A Fractured Diagnosis
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《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 44-year-old woman came to the emergency department because of pain in her right thigh shortly after she had a minor fall. A right femoral-neck fracture was diagnosed, and she was admitted to the orthopedic ward to await surgery. Six months before hospitalization, and before she fell, limb pain had developed, which had become progressively worse. The patient also reported a weight loss of 30 kg and fatigue.
A fractured femoral neck after a minor fall in a patient 44 years of age is very uncommon. The associated limb pain and severe weight loss suggest the possibility of cancer, chronic infection, or autoimmune disease. A fracture may also be secondary to osteosclerosis or osteoporosis caused by immobilization, low intake of calcium and vitamin D or malabsorption, endocrine disorders such as Cushing's syndrome or hyperparathyroidism, renal disease, or adverse effects of drugs such as glucocorticoids or anticonvulsants. The possibility of an eating disorder should also be considered. I would want to know whether the patient has anorexia or difficulty in eating, whether she has other manifestations of systemic disease (such as fever, rash, or neurologic symptoms), and whether she takes any medications.
The patient was a housewife with four healthy children. She reported mild difficulty in swallowing solid food, which caused her to eat less. She said that she had not had nausea, vomiting, diarrhea or constipation, fevers, sweats, itching, or rash in the past several months. She did not smoke and reported no drug use.
On physical examination, the patient appeared cachectic and pale. She had poor oral hygiene and mild cervical lymphadenopathy. She had substantial bone tenderness on palpation of her limbs and chest. The remainder of the physical examination, which included breast, rectal, and neurologic examination, showed no abnormalities.
The hemoglobin level was 11.2 g per deciliter, and the mean corpuscular volume 90 μm3. The white-cell count, platelet count, levels of liver enzymes, and the prothrombin time and partial-thromboplastin time were within normal ranges. The level of blood urea nitrogen was 4.2 mmol per liter (normal range, 3.3 to 6.5), and the level of serum creatinine 67 μmol per liter (normal, 60 to 106). The serum potassium levels were persistently low (2.3 to 3 mmol per liter) and were not corrected by oral supplementation with 9 g of potassium chloride daily for four days. The orthopedic operation was postponed, and the patient was transferred to the internal medicine ward for further evaluation.
A metastatic cancer could explain the dysphagia, bone pain, and reduced food intake. A collagen vascular disease such as scleroderma with esophageal dysmotility or myositis might be an alternative explanation. The absence of fever makes a chronic infection less likely. Multiple myeloma may explain the bone pain, fatigue, anemia, weight loss, and hypokalemia (which could result from renal tubular dysfunction); serum and urinary protein electrophoresis should be performed. A skeletal survey may aid in the diagnosis of lytic lesions and other bone abnormalities.
The persistent hypokalemia could be caused by renal wasting or, alternatively, could indicate gastrointestinal losses. Measurement of the levels of other electrolytes, such as chloride and phosphate, and determination of the blood pH, partial pressure of carbon dioxide, and bicarbonate concentration are required.
Additional laboratory testing revealed a serum phosphate level of 1.7 mg per liter (0.55 mmol per liter; normal range, 2.5 to 4.5 mg per liter [0.8 to 1.45 mmol per liter]); serum calcium level of 8.2 mg per deciliter (2.0 mmol per liter; normal range, 8 to 10 mg per deciliter [2.0 to 2.5 mmol per liter]); sodium, 144 mmol per liter; potassium, 2.8 mmol per liter; chloride, 119 mmol per liter; magnesium, 2.2 mg per deciliter (0.9 mmol per liter); uric acid, 2.6 mg per deciliter (154.6 μmol per liter; normal range, 2.5 to 6.3 mg per deciliter [148.7 to 374.7 μmol per liter]); alkaline phosphatase, 168 U per liter (normal range, 40 to 130) and albumin, 3.2 g per deciliter. The blood pH was 7.32, the partial pressure of carbon dioxide 37 mm Hg, and the bicarbonate level 18.7 mmol per liter, with a normal value for the serum anion gap.
The results of protein electrophoresis in the blood and urine were normal. Radiographs of the spine, hips, and limbs showed diffuse osteopenia without lytic lesions or fractures. A reevaluation of the right femur radiograph showed osteopenia with a Looser–Milkman pseudofracture (Figure 1). A computed tomographic (CT) scan of the chest showed several pseudofractures of the ribs (Figure 2). These findings indicated that the canceled surgery would not be required.
Figure 1. A Radiograph of the Right Hip Joint.
A pseudofracture is visible at the medial aspect of the neck of the femur (arrow).
Figure 2. A Computed Tomographic Scan of the Chest.
A pseudofracture is visible at the anterior aspect of the sixth rib (arrow).
This patient has radiologic findings that are consistent with osteomalacia, with low serum phosphate, normal calcium levels, and raised levels of alkaline phosphatase. A low bone density is also characteristic of osteomalacia, although this finding would not distinguish it from osteoporosis. Whereas the gold standard for the diagnosis of osteomalacia involves bone biopsy with double tetracycline labeling, the radiologic findings combined with the abnormalities in phosphate and alkaline phosphatase levels in this case are sufficient to establish the working diagnosis of osteomalacia. The osteomalacia may be secondary to abnormal vitamin D metabolism (where secondary hyperparathyroidism would be expected), or it could be secondary to a phosphate deficiency, such as in hyperparathyroidism, Fanconi's syndrome, hypophosphatemic rickets, oncogenic osteomalacia, or other conditions that cause mineralization defects (for example, abnormal pH or abnormal alkaline phosphatase bioactivity). In this patient, the coexistence of osteomalacia, persistent hypokalemia, and hyperchloremic normal anion-gap metabolic acidosis suggests a renal tubular disorder (such as renal tubular acidosis) or a malabsorptive process (such as celiac or inflammatory bowel disease) that causes the loss of potassium and bicarbonate and malabsorption of vitamin D. Because the patient did not report diarrhea among her symptoms, the diagnosis is more likely to favor a renal tubular disorder, although the possibility of malabsorption has not been ruled out. Additional testing would be warranted at this point, including measurement of urinary pH and urine levels of urea nitrogen and creatinine, the osmolality of a spot-urine sample, and a 24-hour urine collection for electrolytes — including phosphorus and calcium. The presence of glycosuria and aminoaciduria would support the diagnosis of Fanconi's syndrome. Measurement of the level of serum parathyroid hormone could be helpful; the level does not increase in some primary renal-phosphate–wasting syndromes, such as oncogenic osteomalacia. An endoscopy with duodenal biopsy could rule out malabsorption due to celiac disease.
The urinary pH was 8; the daily urine output was 2.2 liters (55 ml per kilogram of body weight per day [normal, less than 50]); the level of urine urea nitrogen was 69.5 mmol per liter; creatinine, 2730 μmol per liter; sodium, 66 mmol per liter; chloride, 79 mmol per liter; potassium, 32.6 mmol per liter; calcium, 7.5 mg per deciliter (1.9 mmol per liter) and daily calcium excretion, 165 mg (4.1 mg per kilogram of body weight per day [normal, less than 4]); phosphate, 16.5 mg per deciliter (5.32 mmol per liter), and daily phosphate excretion, 380 mg; magnesium, 0.8 mmol per liter; urine osmolality, 279 mOsm per kilogram of water; plasma osmolality, 295 mOsm per kilogram of water; range in urinary potassium-to-creatinine ratio, 9.1 to 11.9; urinary anion gap (urine:Na+K–Cl), 19.6 mmol per liter; and urinary osmolal gap (osmu = [2Nau + 2Ku + ureau + glucoseu]), 12.3 mmol per liter. No glycosuria and aminoaciduria were detected. The fractional excretion of phosphate was 23.7 percent (normal, 5 to 20); tubular reabsorption of phosphorus, 77 percent; and tubular reabsorption of calcium, 97.5 percent. Serum parathyroid hormone levels were 55 to 79 pg per milliliter (normal, 10 to 60), associated with serum calcium levels of 8.2 to 8.4 mg per deciliter (2.0 to 2.1 mmol per liter). Endoscopy revealed no pathologic findings, and a biopsy specimen obtained from the distal part of the duodenum appeared normal.
In the presence of depleted plasma potassium, the appropriate renal response would be to excrete less than 15 mmol of potassium daily, with a spot urinary ratio of potassium to creatinine of 1 to 1.5. This patient's daily urinary potassium level of 71.7 mmol and the high ratio of potassium to creatinine in the spot urinary sample indicate renal loss. Furthermore, the absence of diarrhea and the normal duodenal-biopsy specimen argue against gastrointestinal losses of potassium. The high level of urinary phosphate excretion and low tubular reabsorption of phosphorus indicate that there is also renal phosphate wasting. Hyperparathyroidism is a common cause of phosphate wasting but it is unlikely in this case, given the consistently normal levels of serum calcium. Vitamin D deficiency, another possible cause of phosphate wasting, is typically associated with a higher value of parathyroid hormone (above 100 pg per milliliter) and also could not account for the potassium wasting. More likely causes in this case include primary defects such as X-linked hypophosphatemic rickets or secondary defects such as renal tubular acidosis or oncogenic osteomalacia. Primary or acquired Fanconi's syndrome could also cause renal phosphate wasting, although this would be associated with glycosuria, aminoaciduria, and hypouricemia; however, an isolated defect in proximal tubular function that led to a decrease in phosphate reabsorption may still be a possibility.
The defective urinary concentrating ability and mild polyuria are most likely due to hypokalemia. Other disorders that may affect the collecting tubules, such as amyloidosis or Sj?gren's syndrome, are also possible.
In the absence of diarrhea, the presence of a normal anion-gap metabolic acidosis (also called hyperchloremic acidosis) with hypokalemia most likely indicates a renal tubular acidosis. The positive urinary anion gap and the low urinary osmolal gap (below 100 mmol per liter) implicate reduced urinary ammonium excretion (as occurs in types 1 and 4 renal tubular acidosis); the presence of hypokalemia and a urinary pH that was persistently above 6 indicate that this is a type 1 renal tubular acidosis; the presence of hyperkalemia and a urinary pH that is below 5.5 during acidosis would indicate type 4 renal tubular acidosis. At this stage of the differential diagnosis, I would take the medical history again and ask about possible familial renal or bone disease, hearing impairment, or any other hereditary condition that might cause distal renal tubular acidosis, such as Fabry's disease.
An arginine hydrochloride test was performed (to assess effects on urine pH of acidification of the plasma). After the infusion of an arginine hydrochloride solution over the course of two hours, the blood pH was assessed at 7.34, 7.28, and 7.27 at zero, two, and six hours, respectively, although the urine remained at a high-alkaline pH (pH 8) throughout the test. The patient said she knew of no familial disorders.
The inability of the kidney to lower urinary pH below 5.5 after an acid load confirms the impression of a distal renal tubular acidosis. The patient has not received medications that could cause this disorder (such as amphotericin), and there is no clinical or biochemical evidence of primary biliary cirrhosis, chronic active hepatitis, or hypercalciuria with nephrocalcinosis, which may be associated with renal tubular acidosis. Acquired renal tubular acidosis has also been described with rheumatologic diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Sj?gren's syndrome. The patient's dysphagia, combined with her poor oral hygiene, suggest the possibility of a lack of saliva, a hallmark of Sj?gren's syndrome.
On further questioning, the patient said that she had had symptoms of dry mouth and a recurrent sensation of sand in her eyes for the past year. Serologic testing for antinuclear antibodies was positive (+3 out of 4), anti-Ro (SS-A) was 482 U per milliliter, anti-La (SS-B) was 608 U per milliliter (normal for both is less than 25), and C3 was 63 mg per deciliter (normal range, 50 to 120). Schirmer's test for tear production was positive, meaning no tears, and a salivary-gland biopsy showed lymphocytic infiltration (Figure 3).
Figure 3. Biopsy Specimen of the Salivary Gland Showing Lymphocytic Infiltrates (Hematoxylin and Eosin).
The patient meets five of the six so-called European criteria for the diagnosis of Sj?gren's syndrome: the presence of autoantibodies, subjective ocular and oral symptoms, a positive Schirmer's test, and histopathological features. In light of the association between Sj?gren's syndrome and lymphoma, the 30-kg weight loss, and the mild lymphadenopathy, lymphoma should be ruled out.
A CT scan of the chest and abdomen revealed no lymphadenopathy or splenomegaly. Treatment with daily doses of sodium bicarbonate (2 g), potassium citrate (2 g), sodium phosphate (1.5 g), potassium chloride (4 g), calcium carbonate (1 g), calcitriol (0.25 μg), and an artificial tear solution was initiated. The patient's condition responded with gradual, progressive improvement. One year later, at this writing, the patient is well. She is now able to walk, has gained weight, and reports a reduction in her general weakness and limb pain.
Commentary
Fractures, bone pain, and reduced bone density in a relatively young patient require a thorough investigation. It is important to differentiate between early-onset osteoporosis and osteomalacia. The distinction between the two can be made most accurately by bone biopsy with double tetracycline labeling.1 However, this procedure is rarely performed, because the diagnosis can be elicited from the history, physical findings, radiographic evaluation, and laboratory results. In osteoporosis, normal levels of serum calcium, phosphate, alkaline phosphatase, and parathyroid hormone are present; in contrast, abnormalities in at least one of these measurements are common in osteomalacia.
In order for adequate mineralization of the bone to occur, normal concentrations of calcium and phosphate in the extracellular fluid, adequate bioactivity of alkaline phosphatase, a normal pH value at the site of calcification, and the absence of calcification inhibitors are needed.2 When any of these factors is altered, osteomalacia may result. Vitamin D deficiency or vitamin D resistance accounts for the majority of cases of osteomalacia. The most common cause is dietary deficiency and lack of exposure to sunlight3; malabsorptive disorders, such as celiac sprue,4 underlie many other cases.
Chronic metabolic acidosis induces calcium loss from bone associated with hypercalciuria.5 It may also induce renal phosphate depletion by way of its direct effect on the sodium phosphate cotransporter.6 However, there is no agreement whether distal renal tubular acidosis causes osteomalacia.7 The increased urinary phosphate excretion and hypophosphatemia in our patient may suggest the presence of a proximal tubular defect. In the absence of glycosuria, aminoaciduria, and hypouricemia, we were unable to establish the diagnosis of Fanconi's syndrome. The possibility of multiple tubular dysfunctions in this patient is also supported by the hyposthenuria and mild polyuria, suggesting a defective urine-concentrating capacity, although hypokalemia may also underlie these findings.
In adults, secondary distal renal tubular acidosis may develop as a consequence of calcium disorders (idiopathic hypercalciuria with nephrocalcinosis, primary hyperparathyroidism), use of drugs or toxins (amphotericin, trimethoprim, pentamidine, toluene), or autoimmune diseases (Sj?gren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, chronic liver diseases).8 In this patient, the dysphagia, poor oral hygiene, and eye dryness gave the clues to the diagnosis of Sj?gren's syndrome. The most common clinical manifestations of Sj?gren's syndrome are exocrine gland involvement: keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth and salivary-gland enlargement). Xerostomia can be made manifest in many ways, including dysphagia, dental caries, oral candidiasis, difficulty in speaking, weight loss, or even chronic esophagitis. Abnormal esophageal peristalsis causes severe dysphagia in Sj?gren's syndrome.9
The patient under discussion met the revised European criteria for the diagnosis of Sj?gren's syndrome.10 The clinical picture suggests primary Sj?gren's syndrome because of the lack of clinical features associated with rheumatoid arthritis or other autoimmune disorders.
Tubulointerstitial nephritis is the most common renal complication in Sj?gren's syndrome. It is usually recognized in association with distal renal tubular acidosis, nephrogenic diabetes insipidus, and more rarely, proximal tubular abnormalities and Fanconi's syndrome. Up to 25 percent of patients with Sj?gren's syndrome have some defect in distal acidification that may be associated with other tubular dysfunctions.11,12
There is no consensus regarding treatment. When interstitial nephritis occurs, a course of corticosteroids is usually beneficial; less is known about the benefits of such treatment in the case of distal renal tubular acidosis. There are a few case reports in the literature describing osteomalacia as the presenting manifestation of Sj?gren's syndrome.13,14,15 In two cases, treatment with alkali, vitamin D, and calcium resulted in improvement; in one case, steroid treatment resulted in similar improvement. In light of the prominent tubular acidification abnormality, this patient was treated with bicarbonate, potassium, and phosphate supplementation along with calcitriol, and she had a good clinical response.
Source Information
From the Department of Medicine, Hadassah–Hebrew University Medical Center, Mount Scopus, Jerusalem.
Address reprint requests to Dr. Chajek-Shaul at the Department of Medicine, Hadassah–Hebrew University Medical Center, Mount Scopus, P.O. Box 24035, Jerusalem 91240, Israel, or at chajek@hadasssah.org.il.
References
Bingham CT, Fitzpatrick LA. Noninvasive testing in the diagnosis of osteomalacia. Am J Med 1993;95:519-523.
Russell JA. Osteomalacic myopathy. Muscle Nerve 1994;17:578-580.
Lamberg-Allardt CJ, Outila TA, Karkkainen MU, Rita HJ, Valsta LM. Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? J Bone Miner Res 2001;16:2066-2073.
Tovey FI, Hall ML, Ell PJ, Hobsley M. A review of postgastrectomy bone disease. J Gastroenterol Hepatol 1992;7:639-645.
Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone resorption. Curr Opin Nephrol Hypertens 2004;13:423-436.
Wiederkehr M, Krapf R. Metabolic and endocrine effects of metabolic acidosis in humans. Swiss Med Wkly 2001;131:127-132.
Fulop M, Mackay M. Renal tubular acidosis, Sjogren syndrome, and bone disease. Arch Intern Med 2004;164:905-909.
Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160-2170.
Anselmino M, Zaninotto G, Costantini M, et al. Esophageal motor function in primary Sjogren's syndrome: correlation with dysphagia and xerostomia. Dig Dis Sci 1997;42:113-118.
Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjogren's syndrome: results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993;36:340-347.
Bossini N, Savoldi S, Franceschini F, et al. Clinical and morphological features of kidney involvement in primary Sjogren's syndrome. Nephrol Dial Transplant 2001;16:2328-2336.
Vitali C, Tavoni A, Sciuto M, Maccheroni M, Moriconi L, Bombardieri S. Renal involvement in primary Sjogren's syndrome: a retrospective-prospective study. Scand J Rheumatol 1991;20:132-136.
Okada M, Suzuki K, Hidaka T, et al. Rapid improvement of osteomalacia by treatment in a case of Sjogren's syndrome, rheumatoid arthritis and renal tubular acidosis type 1. Intern Med 2001;40:829-832.
Hajjaj-Hassouni N, Guedira N, Lazrak N, et al. Osteomalacia as a presenting manifestation of Sjogren's syndrome. Rev Rhum Engl Ed 1995;62:529-532.
Monto Neto JT, Sesso R, Kirsztajn GM, Da Silva LC, De Carvalho AB, Pereira AB. Osteomalacia secondary to renal tubular acidosis in a patient with primary Sjogren's syndrome. Clin Exp Rheumatol 1991;9:625-627.(Tali Cukierman, M.D., Mos)
A 44-year-old woman came to the emergency department because of pain in her right thigh shortly after she had a minor fall. A right femoral-neck fracture was diagnosed, and she was admitted to the orthopedic ward to await surgery. Six months before hospitalization, and before she fell, limb pain had developed, which had become progressively worse. The patient also reported a weight loss of 30 kg and fatigue.
A fractured femoral neck after a minor fall in a patient 44 years of age is very uncommon. The associated limb pain and severe weight loss suggest the possibility of cancer, chronic infection, or autoimmune disease. A fracture may also be secondary to osteosclerosis or osteoporosis caused by immobilization, low intake of calcium and vitamin D or malabsorption, endocrine disorders such as Cushing's syndrome or hyperparathyroidism, renal disease, or adverse effects of drugs such as glucocorticoids or anticonvulsants. The possibility of an eating disorder should also be considered. I would want to know whether the patient has anorexia or difficulty in eating, whether she has other manifestations of systemic disease (such as fever, rash, or neurologic symptoms), and whether she takes any medications.
The patient was a housewife with four healthy children. She reported mild difficulty in swallowing solid food, which caused her to eat less. She said that she had not had nausea, vomiting, diarrhea or constipation, fevers, sweats, itching, or rash in the past several months. She did not smoke and reported no drug use.
On physical examination, the patient appeared cachectic and pale. She had poor oral hygiene and mild cervical lymphadenopathy. She had substantial bone tenderness on palpation of her limbs and chest. The remainder of the physical examination, which included breast, rectal, and neurologic examination, showed no abnormalities.
The hemoglobin level was 11.2 g per deciliter, and the mean corpuscular volume 90 μm3. The white-cell count, platelet count, levels of liver enzymes, and the prothrombin time and partial-thromboplastin time were within normal ranges. The level of blood urea nitrogen was 4.2 mmol per liter (normal range, 3.3 to 6.5), and the level of serum creatinine 67 μmol per liter (normal, 60 to 106). The serum potassium levels were persistently low (2.3 to 3 mmol per liter) and were not corrected by oral supplementation with 9 g of potassium chloride daily for four days. The orthopedic operation was postponed, and the patient was transferred to the internal medicine ward for further evaluation.
A metastatic cancer could explain the dysphagia, bone pain, and reduced food intake. A collagen vascular disease such as scleroderma with esophageal dysmotility or myositis might be an alternative explanation. The absence of fever makes a chronic infection less likely. Multiple myeloma may explain the bone pain, fatigue, anemia, weight loss, and hypokalemia (which could result from renal tubular dysfunction); serum and urinary protein electrophoresis should be performed. A skeletal survey may aid in the diagnosis of lytic lesions and other bone abnormalities.
The persistent hypokalemia could be caused by renal wasting or, alternatively, could indicate gastrointestinal losses. Measurement of the levels of other electrolytes, such as chloride and phosphate, and determination of the blood pH, partial pressure of carbon dioxide, and bicarbonate concentration are required.
Additional laboratory testing revealed a serum phosphate level of 1.7 mg per liter (0.55 mmol per liter; normal range, 2.5 to 4.5 mg per liter [0.8 to 1.45 mmol per liter]); serum calcium level of 8.2 mg per deciliter (2.0 mmol per liter; normal range, 8 to 10 mg per deciliter [2.0 to 2.5 mmol per liter]); sodium, 144 mmol per liter; potassium, 2.8 mmol per liter; chloride, 119 mmol per liter; magnesium, 2.2 mg per deciliter (0.9 mmol per liter); uric acid, 2.6 mg per deciliter (154.6 μmol per liter; normal range, 2.5 to 6.3 mg per deciliter [148.7 to 374.7 μmol per liter]); alkaline phosphatase, 168 U per liter (normal range, 40 to 130) and albumin, 3.2 g per deciliter. The blood pH was 7.32, the partial pressure of carbon dioxide 37 mm Hg, and the bicarbonate level 18.7 mmol per liter, with a normal value for the serum anion gap.
The results of protein electrophoresis in the blood and urine were normal. Radiographs of the spine, hips, and limbs showed diffuse osteopenia without lytic lesions or fractures. A reevaluation of the right femur radiograph showed osteopenia with a Looser–Milkman pseudofracture (Figure 1). A computed tomographic (CT) scan of the chest showed several pseudofractures of the ribs (Figure 2). These findings indicated that the canceled surgery would not be required.
Figure 1. A Radiograph of the Right Hip Joint.
A pseudofracture is visible at the medial aspect of the neck of the femur (arrow).
Figure 2. A Computed Tomographic Scan of the Chest.
A pseudofracture is visible at the anterior aspect of the sixth rib (arrow).
This patient has radiologic findings that are consistent with osteomalacia, with low serum phosphate, normal calcium levels, and raised levels of alkaline phosphatase. A low bone density is also characteristic of osteomalacia, although this finding would not distinguish it from osteoporosis. Whereas the gold standard for the diagnosis of osteomalacia involves bone biopsy with double tetracycline labeling, the radiologic findings combined with the abnormalities in phosphate and alkaline phosphatase levels in this case are sufficient to establish the working diagnosis of osteomalacia. The osteomalacia may be secondary to abnormal vitamin D metabolism (where secondary hyperparathyroidism would be expected), or it could be secondary to a phosphate deficiency, such as in hyperparathyroidism, Fanconi's syndrome, hypophosphatemic rickets, oncogenic osteomalacia, or other conditions that cause mineralization defects (for example, abnormal pH or abnormal alkaline phosphatase bioactivity). In this patient, the coexistence of osteomalacia, persistent hypokalemia, and hyperchloremic normal anion-gap metabolic acidosis suggests a renal tubular disorder (such as renal tubular acidosis) or a malabsorptive process (such as celiac or inflammatory bowel disease) that causes the loss of potassium and bicarbonate and malabsorption of vitamin D. Because the patient did not report diarrhea among her symptoms, the diagnosis is more likely to favor a renal tubular disorder, although the possibility of malabsorption has not been ruled out. Additional testing would be warranted at this point, including measurement of urinary pH and urine levels of urea nitrogen and creatinine, the osmolality of a spot-urine sample, and a 24-hour urine collection for electrolytes — including phosphorus and calcium. The presence of glycosuria and aminoaciduria would support the diagnosis of Fanconi's syndrome. Measurement of the level of serum parathyroid hormone could be helpful; the level does not increase in some primary renal-phosphate–wasting syndromes, such as oncogenic osteomalacia. An endoscopy with duodenal biopsy could rule out malabsorption due to celiac disease.
The urinary pH was 8; the daily urine output was 2.2 liters (55 ml per kilogram of body weight per day [normal, less than 50]); the level of urine urea nitrogen was 69.5 mmol per liter; creatinine, 2730 μmol per liter; sodium, 66 mmol per liter; chloride, 79 mmol per liter; potassium, 32.6 mmol per liter; calcium, 7.5 mg per deciliter (1.9 mmol per liter) and daily calcium excretion, 165 mg (4.1 mg per kilogram of body weight per day [normal, less than 4]); phosphate, 16.5 mg per deciliter (5.32 mmol per liter), and daily phosphate excretion, 380 mg; magnesium, 0.8 mmol per liter; urine osmolality, 279 mOsm per kilogram of water; plasma osmolality, 295 mOsm per kilogram of water; range in urinary potassium-to-creatinine ratio, 9.1 to 11.9; urinary anion gap (urine:Na+K–Cl), 19.6 mmol per liter; and urinary osmolal gap (osmu = [2Nau + 2Ku + ureau + glucoseu]), 12.3 mmol per liter. No glycosuria and aminoaciduria were detected. The fractional excretion of phosphate was 23.7 percent (normal, 5 to 20); tubular reabsorption of phosphorus, 77 percent; and tubular reabsorption of calcium, 97.5 percent. Serum parathyroid hormone levels were 55 to 79 pg per milliliter (normal, 10 to 60), associated with serum calcium levels of 8.2 to 8.4 mg per deciliter (2.0 to 2.1 mmol per liter). Endoscopy revealed no pathologic findings, and a biopsy specimen obtained from the distal part of the duodenum appeared normal.
In the presence of depleted plasma potassium, the appropriate renal response would be to excrete less than 15 mmol of potassium daily, with a spot urinary ratio of potassium to creatinine of 1 to 1.5. This patient's daily urinary potassium level of 71.7 mmol and the high ratio of potassium to creatinine in the spot urinary sample indicate renal loss. Furthermore, the absence of diarrhea and the normal duodenal-biopsy specimen argue against gastrointestinal losses of potassium. The high level of urinary phosphate excretion and low tubular reabsorption of phosphorus indicate that there is also renal phosphate wasting. Hyperparathyroidism is a common cause of phosphate wasting but it is unlikely in this case, given the consistently normal levels of serum calcium. Vitamin D deficiency, another possible cause of phosphate wasting, is typically associated with a higher value of parathyroid hormone (above 100 pg per milliliter) and also could not account for the potassium wasting. More likely causes in this case include primary defects such as X-linked hypophosphatemic rickets or secondary defects such as renal tubular acidosis or oncogenic osteomalacia. Primary or acquired Fanconi's syndrome could also cause renal phosphate wasting, although this would be associated with glycosuria, aminoaciduria, and hypouricemia; however, an isolated defect in proximal tubular function that led to a decrease in phosphate reabsorption may still be a possibility.
The defective urinary concentrating ability and mild polyuria are most likely due to hypokalemia. Other disorders that may affect the collecting tubules, such as amyloidosis or Sj?gren's syndrome, are also possible.
In the absence of diarrhea, the presence of a normal anion-gap metabolic acidosis (also called hyperchloremic acidosis) with hypokalemia most likely indicates a renal tubular acidosis. The positive urinary anion gap and the low urinary osmolal gap (below 100 mmol per liter) implicate reduced urinary ammonium excretion (as occurs in types 1 and 4 renal tubular acidosis); the presence of hypokalemia and a urinary pH that was persistently above 6 indicate that this is a type 1 renal tubular acidosis; the presence of hyperkalemia and a urinary pH that is below 5.5 during acidosis would indicate type 4 renal tubular acidosis. At this stage of the differential diagnosis, I would take the medical history again and ask about possible familial renal or bone disease, hearing impairment, or any other hereditary condition that might cause distal renal tubular acidosis, such as Fabry's disease.
An arginine hydrochloride test was performed (to assess effects on urine pH of acidification of the plasma). After the infusion of an arginine hydrochloride solution over the course of two hours, the blood pH was assessed at 7.34, 7.28, and 7.27 at zero, two, and six hours, respectively, although the urine remained at a high-alkaline pH (pH 8) throughout the test. The patient said she knew of no familial disorders.
The inability of the kidney to lower urinary pH below 5.5 after an acid load confirms the impression of a distal renal tubular acidosis. The patient has not received medications that could cause this disorder (such as amphotericin), and there is no clinical or biochemical evidence of primary biliary cirrhosis, chronic active hepatitis, or hypercalciuria with nephrocalcinosis, which may be associated with renal tubular acidosis. Acquired renal tubular acidosis has also been described with rheumatologic diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Sj?gren's syndrome. The patient's dysphagia, combined with her poor oral hygiene, suggest the possibility of a lack of saliva, a hallmark of Sj?gren's syndrome.
On further questioning, the patient said that she had had symptoms of dry mouth and a recurrent sensation of sand in her eyes for the past year. Serologic testing for antinuclear antibodies was positive (+3 out of 4), anti-Ro (SS-A) was 482 U per milliliter, anti-La (SS-B) was 608 U per milliliter (normal for both is less than 25), and C3 was 63 mg per deciliter (normal range, 50 to 120). Schirmer's test for tear production was positive, meaning no tears, and a salivary-gland biopsy showed lymphocytic infiltration (Figure 3).
Figure 3. Biopsy Specimen of the Salivary Gland Showing Lymphocytic Infiltrates (Hematoxylin and Eosin).
The patient meets five of the six so-called European criteria for the diagnosis of Sj?gren's syndrome: the presence of autoantibodies, subjective ocular and oral symptoms, a positive Schirmer's test, and histopathological features. In light of the association between Sj?gren's syndrome and lymphoma, the 30-kg weight loss, and the mild lymphadenopathy, lymphoma should be ruled out.
A CT scan of the chest and abdomen revealed no lymphadenopathy or splenomegaly. Treatment with daily doses of sodium bicarbonate (2 g), potassium citrate (2 g), sodium phosphate (1.5 g), potassium chloride (4 g), calcium carbonate (1 g), calcitriol (0.25 μg), and an artificial tear solution was initiated. The patient's condition responded with gradual, progressive improvement. One year later, at this writing, the patient is well. She is now able to walk, has gained weight, and reports a reduction in her general weakness and limb pain.
Commentary
Fractures, bone pain, and reduced bone density in a relatively young patient require a thorough investigation. It is important to differentiate between early-onset osteoporosis and osteomalacia. The distinction between the two can be made most accurately by bone biopsy with double tetracycline labeling.1 However, this procedure is rarely performed, because the diagnosis can be elicited from the history, physical findings, radiographic evaluation, and laboratory results. In osteoporosis, normal levels of serum calcium, phosphate, alkaline phosphatase, and parathyroid hormone are present; in contrast, abnormalities in at least one of these measurements are common in osteomalacia.
In order for adequate mineralization of the bone to occur, normal concentrations of calcium and phosphate in the extracellular fluid, adequate bioactivity of alkaline phosphatase, a normal pH value at the site of calcification, and the absence of calcification inhibitors are needed.2 When any of these factors is altered, osteomalacia may result. Vitamin D deficiency or vitamin D resistance accounts for the majority of cases of osteomalacia. The most common cause is dietary deficiency and lack of exposure to sunlight3; malabsorptive disorders, such as celiac sprue,4 underlie many other cases.
Chronic metabolic acidosis induces calcium loss from bone associated with hypercalciuria.5 It may also induce renal phosphate depletion by way of its direct effect on the sodium phosphate cotransporter.6 However, there is no agreement whether distal renal tubular acidosis causes osteomalacia.7 The increased urinary phosphate excretion and hypophosphatemia in our patient may suggest the presence of a proximal tubular defect. In the absence of glycosuria, aminoaciduria, and hypouricemia, we were unable to establish the diagnosis of Fanconi's syndrome. The possibility of multiple tubular dysfunctions in this patient is also supported by the hyposthenuria and mild polyuria, suggesting a defective urine-concentrating capacity, although hypokalemia may also underlie these findings.
In adults, secondary distal renal tubular acidosis may develop as a consequence of calcium disorders (idiopathic hypercalciuria with nephrocalcinosis, primary hyperparathyroidism), use of drugs or toxins (amphotericin, trimethoprim, pentamidine, toluene), or autoimmune diseases (Sj?gren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, chronic liver diseases).8 In this patient, the dysphagia, poor oral hygiene, and eye dryness gave the clues to the diagnosis of Sj?gren's syndrome. The most common clinical manifestations of Sj?gren's syndrome are exocrine gland involvement: keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth and salivary-gland enlargement). Xerostomia can be made manifest in many ways, including dysphagia, dental caries, oral candidiasis, difficulty in speaking, weight loss, or even chronic esophagitis. Abnormal esophageal peristalsis causes severe dysphagia in Sj?gren's syndrome.9
The patient under discussion met the revised European criteria for the diagnosis of Sj?gren's syndrome.10 The clinical picture suggests primary Sj?gren's syndrome because of the lack of clinical features associated with rheumatoid arthritis or other autoimmune disorders.
Tubulointerstitial nephritis is the most common renal complication in Sj?gren's syndrome. It is usually recognized in association with distal renal tubular acidosis, nephrogenic diabetes insipidus, and more rarely, proximal tubular abnormalities and Fanconi's syndrome. Up to 25 percent of patients with Sj?gren's syndrome have some defect in distal acidification that may be associated with other tubular dysfunctions.11,12
There is no consensus regarding treatment. When interstitial nephritis occurs, a course of corticosteroids is usually beneficial; less is known about the benefits of such treatment in the case of distal renal tubular acidosis. There are a few case reports in the literature describing osteomalacia as the presenting manifestation of Sj?gren's syndrome.13,14,15 In two cases, treatment with alkali, vitamin D, and calcium resulted in improvement; in one case, steroid treatment resulted in similar improvement. In light of the prominent tubular acidification abnormality, this patient was treated with bicarbonate, potassium, and phosphate supplementation along with calcitriol, and she had a good clinical response.
Source Information
From the Department of Medicine, Hadassah–Hebrew University Medical Center, Mount Scopus, Jerusalem.
Address reprint requests to Dr. Chajek-Shaul at the Department of Medicine, Hadassah–Hebrew University Medical Center, Mount Scopus, P.O. Box 24035, Jerusalem 91240, Israel, or at chajek@hadasssah.org.il.
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