiore Medical Center sites and discharged with hospice services. Of those, 1688 were dual eligible for Medicare and Medicaid, and 1067 were not. Specifically, 695 patients had Medicare only, 148 had private insurance only, 126 had Medicaid only, 78 had Medicare and private insurance, and 19 had Medicaid and private insurance. Univariable relationships between patient characteristics, insurance status, and readmission are shown in Table 1.

In this sample, 9.2% of patients in the dual eligible group were readmitted within 30 days compared with 13.1% of others (² = 10.3, P = 0.001). Of the total cohort, 1500 patients, including 862 dual eligible patients, were discharged to a facility, and 1255 patients, including 826 dual eligible patients, were discharged home. Dual eligible patients had a lower readmission rate compared with others in both settings (Figure 1). In univariable analysis, gender, age, hospital length of stay, race/ethnicity, SES, English as a primary language, LAPS, BUN, Charlson score, and comorbid peripheral vascular disease, cerebrovascular disease, heart disease, dementia, cancer, and liver disease were found to be related both to the predictor and the outcome variables and were included in the logistic regression model. While controlling for these variables, dual eligible patients had a lower odds of readmission within 30 days compared with others (odds ratio [OR]: 0.77; P = 0.041; 95% confidence interval [CI]: 0.59‐0.98) (Table 2). The Hosmer‐Lemeshow test was not significant, indicating that the overall model fit was good.

Figure 1

In the secondary analysis, we found that disposition (hospice services in a nursing home or hospice residence vs home hospice) partially mediates the relationship between insurance status and readmission, explaining 30% of the total effect (z = 5.06, P < 0.001). When accounting for disposition as a mediator, dual eligible patients still had a lower odds of readmission within 30 days compared with others, although the difference was no longer statistically significant (OR: 0.86; P = 0.24; 95% CI: 0.66‐ 1.11). Patients discharged with hospice services in a nursing home or hospice residence were less likely to be readmitted within 30 days (OR: 0.41; P < 0.001; 95% CI: 0.31‐0.54) (Table 3).

DISCUSSION

This study showed an association between dual coverage and lower odds of 30‐day readmission for patients discharged to hospice compared to all other insurance categories, excluding uninsured. This is the first study to date looking specifically at the association between insurance and readmission rates of patients discharged with hospice services. This association was attenuated, and no longer statistically significant, when accounting for discharge location.

These findings suggest that the added services available to patients enrolled in Medicare and Medicaid likely provide an enhanced level of postacute care. Patients with Medicaid have access to increased hours of personal care attendants as well as residential care, which often provides 24‐hour trained staff for rapid assessment of a change in clinical status and adjustment to therapeutic management. Combined with the Medicare hospice benefit, which provides better attention to symptom management, better supervision, and improved compliance with medications, as well as education of family and caregivers,[21, 22, 23] additional coverage with Medicaid is associated with a decrease in early readmission to the hospital.

It is often a financial hardship for family members or caregivers to take time off work to care for a dying patient. Without adequate postdischarge resources, the hospital to home transition will be ineffective, which has been shown to increase readmissions.[24] The option of increased attendant hours or residential care can have a positive impact on the financial and psychosocial stressors of caring for a family member at the end of life. Although we did not assess for this in our study, caregiver burnout often plays a role in emergency room visits and admissions of patients at the end of life.[25] The average age of the patients in our cohorts was 81 and 79 years; primary caregivers are often elderly with multiple medical conditions themselves and often struggle to provide the patient's care.[26, 27]

The main limitation of this study is that it is a retrospective observational study rather than a prospective randomized controlled trial. Many patients become dual eligible after requiring institutional custodial care, making the relationship between insurance status, discharge location, and readmissions complex and the causal relationship bidirectional. Patients discharged to hospice residence or to a nursing home with hospice services, who are more often dual eligible patients, are likely to receive more timely management of medical crises or changes in medical status, thus preventing readmission, whereas patients who receive home hospice with family providing the bulk of care may have a lower threshold for emergency room visits, possibly leading to greater incidence of readmission. Therefore, our results may be more a reflection of where the care is provided than what insurance the patient has. However, dual eligible patients discharged home also had a lower readmission rate compared with others, suggesting that insurance status has an independent association with readmission.

Unmeasured variables may explain the relationship between dual eligibility and 30‐day readmission rates. Some variables that we were not able to reliably measure in this study include functional status, number of hospitalizations in last year, patient educational level, patient self‐reported health status, quality of life, cognitive functioning, hearing or vision impairment, income, employment status, number of people in the home, and caregiver availability.[11, 12, 13, 19] However, omitting these variables from this study is more likely to bias our results toward the null, because these variables are likely related to dual eligibility and a higher, rather than lower, rate of readmission. We also did not measure whether participating decision makers were involved in the hospice admission or whether patients and families contacted their PCPs after discharge, variables found to be important in a previous pilot study.[5]

The generalizability of the results may be affected by the relative generosity of the New York State Medicaid benefits compared to many other states. New York State ranks third in the nation for eligibility and first for scope of services, including increased access to home‐ and community‐based services.[28] In addition, this study was a single‐center study in an urban, socioeconomically disadvantaged environment, explaining the higher rate of readmission compared to hospice patients nationally,[29] which is similar to other urban, academic medical centers.[5] For patients in our practice setting, the financial burden of paying privately for home care or residential custodial services is often prohibitive, which may not be the case in other settings.

Further research to identify whether discharge with hospice services mediates the relationship between insurance status and readmission could help confirm these findings. In addition, the relationship between caregiver burden and quality of life, and increased healthcare costs at the end of life should be explored. Overwhelming evidence suggests that being socioeconomically disadvantaged is a significant risk factor for early readmission, and enrolling these patients in Medicaid may modify this risk.[10, 30] Further research should explore whether policies that expand access to Medicaid or otherwise increase access to custodial care services can decrease burdensome hospital readmissions near the end of life.

Palliative care and hospice specialists consult on a variety of patients in the acute care setting that span all diagnoses and specialties. These include patients in the intensive care units, oncology units, as well as patients with end‐stage pulmonary, cardiac, and renal diseases. Discharge of these patients is often complicated by social issues, intensive personal care needs, and decreased functional status, as well as by the patient's insurance. Options for discharge disposition for patients accepting enrollment in hospice are often limited by financial constraints. Medicare pays for a set package of hospice benefits that do not include payment for room and board for hospice residential care and have a limited number of hours for a personal care attendant.[1] Hospice inpatient units are typically covered only for patients with acute care needs. Patients with secondary commercial insurance similarly find that custodial care benefits are often lacking, as most private and managed care plans mimic the Medicare hospice benefit.[2]

Palliative care inpatient consultation and palliative or hospice home care are associated with decreased 30‐day readmission rates.[3, 4, 5, 6] None of these studies, however, evaluated the effect of insurance status on readmission rates. Patients with dual coverage of Medicare and Medicaid are eligible for coverage of room and board (covered by Medicaid) in addition to the standard hospice benefit (covered by Medicare), and therefore have more options for discharge planning, including admission to a hospice residence, nursing home care with hospice services, or increased personal care attendant hours at home. Dual eligible patients (those with both Medicare and Medicaid) represent 20% of the Medicare population. They are generally poorer and with worse health status that those with Medicare alone; they have on average 25% more medical conditions than Medicare‐only patients.[7] Previous studies of readmissions and healthcare costs in the general population have found that dual eligible patients have higher rates of readmissions and higher overall healthcare costs compared with other groups.[7, 8, 9] However, these studies did not specifically look at patients near the end of life receiving hospice services. We hypothesize that dual eligible patients may actually have a lower rate of readmission at end of life compared with other groups, and that this effect may be partially mediated by discharge location (facility or home).

Previous studies have identified risk factors for 30‐day readmission to hospital, including living alone, insurance status, and poor or fair satisfaction with their primary care provider (PCP).[10] This study aims to evaluate, in the cohort of patients who have received a palliative care consultation during their hospital stay and who were discharged with hospice services, whether type of insurance is associated with risk of early readmission.

METHODS

Data were extracted from a replicate of Montefiore's Clinical Information System using healthcare surveillance software (Clinical Looking Glass; Emerging Health Information Technology, Yonkers, NY). We queried this database to find patients who received palliative care consultation from August 2010 to January 2014 at Montefiore Medical Center, an academic medical center in Bronx, NY, consisting of 3 general hospitals with 1491 beds. The medical center provides care to many underserved and minority patients and serves as the University Hospital of the Albert Einstein College of Medicine.

RESULTS

A total of 2755 inpatients were seen by the palliative care consultation service across the Montefiore Medical Center sites and discharged with hospice services. Of those, 1688 were dual eligible for Medicare and Medicaid, and 1067 were not. Specifically, 695 patients had Medicare only, 148 had private insurance only, 126 had Medicaid only, 78 had Medicare and private insurance, and 19 had Medicaid and private insurance. Univariable relationships between patient characteristics, insurance status, and readmission are shown in Table 1.

In this sample, 9.2% of patients in the dual eligible group were readmitted within 30 days compared with 13.1% of others (² = 10.3, P = 0.001). Of the total cohort, 1500 patients, including 862 dual eligible patients, were discharged to a facility, and 1255 patients, including 826 dual eligible patients, were discharged home. Dual eligible patients had a lower readmission rate compared with others in both settings (Figure 1). In univariable analysis, gender, age, hospital length of stay, race/ethnicity, SES, English as a primary language, LAPS, BUN, Charlson score, and comorbid peripheral vascular disease, cerebrovascular disease, heart disease, dementia, cancer, and liver disease were found to be related both to the predictor and the outcome variables and were included in the logistic regression model. While controlling for these variables, dual eligible patients had a lower odds of readmission within 30 days compared with others (odds ratio [OR]: 0.77; P = 0.041; 95% confidence interval [CI]: 0.59‐0.98) (Table 2). The Hosmer‐Lemeshow test was not significant, indicating that the overall model fit was good.

Figure 1

In the secondary analysis, we found that disposition (hospice services in a nursing home or hospice residence vs home hospice) partially mediates the relationship between insurance status and readmission, explaining 30% of the total effect (z = 5.06, P < 0.001). When accounting for disposition as a mediator, dual eligible patients still had a lower odds of readmission within 30 days compared with others, although the difference was no longer statistically significant (OR: 0.86; P = 0.24; 95% CI: 0.66‐ 1.11). Patients discharged with hospice services in a nursing home or hospice residence were less likely to be readmitted within 30 days (OR: 0.41; P < 0.001; 95% CI: 0.31‐0.54) (Table 3).

DISCUSSION

This study showed an association between dual coverage and lower odds of 30‐day readmission for patients discharged to hospice compared to all other insurance categories, excluding uninsured. This is the first study to date looking specifically at the association between insurance and readmission rates of patients discharged with hospice services. This association was attenuated, and no longer statistically significant, when accounting for discharge location.

These findings suggest that the added services available to patients enrolled in Medicare and Medicaid likely provide an enhanced level of postacute care. Patients with Medicaid have access to increased hours of personal care attendants as well as residential care, which often provides 24‐hour trained staff for rapid assessment of a change in clinical status and adjustment to therapeutic management. Combined with the Medicare hospice benefit, which provides better attention to symptom management, better supervision, and improved compliance with medications, as well as education of family and caregivers,[21, 22, 23] additional coverage with Medicaid is associated with a decrease in early readmission to the hospital.

It is often a financial hardship for family members or caregivers to take time off work to care for a dying patient. Without adequate postdischarge resources, the hospital to home transition will be ineffective, which has been shown to increase readmissions.[24] The option of increased attendant hours or residential care can have a positive impact on the financial and psychosocial stressors of caring for a family member at the end of life. Although we did not assess for this in our study, caregiver burnout often plays a role in emergency room visits and admissions of patients at the end of life.[25] The average age of the patients in our cohorts was 81 and 79 years; primary caregivers are often elderly with multiple medical conditions themselves and often struggle to provide the patient's care.[26, 27]

The main limitation of this study is that it is a retrospective observational study rather than a prospective randomized controlled trial. Many patients become dual eligible after requiring institutional custodial care, making the relationship between insurance status, discharge location, and readmissions complex and the causal relationship bidirectional. Patients discharged to hospice residence or to a nursing home with hospice services, who are more often dual eligible patients, are likely to receive more timely management of medical crises or changes in medical status, thus preventing readmission, whereas patients who receive home hospice with family providing the bulk of care may have a lower threshold for emergency room visits, possibly leading to greater incidence of readmission. Therefore, our results may be more a reflection of where the care is provided than what insurance the patient has. However, dual eligible patients discharged home also had a lower readmission rate compared with others, suggesting that insurance status has an independent association with readmission.

Unmeasured variables may explain the relationship between dual eligibility and 30‐day readmission rates. Some variables that we were not able to reliably measure in this study include functional status, number of hospitalizations in last year, patient educational level, patient self‐reported health status, quality of life, cognitive functioning, hearing or vision impairment, income, employment status, number of people in the home, and caregiver availability.[11, 12, 13, 19] However, omitting these variables from this study is more likely to bias our results toward the null, because these variables are likely related to dual eligibility and a higher, rather than lower, rate of readmission. We also did not measure whether participating decision makers were involved in the hospice admission or whether patients and families contacted their PCPs after discharge, variables found to be important in a previous pilot study.[5]

The generalizability of the results may be affected by the relative generosity of the New York State Medicaid benefits compared to many other states. New York State ranks third in the nation for eligibility and first for scope of services, including increased access to home‐ and community‐based services.[28] In addition, this study was a single‐center study in an urban, socioeconomically disadvantaged environment, explaining the higher rate of readmission compared to hospice patients nationally,[29] which is similar to other urban, academic medical centers.[5] For patients in our practice setting, the financial burden of paying privately for home care or residential custodial services is often prohibitive, which may not be the case in other settings.

Further research to identify whether discharge with hospice services mediates the relationship between insurance status and readmission could help confirm these findings. In addition, the relationship between caregiver burden and quality of life, and increased healthcare costs at the end of life should be explored. Overwhelming evidence suggests that being socioeconomically disadvantaged is a significant risk factor for early readmission, and enrolling these patients in Medicaid may modify this risk.[10, 30] Further research should explore whether policies that expand access to Medicaid or otherwise increase access to custodial care services can decrease burdensome hospital readmissions near the end of life.