Fuller Albright and our current understanding of calcium and phosphorus regulation and primary hyperparathyroidism

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Although increasingly disabled by Parkinson’s disease from the mid 1930s, Albright continued to make important contributions to our knowledge of calcium and phosphorus disorders1. His book, "Parathyroid Glands and Metabolic Bone Disease", published in 1948, is a testimony to his many important observations2. Our goal is to highlight some of the many contributions made by Albright on calcium and phosphorus regulation and primary hyperparathyroidism and to integrate the findings of Albright with more recent studies. Albright’s contributions to our understanding of renal phosphate transport have been discussed elsewhere3. Virtually all that Albright observed remains valid today, but as often happens, the explanations and their complexity continue to evolve.Our retrospective highlights Albright’s enduring legacy to the modern study of calcium and phosphorus regulation and primary hyperparathyroidism. The following topics are discussed: 1) the resources available to Albright to study calcium and phosphorus regulation and primary hyperparathyroidism; 2) Albright’s studies of calcium balance; 3) phosphaturia resulting from the correction of hypocalcemia in hypoparathyroid patients; 4) primary hyperparathyroidism as a surgically curable disorder; and 5) several clinical vignettes which include: a) a prelude to the trade-off hypothesis of Slatopolsky and Bricker advanced by Albright to explain the development of secondary hyperparathyroidism in renal failure; b) the suggestion that a malignant tumor could be responsible for ectopic hormone production; c) the realization that vitamin D deficiency can be associated with the failure to respond to parathyroid hormone (PTH); and d) the appreciation that immobilization can be a cause of hypercalcemia.TOOLS OF THE TRADEIn the late 1920s when Albright first started his studies of calcium and phosphorus regulation and primary hyperparathyroidism, his primary tools were: 1) parathyroid extract (PTE), which was a bovine preparation from Eli Lilly and Company; 2) the personnel on the newly organized Ward 4 at Massachusetts General Hospital who were trained to perform balance studies in which dietary calcium and phosphorus could be prepared with accuracy and the fecal and urine excretion of calcium and phosphorus collected with precision4; and 3) the measurement of calcium and phosphorus in the blood, urine and feces. As a result of balance studies it became possible to determine how variations in dietary calcium and phosphate content and the administration of PTE affected: 1) serum calcium and phosphorus concentration; 2) fecal and urinary excretion of calcium and phosphorus; and 3) retention or loss of calcium and phosphorus from the body (figure 1). Because PTH could not be measured, Albright could not know whether PTH values were modified by serum calcium.EFFECT OF PARATHYROID EXTRACT AND DIETARY CALCIUM ANS PHOSPHATE ON CALCIUM BALANCE IN NORMAL SUBJECTS AND IN PATIENTS WITH HYPOPARATHYROIDISM AND HYPERPARATHYROIDISM In an early study, Albright infused PTE into a patient with longstanding idiopathic hypoparathyroidism (Figure 2)5. Albright observed that: 1) urine phosphorus excretion immediately increased and peaked within two hours; 2) the increase in serum calcium and decrease in serum phosphorus followed the increase in phosphorus excretion; and 3) there was a critical serum calcium value at about 8.5 mg/dl at which a negligible urinary calcium excretion suddenly became appreciable. Albright concluded that the action of PTE was rapid, its first effect was phosphaturia, and the increase in serum calcium followed the increase in phosphorus excretion. Thus, Albright developed the hypothesis that PTH primarily modified phosphorus rather than calcium, a view that he still championed when his book was published almost 20 years later2. Albright argued that the PTH-induced increase in phosphorus excretion and the resulting decrease in serum phosphorus promoted bone dissolution releasing calcium. While such a conclusion might sound somewhat fanciful today, it should be remembered that Albright had participated in studies in which ammonium chloride-induced acidosis increased the serum calcium concentration and urinary calcium excretion without increasing intestinal calcium absorption suggesting that acidosis induced bone dissolution6,7. Today it is recognized that phosphate depletion increases calcium release from bone resulting in hypercalciuria and even hypercalcemia despite a marked reduction in PTH values suggesting that bone dissolution is an important feature8,9. Finally, Albright was correct in his hypothesis that phosphate was a major modifier of the calcemic response of bone to PTH. Many subsequent studies have shown that phosphate loading and restriction change the calcemic response to PTH10-12.As already mentioned, Albright had observed during a PTE-induced increase in serum calcium in a hypoparathyroid patient that the serum calcium threshold at which urinary calcium excretion increased from negligible values was approximately 8.5 mg/dl. However, that threshold value did not account for the now known effect of PTH on urinary calcium excretion. In 1961, one of the authors (CRK) first showed that PTE administration directly increased renal calcium reabsorption13. Subsequently, it was shown that the threshold serum calcium value for excreting calcium during a calcium infusion was seen at serum calcium values between 7 and 8 mg/dl in hypoparathyroid patients14. In 1984, Ogata and associates showed that besides PTH, the active form of vitamin D, calcitriol, directly increased the threshold for renal calcium excretion and also enhanced the responsiveness of the tubule to PTH15. More recently, Bindels and colleagues have shown that the stimulatory effect of both calcitriol and PTH on renal calcium reabsorption results from the activation of an epithelial calcium channel (TRPV5) in the distal convoluted tubule16.VITAMIN D TREATMENT AND CALCIUM INFUSION AS PHOSPHATURIC AGENTSIn 1938 and in 1942, Albright used the newly available analog of vitamin D, dihydrotachysterol, for the treatment of hypocalcemia in patients with hypoparathyroidism17 and also in the newly described disorder of pseudohypoparathyroidism in which there was a failure to respond to administered PTE18. Albright observed that the correction of hypocalcemia increased urine phosphate excretion. This observation had been made earlier by associates of Albright19 and by Howland and Kramer20. In 1965, Eisenberg demonstrated in hypoparathyroid patients that the phosphaturia was independent of vitamin D by showing that a prolonged intravenous infusion of calcium sufficient to normalize the serum calcium concentration at 48 hours was phosphaturic and also lowered the serum phosphorus concentration (figure 3A, figure 3B)21. Evidence has accumulated during the past several years that the recently discovered bone-derived phosphaturic hormone, fibroblast growth factor 23 (FGF23) might be involved. High dietary calcium has been shown to stimulate FGF2322 and the correlation between the serum calcium concentration and FGF23 seen in primary hyperparathyroidism23-25 even remained significant after parathyroidectomy24. However, a study has yet to be performed identifying the specific mechanism for the observation made more than 70 years ago by Albright and others.PRIMARY HYPERPARATHYROIDISM, INTESTINAL CALCIUM ABSORPTION, AND RENAL FAILUREIn patients with primary hyperparathyroidism, Albright showed that changes in dietary calcium and phosphate affected calcium balance. The first patient studied was Captain Martell26, who was to have seven parathyroid operations before an ectopic parathyroid gland was removed from the anterior mediastinum27. From the balance studies in Captain Martell, who had serum calcium values between 13.1 and 15.3 mg/dl, Albright made the following observations: 1) the patient’s negative calcium balance on a low calcium diet (0.1 grams/day) was greater than in normal controls (-0.46 vs -1.29 grams per 3 day study period); 2) the increased negative calcium balance in the hyperparathyroid patient was due to increased urinary calcium excretion because fecal calcium excretion was less than in normals; 3) an infusion of PTE in normal volunteers sufficient to increase serum calcium to between 11.5 and 12.8 mg/dl resulted in a negative calcium balance duplicating the results of the hyperparathyroid patient; and 4) a calcium diet of 1.07 grams/day in the hyperparathyroid patient resulted in a positive calcium balance (0.36 grams per day) because urinary calcium excretion increased by only 0.06 grams/day from that on a low calcium diet (0.1 grams/day). Thus, Albright concluded that in primary hyperparathyroidism: 1) adaptation to a low calcium diet did not occur because high urine calcium losses persisted; 2) intestinal calcium absorption was increased; and 3) high PTH values were the likely cause of the negative calcium balance.Albright also evaluated the effect of dietary phosphate on calcium balance in hyperparathyroidism. He showed that a high phosphate diet improved calcium balance in hyperparathyroid patients on both low (0.07 g/day) and normal (0.9 g/day) intakes of dietary calcium28. When high dietary phosphate was given to patients with primary hyperparathyroidism, there was: 1) almost complete intestinal absorption of phosphate; 2) rapid excretion of the absorbed phosphate by the kidneys; 3) a rise in the previously low serum phosphorus; 4) a fall in the previously elevated serum calcium; 5) a rise in the serum calcium-phosphorus product; and 6) a fall in urinary calcium excretion. While a high phosphate diet seemed to have certain beneficial effects such as lowering the serum calcium concentration and decreasing urinary calcium excretion, Albright recognized that there were two potential dangers associated with increased phosphate ingestion in patients with primary hyperparathyroidism: 1) parathyroid poisoning with soft tissue calcium deposition including the kidney and lungs; and 2) calcium-phosphate kidney stones. Today, the recognition that hyperphosphatemia in CKD patients and perhaps even high normal serum phosphorus values in the general population are associated with increased vascular disease and mortality probably from increased vascular calcification29,30 could be considered an extension of the pioneering studies of Albright.By 1934, Albright came to understand that renal failure had a specific effect on calcium and phosphorus regulation31. When a 13 year old girl with moderate renal failure was referred for hypercalcemia (13.6 mg/dl), bone demineralization, a markedly elevated serum alkaline phosphatase, and a serum phosphorus of 4.3 mg/dl, balance studies were performed before the parathyroid surgery during which an adenoma was removed. The balance studies showed that on a low calcium diet (0.1 g/day), urine calcium excretion despite hypercalcemia was only marginally greater than in controls on a similar diet (94 mg vs 63 mg/day). This value was much less than in non-azotemic patients with primary hyperparathyroidism and hypercalcemia (435 mg/day). Also, fecal calcium excretion was greater than in controls and much greater than in hyperparathyroid patients without renal failure. Because of the results in this young girl with renal failure, Albright reviewed the results of the series of balance studies which had been performed on Captain Martell before and after he developed renal failure. As shown in table 1, for a similar magnitude of hypercalcemia (14 mg/dl vs 14.4 mg/dl), for the same low calcium diet after the onset of renal failure, intestinal calcium absorption was less (0.06 vs 0.26 g/day) as was urine calcium excretion (0.09 vs 0.44 g/day). Thus, Albright was the first to recognize that the development of renal failure in primary hyperparathyroidism dramatically decreased both intestinal absorption and the renal excretion of calcium. Today, it is known that PTH stimulates renal production of the active form of vitamin D, calcitriol, which in turn enhances intestinal absorption of calcium. With loss of renal function, calcitriol production is decreased despite high PTH values, a result which may in part be due to increased FGF23 values. Consequently, both intestinal calcium absorption and renal calcium excretion are reduced in renal failure. The latter results from both a decrease in the glomerular filtration of calcium and increased tubular calcium reabsorption from high PTH values.PRIMARY HYPERPARATHYROIDISMIn several patients in his original series of 17 patients published in 193432, Albright made the diagnosis of hyperparathyroidism only because he had the insight to measure serum calcium and phosphorus values in all patients who presented with kidney stones. In the first 14 patients to undergo parathyroid surgery, parathyroid adenomas were found. Two of these patients had ectopic parathyroid adenomas located in the anterior mediastinum. Cases 15 to 17 had hyperplasia of all the parathyroid glands. Because hyperplasia had not been previously recognized as an entity, Case 15 required three parathyroid operations to remove a sufficient amount of the hyperplastic glands before the hypercalcemia resolved. Between the second and third operations, estrogen treatment and irradiation of the pituitary and parathyroid glands were tried without success33.In this series of 17 patients, the dimensions, but not the weights of the removed parathyroid glands were provided32. The mean amount of parathyroid tissue removed per patient was approximately 83 times greater than the combined size of four normal human parathyroid glands, which subsequently were shown to have a combined weight of approximately 140 mg34. Based on these results, the average estimated weight of removed parathyroid tissue for each patient was approximately 11 grams. In severe cases of primary hyperparathyroidism with marked hypercalcemia, cachexia and debilitating fractures were sometimes seen and parathyroidectomy was life saving (figure 4). The different magnitude of primary hyperparathyroidism in patients presenting in the 1930s and today is shown by the very high preoperative serum calcium values in Albright’s patients (figure 5). Finally, Albright was the first to describe the "hungry bone syndrome" in which severe hypocalcemia developed values shortly after parathyroidectomy (figure 6). He also showed that the decrease in serum calcium correlated with the pre-operative serum alkaline phosphatase value. When the serum calcium decreased to less than 7 mg/dl, Albright reported that tetany and visual disturbances were often seen. In actuality, the subsequent recognition of the "hungry bone syndrome" in dialysis patients after parathyroidectomy is an extension of the results in primary hyperparathyroidism by Albright.In 1934, Albright also recognized that patients with primary hyperparathyroidism presented with either bone disease or stone disease, but rarely both together32. In patients with bone disease, skeletal symptoms associated with bone loss, bone cysts, brown tumors, and fractures predominated. In patients with stone disease, presenting symptoms were those associated with nephrolithiasis and skeletal problems were generally absent. Albright questioned why there should be two separate presentations for the same disease. He hypothesized that the extent of bone disease was proportional to the duration of disease times the daily loss of calcium32. Thus, according to Albright a short duration of disease would lessen the risk of bone disease. Moreover, a high calcium intake would make bone disease less likely because as Albright had previously observed in studies of patients with primary hyperparathyroidism, a high calcium diet resulted in a positive calcium balance26.In 1945, Keating reported 24 patients with primary hyperparathyroidism in whom the magnitude of hypercalcemia, hypophosphatemia and serum alkaline phosphatase elevation was greater in patients with bone disease than with stone disease35. In contradiction to the hypothesis advanced by Albright, the patients with bone disease had a shorter duration of symptoms before presentation. In 1956, Dent also reported that patients with bone disease had a shorter duration of symptoms36. Subsequently, Dent reported that there was no difference in dietary intake of calcium between patients with bone or stone disease37.In 1968, Lloyd reviewed 138 consecutive cases of primary hyperparathyroidism accumulated by Dent in London from 1950 to 196538. Patients were divided into overt bone disease without kidney stones (Type 1, n = 44) and kidney stones without overt bone disease (Type 2, n = 88). The remaining six patients had neither overt bone disease nor kidney stones. As shown in table 2, the adenoma weight was greater, the growth rate of the parathyroid tissue more rapid, and the duration of symptoms was shorter in patients with bone disease. These results contradicted Albright’s hypothesis that patients with bone disease have a longer duration of disease.One explanation for the shorter duration of disease together with more severe hypercalcemia and larger adenomas in patients with bone disease is simply a more rapid growth rate of the parathyroid adenomas in patients with bone disease. In the early 1970s, both Woodhouse et al39 and Lumb and Stanbury40 suggested that the more rapid growth of adenomas in patients with bone disease might be from a lack of vitamin D. In 1987, one of the authors (CRK) wrote an editorial in support of this possibility41. Also in 1987, Paillard and associates reported that patients with bone disease had lower values of the stored form of vitamin D, 25-hydroxyvitamin D (25[OH]D), 3.4 ± 2.0 vs 17.6 ± 13.6 ng/ml (P <0.001) and three-fold greater PTH values than patients with stone disease42. In more recent studies, Silverberg et al in a longitudinal study of patients with mild hyperparathyroidism, found that patients in the lowest tertile of 25(OH)D measurements (12 ± 3 ng/ml) had the highest PTH values43. Rao, et al., in a study of 148 consecutive patients operated for primary hyperparathyroidism with a mean resected parathyroid gland weight of 1.27 grams, reported an inverse correlation between 25(OH)D and parathyroid gland weight while the correlation between the active form of vitamin D, calcitriol, and parathyroid gland weight was not significant44. These results suggest that a suboptimal vitamin D status may stimulate parathyroid adenoma growth. The presence of 1 alpha-hydroxylase, the enzyme responsible for conversion of 25(OH)D to calcitriol, in parathyroid cells suggests the possibility that 25(OH)D may directly affect PTH secretion and parathyroid gland growth45,46. Also contributing to the lowering of 25(OH)D levels in primary hyperparathyroidism is that high PTH levels decrease 25(OH)D levels by increasing conversion of 25(OH)D to calcitriol47. In summary, even in the studies of Silverberg and Rao in which the increased weight of the parathyroid adenoma was modest and the diagnosis of primary hyperparathyroidism was made relatively early in the course of the disease, vitamin D status seemed to play a role43,44.Since the 1970s, the clear demarcation between patients with bone and stone disease previously seen in patients with primary hyperparathyroidism starting with the report of Albright in 1934 and continuing through the 1960s has been lost32,35,38,48-51. Beginning in the 1930s and continuing for the next three decades, the sequence of events in diagnosing bone disease in primary hyperparathyroidism often was as described by Albright, "appearance of a bone tumor, biopsy, diagnosis of benign giant cell tumor, local treatment, and finally recognition of generalized disease only years later"2. However, the introduction of multichannel analyzers in which serum calcium and phosphorus values were routinely measured resulted in the detection of many asymptomatic hyperparathyroid patients with mild hypercalcemia.In a recent review of primary hyperparathyroidism, the average weight of the removed adenoma was 400 to 600 mg, values which are only three to four times greater than the combined weight of four normal parathyroid glands52. In contrast, the mean weight of the removed parathyroid adenomas in the Albright study from 1934 was approximately 11 grams32. In 1947, Norris reviewed 322 cases from the existing world literature and reported that the average weight of a removed parathyroid adenoma was 8 grams48. In 1963, Hodgkinson reported that the mean weight of the removed adenoma was 5.1 grams in patients with bone disease and 1.4 grams in patients with stone disease49. Similar differences in the weight of parathyroid adenomas between patients with bone and those with stone disease were reported by Lloyd in his analysis of Dent’s patients38 and by O’Riordan51. The mean weight of the parathyroid adenoma in patients with bone disease was 5.9 grams in the former and 4.2 grams in the latter series.In areas of the world with limited access to medical care, vitamin D insufficiency/deficiency appears to be more common and the duration of primary hyperparathyroidism much longer before diagnosis and treatment. In recent studies of primary hyperparathyroidism from India and China, the presence of large parathyroid adenomas and bone disease has been associated with vitamin D insufficiency/deficiency (figure 7)53-57. In a study from China, the presenting PTH value was 21 times greater than normal55. Similarly, in a study from India, the mean weight of the removed parathyroid adenoma was 10.75 g in hypercalcemic patients and 3.9 g in normocalcemic patients54. In another study from India, the mean weight of the removed parathyroid adenoma was 7.9 g56. Moreover, the 25(OH)D value was less than 10 ng/ml in the majority of these patients. In the cited studies, pathologic bone fractures, bone cysts, and brown tumors were commonly encountered54-56. In summary, the severe form of primary hyperparathyroidism characterized by large adenomas and disabling bone disease, first described by Albright in the 1930s, is still commonly encountered in areas of the world with limited access to medical care. Furthermore, the severe form of primary hyperparathyroidism seen in these patients is often associated with vitamin D insufficiency/deficiency.  VIGNETTES IN WICH OBSERVATIONS BY ALBRIGHT HAVE HAD CONTINUED CLINICAL RELEVANCE1937. Prelude to the "Trade-Off Hypothesis" of Slatopolsky and Bricker10,58 which was Advanced to Explain the Development of Secondary HyperparathyroidismAlbright made the following statement in a 1937 publication59: "It has been suggested above that the parathyroid hyperplasia is a compensation for the disturbed equilibrium occasioned by phosphate retention resulting from the renal insufficiency. In the absence of the hyperplasia there would probably be greater phosphate retention in the blood with a lowering of the blood calcium level and severe tetany. If these concepts are correct, the hyperplasia would have to be considered beneficial. The one reservation might have to be made that, while helping homeostasis, the parathyroid hyperplasia may lead to bone disease". Confirmation of the Albright hypothesis has been shown in many animal and clinical studies of phosphate loading. Also in studies of patients with stage 3 and 4 CKD treated with the calcimimetic, cinacalcet, the reduction in PTH values has increased the serum phosphorus concentration60.1941. Hypothesis that Hypercalcemia in Malignancy could be from Ectopic Hormone Production At a clinicopathological conference, a 51 year old male presenting with hypercalcemia and hypophosphatemia was discussed61. A neck exploration for presumed hyperparathyroidism was performed, but no abnormality was found. Bone x-rays showed a destructive lesion in the right ilium, which on biopsy was reported to originate from a renal cell carcinoma. The comment of Albright at the end of the conference was "Why a person should have high serum calcium and low serum phosphorus when the cause of the disturbance is a tumor destroying bone is an interesting theoretical question. We treated this case by radiation of the tumor masses; the serum calcium went down to normal, and the serum phosphorus went up to normal. Gradually, both values became abnormal again. I suspected that the tumor might be producing parathyroid hormone. I therefore had it assayed by Dr. J. B. Collip, but no hormone was found". In essence, Albright was the first to suggest the possibility of ectopic hormone production by a tumor. Today we know the causal agent responsible for the hypercalcemia and hypophosphatemia to be PTH-related protein and not PTH.1941. Pseudohypoparathyroidism in Vitamin D DeficiencyA year before Albright reported the clinical entity of pseudohypoparathyroidism in which there was a failure to respond to PTE in patients with characteristic body features18, he recognized a subset of patients with vitamin D deficiency in whom the serum calcium was low and the serum phosphorus was normal. Albright logically but incorrectly thought that the problem was because the necessary compensatory increase in parathyroid function had not taken place62. Subsequently, there continued to be reports of patients with vitamin D deficiency in whom hypocalcemia was accompanied by normal or even high serum phosphorus values40,63-65. In 1985, Rao et al established that the hypocalcemia associated with vitamin D depletion can impair the phosphaturic response to PTH despite an appropriately increased nephrogenous cyclic AMP response66. Correction of hypocalcemia with vitamin D and calcium treatment restored the phosphaturic response to PTH despite a reduction in nephrogenous cyclic AMP. Thus, these patients had an acquired form of pseudohypoparathyroidism type II, which was subsequently shown to be from a postreceptor G protein defect67. In the opinion of the authors, another possibility which should be evaluated is that the vitamin D deficiency and the hypocalcemia combine to impair FGF23 production22-25.1941. Immobilization and HypercalcemiaAlbright reported the case of a 14 year old boy who in an athletic injury, fractured his right femur at the site of a bone cyst68. After an open reduction, the boy was placed in a spica cast immobilizing him from the waist down. Shortly thereafter anorexia and vomiting developed. Because the presence of the bone cyst raised the possibility of primary hyperparathyroidism, serum calcium was measured and found to be 14.6 mg/dl with a serum phosphorus of 4.5 mg/dl. Mild renal insufficiency also developed. Because of the persistent hypercalcemia, the boy underwent a parathyroid exploration at which only normal parathyroid glands were identified. Six weeks later because of persistent hypercalemia, the anterior mediastinum was explored but no parathyroid tissue was identified. Once the patient was mobilized, the serum calcium decreased to normal values. Albright concluded that the sequence of events was: a) solitary bone cyst; b) fracture through cyst; c) immobilization of a large part of a previously active skeleton; d) osteoporosis from disuse with an excess of calcium from bone being presented to the kidney; e) an inability of the kidney to excrete promptly all the calcium; f) resulting in hypercalcemia; and g) kidney damage from excess of calcium being excreted through the kidney. Albright further added that once renal insufficiency developed, it probably increased the tendency to hypercalcemia. From this case, Albright learned that immobilization of an individual with active skeletal remodeling increases calcium efflux from bone and he also recognized that a decreased glomerular filtration rate reduces the capacity to excrete calcium, which in turn, exacerbates hypercalcemia.CONCLUSIONIn the late 1920s, Albright joined Joseph Aub and Walter Bauer to pursue studies of calcium and phosphorus metabolism. First Aub and then Bauer were appointed to academic positions in other subspecialties at Harvard, which by 1930 left the young Albright as the primary investigator of calcium and phosphorus metabolism in Boston. Through inductive reasoning, which has been defined by the late Jacob Bronowski as that unpredictable blend of speculation and insight, Albright came to recognize in normal volunteers and in hypo- and hyperparathyroid patients, the presence of consistent patterns of response for calcium and phosphorus metabolism. Fuller Albright was truly the first person to establish a sense of order out of the existing chaos in the new field of calcium and phosphorus metabolism. As one of the 20th century’s preeminent philosophers of science, Karl Popper has stated, "Science does not rest upon rock-bottom. The bold structure of its theories rises, as it were, above a swamp, but not down to any natural or given base; and when we cease our attempts to drive our piles into a deeper layer, it is not because we have reached firm ground. We simply stop when we are satisfied that they are firm enough to carry the structure, at least for the time being". Albright was the first to establish a functional system which explained calcium and phosphorus metabolism. His classic book, The Parathyroid Glands and Metabolic Bone Disease, published in 1948, became the standard reference for a generation of students of calcium and phosphorus metabolism. Albright trained many future investigators and became an inspiration for the next generation of clinical investigators studying calcium and phosphorus disorders. As the importance of translational research is again rightfully being emphasized, the contributions of Fuller Albright should be recognized and he should be celebrated as a role model for a new generation of young clinical investigators.<a href="grande/10774_108_11836_en_10774_t1.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11836_en_10774_t1.jpg" alt="A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before and after the development of renal impairment "></img></a>Table 1. A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before and after the development of renal impairment <a href="grande/10774_108_11837_en_10774_t2.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11837_en_10774_t2.jpg" alt="Comparison of two types of primary hyperparathyroidism based on a series analyzed by Lloyd"></img></a>Table 2. Comparison of two types of primary hyperparathyroidism based on a series analyzed by Lloyd<a href="grande/10774_108_11838_en_10774_f1.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11838_en_10774_f1.jpg" alt="Graphic representation of balance data. "></img></a>Figure 1. Graphic representation of balance data. <a href="grande/10774_108_11839_en_10774_f2.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11839_en_10774_f2.jpg" alt="Effect of parathyroid extract on urinary calcium and phosphorus excretion in a patient with idiopathic hypoparathyroidism. "></img></a>Figure 2. Effect of parathyroid extract on urinary calcium and phosphorus excretion in a patient with idiopathic hypoparathyroidism. <a href="grande/10774_108_11840_en_10774_f3.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11840_en_10774_f3.jpg" alt="Effect of a 48 hour calcium infusion with normalization of the serum calcium concentration on phosphate excretion in hypoparathyroid patients. "></img></a>Figure 3. Effect of a 48 hour calcium infusion with normalization of the serum calcium concentration on phosphate excretion in hypoparathyroid patients. <a href="grande/10774_108_11841_en_10774_f4.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11841_en_10774_f4.jpg" alt="The same patient before and after parathyroidectomy from original series of Albright."></img></a>Figure 4. The same patient before and after parathyroidectomy from original series of Albright.<a href="grande/10774_108_11842_en_10774_f5.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11842_en_10774_f5.jpg" alt="Average preoperative serum calcium values of the first 35 patients with primary hyperparathyroidism from the Massachusetts General Hospital series. "></img></a>Figure 5. Average preoperative serum calcium values of the first 35 patients with primary hyperparathyroidism from the Massachusetts General Hospital series. <a href="grande/10774_108_11843_en_10774_f6.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11843_en_10774_f6.jpg" alt="Fall in serum calcium values after parathyroidectomy in 35 cases of primary hyperparathyroidism (first demonstration of hungry bone syndrome). "></img></a>Figure 6. Fall in serum calcium values after parathyroidectomy in 35 cases of primary hyperparathyroidism (first demonstration of hungry bone syndrome). <a href="grande/10774_108_11844_en_10774_f7.jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11844_en_10774_f7.jpg" alt="A global view of vitamin D levels and the magnitude of hyperparathyroidism as determined by the elevation in PTH. "></img></a>Figure 7. A global view of vitamin D levels and the magnitude of hyperparathyroidism as determined by the elevation in PTH. " "pdfFichero" => "P1-E521-S2968-A10774-EN.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441140" "palabras" => array:1 [ 0 => "Phosphorus" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441142" "palabras" => array:1 [ 0 => "Parathyroid hormone" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441144" "palabras" => array:1 [ 0 => "Hypoparathyroidism" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441146" "palabras" => array:1 [ 0 => "Hyperparathyroidism" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441148" "palabras" => array:1 [ 0 => "Calcium" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "The major contributions of Fuller Albright to our understanding of calcium and phosphorus regulation and primary hyperparathyroidism are highlighted. Albright was the first investigator to initiate a systematic study of mineral metabolism. With resources limited to the measurement of serum calcium and phosphorus and the infusion of parathyroid extract, Albright used balance studies to establish a framework for our understanding of calcium and phosphorus regulation and primary hyperparathyroidism. Albright was the first to show that the etiology of primary hyperparathyroidism could be from either an adenoma or hyperplasia of the parathyroid glands and stone disease was a separate manifestation of primary hyperparathyroidism. Albright also showed that: 1) a renal threshold for calcium excretion was present in hypoparathyroid patients; 2) correction of hypocalcemia in hypoparathyroid patients with vitamin D had a phosphaturic action; 3) renal failure reduced the intestinal absorption of calcium in primary hyperparathyroidism; 4) the «hungry bone» syndrome developed after parathyroidectomy in severe primary hyperparathyroidism; and 5) a target organ can fail to respond to a hormone. He also suggested that a malignant tumor could be responsible for ectopic hormone production. Finally, our review integrates the observations of Albright with our current knowledge of calcium regulation and disorders." ] ] "multimedia" => array:9 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11836_en_10774_t1.jpg" "Alto" => 182 "Ancho" => 600 "Tamanyo" => 92944 ] ] "descripcion" => array:1 [ "en" => "A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before and after the development of renal impairment" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11837_en_10774_t2.jpg" "Alto" => 506 "Ancho" => 520 "Tamanyo" => 275874 ] ] "descripcion" => array:1 [ "en" => "Comparison of two types of primary hyperparathyroidism based on a series analyzed by Lloyd" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11838_en_10774_f1.jpg" "Alto" => 454 "Ancho" => 591 "Tamanyo" => 224855 ] ] "descripcion" => array:1 [ "en" => "Graphic representation of balance data." ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11839_en_10774_f2.jpg" "Alto" => 584 "Ancho" => 381 "Tamanyo" => 169588 ] ] "descripcion" => array:1 [ "en" => "Effect of parathyroid extract on urinary calcium and phosphorus excretion in a patient with idiopathic hypoparathyroidism." ] ] 4 => array:8 [ "identificador" => "fig5" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11840_en_10774_f3.jpg" "Alto" => 836 "Ancho" => 381 "Tamanyo" => 249713 ] ] "descripcion" => array:1 [ "en" => "Effect of a 48 hour calcium infusion with normalization of the serum calcium concentration on phosphate excretion in hypoparathyroid patients." ] ] 5 => array:8 [ "identificador" => "fig6" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11841_en_10774_f4.jpg" "Alto" => 926 "Ancho" => 385 "Tamanyo" => 227518 ] ] "descripcion" => array:1 [ "en" => "The same patient before and after parathyroidectomy from original series of Albright." ] ] 6 => array:8 [ "identificador" => "fig7" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11842_en_10774_f5.jpg" "Alto" => 380 "Ancho" => 383 "Tamanyo" => 87412 ] ] "descripcion" => array:1 [ "en" => "Average preoperative serum calcium values of the first 35 patients with primary hyperparathyroidism from the Massachusetts General Hospital series." ] ] 7 => array:8 [ "identificador" => "fig8" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11843_en_10774_f6.jpg" "Alto" => 507 "Ancho" => 381 "Tamanyo" => 210039 ] ] "descripcion" => array:1 [ "en" => "Fall in serum calcium values after parathyroidectomy in 35 cases of primary hyperparathyroidism (first demonstration of hungry bone syndrome)." ] ] 8 => array:8 [ "identificador" => "fig9" "etiqueta" => "Fig. 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10774_108_11844_en_10774_f7.jpg" "Alto" => 262 "Ancho" => 381 "Tamanyo" => 75255 ] ] "descripcion" => array:1 [ "en" => "A global view of vitamin D levels and the magnitude of hyperparathyroidism as determined by the elevation in PTH." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:71 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kleeman CR, Levine BS, Felsenfeld AJ. 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A.J.. Felsenfelda, B.S.. Levinea, C. R.. Kleemana

a Department of Medicine, VA Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA,

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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">Fuller Albright&#8217;s academic career began in the late 1920s and ended in 1956 after brain surgery for Parkinson&#8217;s disease resulted in a non-functional state until his death in 1969&#46; Although increasingly disabled by Parkinson&#8217;s disease from the mid 1930s&#44; Albright continued to make important contributions to our knowledge of calcium and phosphorus disorders<span class="elsevierStyleSup">1</span>&#46; His book&#44; &#34;Parathyroid Glands and Metabolic Bone Disease&#34;&#44; published in 1948&#44; is a testimony to his many important observations<span class="elsevierStyleSup">2</span>&#46; Our goal is to highlight some of the many contributions made by Albright on calcium and phosphorus regulation and primary hyperparathyroidism and to integrate the findings of Albright with more recent studies&#46; Albright&#8217;s contributions to our understanding of renal phosphate transport have been discussed elsewhere<span class="elsevierStyleSup">3</span>&#46; Virtually all that Albright observed remains valid today&#44; but as often happens&#44; the explanations and their complexity continue to evolve&#46;</p><p class="elsevierStylePara">Our retrospective highlights Albright&#8217;s enduring legacy to the modern study of calcium and phosphorus regulation and primary hyperparathyroidism&#46; The following topics are discussed&#58; <span class="elsevierStyleItalic">1&#41;</span> the resources available to Albright to study calcium and phosphorus regulation and primary hyperparathyroidism&#59; <span class="elsevierStyleItalic">2&#41;</span> Albright&#8217;s studies of calcium balance&#59; <span class="elsevierStyleItalic">3&#41;</span> phosphaturia resulting from the correction of hypocalcemia in hypoparathyroid patients&#59; <span class="elsevierStyleItalic">4&#41;</span> primary hyperparathyroidism as a surgically curable disorder&#59; and <span class="elsevierStyleItalic">5&#41;</span> several clinical vignettes which include&#58; <span class="elsevierStyleItalic">a&#41;</span> a prelude to the trade-off hypothesis of Slatopolsky and Bricker advanced by Albright to explain the development of secondary hyperparathyroidism in renal failure&#59; <span class="elsevierStyleItalic">b&#41;</span> the suggestion that a malignant tumor could be responsible for ectopic hormone production&#59; <span class="elsevierStyleItalic">c&#41;</span> the realization that vitamin D deficiency can be associated with the failure to respond to parathyroid hormone &#40;PTH&#41;&#59; and <span class="elsevierStyleItalic">d&#41;</span> the appreciation that immobilization can be a cause of hypercalcemia&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TOOLS OF THE TRADE</span></p><p class="elsevierStylePara">In the late 1920s when Albright first started his studies of calcium and phosphorus regulation and primary hyperparathyroidism&#44; his primary tools were&#58; <span class="elsevierStyleItalic">1&#41;</span> parathyroid extract &#40;PTE&#41;&#44; which was a bovine preparation from Eli Lilly and Company&#59; <span class="elsevierStyleItalic">2&#41;</span> the personnel on the newly organized Ward 4 at Massachusetts General Hospital who were trained to perform balance studies in which dietary calcium and phosphorus could be prepared with accuracy and the fecal and urine excretion of calcium and phosphorus collected with precision<span class="elsevierStyleSup">4</span>&#59; and <span class="elsevierStyleItalic">3&#41;</span> the measurement of calcium and phosphorus in the blood&#44; urine and feces&#46; As a result of balance studies it became possible to determine how variations in dietary calcium and phosphate content and the administration of PTE affected&#58; <span class="elsevierStyleItalic">1&#41;</span> serum calcium and phosphorus concentration&#59; <span class="elsevierStyleItalic">2&#41;</span> fecal and urinary excretion of calcium and phosphorus&#59; and <span class="elsevierStyleItalic">3&#41;</span> retention or loss of calcium and phosphorus from the body &#40;figure 1&#41;&#46; Because PTH could not be measured&#44; Albright could not know whether PTH values were modified by serum calcium&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECT OF PARATHYROID EXTRACT AND DIETARY CALCIUM ANS PHOSPHATE ON CALCIUM BALANCE IN NORMAL SUBJECTS AND IN PATIENTS WITH HYPOPARATHYROIDISM AND HYPERPARATHYROIDISM </span></p><p class="elsevierStylePara">In an early study&#44; Albright infused PTE into a patient with longstanding idiopathic hypoparathyroidism &#40;Figure 2&#41;<span class="elsevierStyleSup">5</span>&#46; Albright observed that&#58; <span class="elsevierStyleItalic">1&#41;</span> urine phosphorus excretion immediately increased and peaked within two hours&#59; <span class="elsevierStyleItalic">2&#41;</span> the increase in serum calcium and decrease in serum phosphorus followed the increase in phosphorus excretion&#59; and <span class="elsevierStyleItalic">3&#41;</span> there was a critical serum calcium value at about 8&#46;5 mg&#47;dl at which a negligible urinary calcium excretion suddenly became appreciable&#46; Albright concluded that the action of PTE was rapid&#44; its first effect was phosphaturia&#44; and the increase in serum calcium followed the increase in phosphorus excretion&#46; Thus&#44; Albright developed the hypothesis that PTH primarily modified phosphorus rather than calcium&#44; a view that he still championed when his book was published almost 20 years later<span class="elsevierStyleSup">2</span>&#46; Albright argued that the PTH-induced increase in phosphorus excretion and the resulting decrease in serum phosphorus promoted bone dissolution releasing calcium&#46; While such a conclusion might sound somewhat fanciful today&#44; it should be remembered that Albright had participated in studies in which ammonium chloride-induced acidosis increased the serum calcium concentration and urinary calcium excretion without increasing intestinal calcium absorption suggesting that acidosis induced bone dissolution<span class="elsevierStyleSup">6</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">7</span>&#46; Today it is recognized that phosphate depletion increases calcium release from bone resulting in hypercalciuria and even hypercalcemia despite a marked reduction in PTH values suggesting that bone dissolution is an important feature<span class="elsevierStyleSup">8</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">9</span>&#46; Finally&#44; Albright was correct in his hypothesis that phosphate was a major modifier of the calcemic response of bone to PTH&#46; Many subsequent studies have shown that phosphate loading and restriction change the calcemic response to PTH<span class="elsevierStyleSup">10-12</span>&#46;</p><p class="elsevierStylePara">As already mentioned&#44; Albright had observed during a PTE-induced increase in serum calcium in a hypoparathyroid patient that the serum calcium threshold at which urinary calcium excretion increased from negligible values was approximately 8&#46;5 mg&#47;dl&#46; However&#44; that threshold value did not account for the now known effect of PTH on urinary calcium excretion&#46; In 1961&#44; one of the authors &#40;CRK&#41; first showed that PTE administration directly increased renal calcium reabsorption<span class="elsevierStyleSup">13</span>&#46; Subsequently&#44; it was shown that the threshold serum calcium value for excreting calcium during a calcium infusion was seen at serum calcium values between 7 and 8 mg&#47;dl in hypoparathyroid patients<span class="elsevierStyleSup">14</span>&#46; In 1984&#44; Ogata and associates showed that besides PTH&#44; the active form of vitamin D&#44; calcitriol&#44; directly increased the threshold for renal calcium excretion and also enhanced the responsiveness of the tubule to PTH<span class="elsevierStyleSup">15</span>&#46; More recently&#44; Bindels and colleagues have shown that the stimulatory effect of both calcitriol and PTH on renal calcium reabsorption results from the activation of an epithelial calcium channel &#40;TRPV5&#41; in the distal convoluted tubule<span class="elsevierStyleSup">16</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">VITAMIN D TREATMENT AND CALCIUM INFUSION AS PHOSPHATURIC AGENTS</span></p><p class="elsevierStylePara">In 1938 and in 1942&#44; Albright used the newly available analog of vitamin D&#44; dihydrotachysterol&#44; for the treatment of hypocalcemia in patients with hypoparathyroidism<span class="elsevierStyleSup">17</span> and also in the newly described disorder of pseudohypoparathyroidism in which there was a failure to respond to administered PTE<span class="elsevierStyleSup">18</span>&#46; Albright observed that the correction of hypocalcemia increased urine phosphate excretion&#46; This observation had been made earlier by associates of Albright<span class="elsevierStyleSup">19</span> and by Howland and Kramer<span class="elsevierStyleSup">20</span>&#46; In 1965&#44; Eisenberg demonstrated in hypoparathyroid patients that the phosphaturia was independent of vitamin D by showing that a prolonged intravenous infusion of calcium sufficient to normalize the serum calcium concentration at 48 hours was phosphaturic and also lowered the serum phosphorus concentration &#40;figure 3A&#44; figure&#160;3B&#41;<span class="elsevierStyleSup">21</span>&#46; Evidence has accumulated during the past several years that the recently discovered bone-derived phosphaturic hormone&#44; fibroblast growth factor 23 &#40;FGF23&#41; might be involved&#46; High dietary calcium has been shown to stimulate FGF23<span class="elsevierStyleSup">22</span> and the correlation between the serum calcium concentration and FGF23 seen in primary hyperparathyroidism<span class="elsevierStyleSup">23-</span><span class="elsevierStyleSup">25</span> even remained significant after parathyroidectomy<span class="elsevierStyleSup">24</span>&#46; However&#44; a study has yet to be performed identifying the specific mechanism for the observation made more than 70 years ago by Albright and others&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">PRIMARY HYPERPARATHYROIDISM&#44; INTESTINAL CALCIUM ABSORPTION&#44; AND RENAL FAILURE</span></p><p class="elsevierStylePara">In patients with primary hyperparathyroidism&#44; Albright showed that changes in dietary calcium and phosphate affected calcium balance&#46; The first patient studied was Captain Martell<span class="elsevierStyleSup">26</span>&#44; who was to have seven parathyroid operations before an ectopic parathyroid gland was removed from the anterior mediastinum<span class="elsevierStyleSup">27</span>&#46; From the balance studies in Captain Martell&#44; who had serum calcium values between 13&#46;1 and 15&#46;3 mg&#47;dl&#44; Albright made the following observations&#58; <span class="elsevierStyleItalic">1&#41;</span> the patient&#8217;s negative calcium balance on a low calcium diet &#40;0&#46;1 grams&#47;day&#41; was greater than in normal controls &#40;-0&#46;46 vs -1&#46;29 grams per 3 day study period&#41;&#59; <span class="elsevierStyleItalic">2&#41;</span> the increased negative calcium balance in the hyperparathyroid patient was due to increased urinary calcium excretion because fecal calcium excretion was less than in normals&#59; <span class="elsevierStyleItalic">3&#41;</span> an infusion of PTE in normal volunteers sufficient to increase serum calcium to between 11&#46;5 and 12&#46;8 mg&#47;dl resulted in a negative calcium balance duplicating the results of the hyperparathyroid patient&#59; and <span class="elsevierStyleItalic">4&#41;</span> a calcium diet of 1&#46;07 grams&#47;day in the hyperparathyroid patient resulted in a positive calcium balance &#40;0&#46;36 grams per day&#41; because urinary calcium excretion increased by only 0&#46;06 grams&#47;day from that on a low calcium diet &#40;0&#46;1 grams&#47;day&#41;&#46; Thus&#44; Albright concluded that in primary hyperparathyroidism&#58; <span class="elsevierStyleItalic">1&#41;</span> adaptation to a low calcium diet did not occur because high urine calcium losses persisted&#59; <span class="elsevierStyleItalic">2&#41;</span> intestinal calcium absorption was increased&#59; and <span class="elsevierStyleItalic">3&#41;</span> high PTH values were the likely cause of the negative calcium balance&#46;</p><p class="elsevierStylePara">Albright also evaluated the effect of dietary phosphate on calcium balance in hyperparathyroidism&#46; He showed that a high phosphate diet improved calcium balance in hyperparathyroid patients on both low &#40;0&#46;07 g&#47;day&#41; and normal &#40;0&#46;9 g&#47;day&#41; intakes of dietary calcium<span class="elsevierStyleSup">28</span>&#46; When high dietary phosphate was given to patients with primary hyperparathyroidism&#44; there was&#58; <span class="elsevierStyleItalic">1&#41;</span> almost complete intestinal absorption of phosphate&#59; <span class="elsevierStyleItalic">2&#41;</span> rapid excretion of the absorbed phosphate by the kidneys&#59; <span class="elsevierStyleItalic">3&#41;</span> a rise in the previously low serum phosphorus&#59; <span class="elsevierStyleItalic">4&#41;</span> a fall in the previously elevated serum calcium&#59; <span class="elsevierStyleItalic">5&#41;</span> a rise in the serum calcium-phosphorus product&#59; and <span class="elsevierStyleItalic">6&#41;</span> a fall in urinary calcium excretion&#46; While a high phosphate diet seemed to have certain beneficial effects such as lowering the serum calcium concentration and decreasing urinary calcium excretion&#44; Albright recognized that there were two potential dangers associated with increased phosphate ingestion in patients with primary hyperparathyroidism&#58; <span class="elsevierStyleItalic">1&#41;</span> parathyroid poisoning with soft tissue calcium deposition including the kidney and lungs&#59; and <span class="elsevierStyleItalic">2&#41;</span> calcium-phosphate kidney stones&#46; Today&#44; the recognition that hyperphosphatemia in CKD patients and perhaps even high normal serum phosphorus values in the general population are associated with increased vascular disease and mortality probably from increased vascular calcification<span class="elsevierStyleSup">29</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">30</span> could be considered an extension of the pioneering studies of Albright&#46;</p><p class="elsevierStylePara">By 1934&#44; Albright came to understand that renal failure had a specific effect on calcium and phosphorus regulation<span class="elsevierStyleSup">31</span>&#46; When a 13 year old girl with moderate renal failure was referred for hypercalcemia &#40;13&#46;6 mg&#47;dl&#41;&#44; bone demineralization&#44; a markedly elevated serum alkaline phosphatase&#44; and a serum phosphorus of 4&#46;3 mg&#47;dl&#44; balance studies were performed before the parathyroid surgery during which an adenoma was removed&#46; The balance studies showed that on a low calcium diet &#40;0&#46;1 g&#47;day&#41;&#44; urine calcium excretion despite hypercalcemia was only marginally greater than in controls on a similar diet &#40;94 mg vs 63 mg&#47;day&#41;&#46; This value was much less than in non-azotemic patients with primary hyperparathyroidism and hypercalcemia &#40;435 mg&#47;day&#41;&#46; Also&#44; fecal calcium excretion was greater than in controls and much greater than in hyperparathyroid patients without renal failure&#46; Because of the results in this young girl with renal failure&#44; Albright reviewed the results of the series of balance studies which had been performed on Captain Martell before and after he developed renal failure&#46; As shown in table 1&#44; for a similar magnitude of hypercalcemia &#40;14 mg&#47;dl vs 14&#46;4 mg&#47;dl&#41;&#44; for the same low calcium diet after the onset of renal failure&#44; intestinal calcium absorption was less &#40;0&#46;06 vs 0&#46;26 g&#47;day&#41; as was urine calcium excretion &#40;0&#46;09 vs 0&#46;44 g&#47;day&#41;&#46; Thus&#44; Albright was the first to recognize that the development of renal failure in primary hyperparathyroidism dramatically decreased both intestinal absorption and the renal excretion of calcium&#46; Today&#44; it is known that PTH stimulates renal production of the active form of vitamin D&#44; calcitriol&#44; which in turn enhances intestinal absorption of calcium&#46; With loss of renal function&#44; calcitriol production is decreased despite high PTH values&#44; a result which may in part be due to increased FGF23 values&#46; Consequently&#44; both intestinal calcium absorption and renal calcium excretion are reduced in renal failure&#46; The latter results from both a decrease in the glomerular filtration of calcium and increased tubular calcium reabsorption from high PTH values&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">PRIMARY HYPERPARATHYROIDISM</span></p><p class="elsevierStylePara">In several patients in his original series of 17 patients published in 1934<span class="elsevierStyleSup">32</span>&#44; Albright made the diagnosis of hyperparathyroidism only because he had the insight to measure serum calcium and phosphorus values in all patients who presented with kidney stones&#46; In the first 14 patients to undergo parathyroid surgery&#44; parathyroid adenomas were found&#46; Two of these patients had ectopic parathyroid adenomas located in the anterior mediastinum&#46; Cases 15 to 17 had hyperplasia of all the parathyroid glands&#46; Because hyperplasia had not been previously recognized as an entity&#44; Case 15 required three parathyroid operations to remove a sufficient amount of the hyperplastic glands before the hypercalcemia resolved&#46; Between the second and third operations&#44; estrogen treatment and irradiation of the pituitary and parathyroid glands were tried without success<span class="elsevierStyleSup">33</span>&#46;</p><p class="elsevierStylePara">In this series of 17 patients&#44; the dimensions&#44; but not the weights of the removed parathyroid glands were provided<span class="elsevierStyleSup">32</span>&#46; The mean amount of parathyroid tissue removed per patient was approximately 83 times greater than the combined size of four normal human parathyroid glands&#44; which subsequently were shown to have a combined weight of approximately 140 mg<span class="elsevierStyleSup">34</span>&#46; Based on these results&#44; the average estimated weight of removed parathyroid tissue for each patient was approximately 11 grams&#46; In severe cases of primary hyperparathyroidism with marked hypercalcemia&#44; cachexia and debilitating fractures were sometimes seen and parathyroidectomy was life saving &#40;figure 4&#41;&#46; The different magnitude of primary hyperparathyroidism in patients presenting in the 1930s and today is shown by the very high preoperative serum calcium values in Albright&#8217;s patients &#40;figure 5&#41;&#46; Finally&#44; Albright was the first to describe the &#34;hungry bone syndrome&#34; in which severe hypocalcemia developed values shortly after parathyroidectomy &#40;figure 6&#41;&#46; He also showed that the decrease in serum calcium correlated with the pre-operative serum alkaline phosphatase value&#46; When the serum calcium decreased to less than 7 mg&#47;dl&#44; Albright reported that tetany and visual disturbances were often seen&#46; In actuality&#44; the subsequent recognition of the &#34;hungry bone syndrome&#34; in dialysis patients after parathyroidectomy is an extension of the results in primary hyperparathyroidism by Albright&#46;</p><p class="elsevierStylePara">In 1934&#44; Albright also recognized that patients with primary hyperparathyroidism presented with either bone disease or stone disease&#44; but rarely both together<span class="elsevierStyleSup">32</span>&#46; In patients with bone disease&#44; skeletal symptoms associated with bone loss&#44; bone cysts&#44; brown tumors&#44; and fractures predominated&#46; In patients with stone disease&#44; presenting symptoms were those associated with nephrolithiasis and skeletal problems were generally absent&#46; Albright questioned why there should be two separate presentations for the same disease&#46; He hypothesized that the extent of bone disease was proportional to the duration of disease times the daily loss of calcium<span class="elsevierStyleSup">32</span>&#46; Thus&#44; according to Albright a short duration of disease would lessen the risk of bone disease&#46; Moreover&#44; a high calcium intake would make bone disease less likely because as Albright had previously observed in studies of patients with primary hyperparathyroidism&#44; a high calcium diet resulted in a positive calcium balance<span class="elsevierStyleSup">26</span>&#46;</p><p class="elsevierStylePara">In 1945&#44; Keating reported 24 patients with primary hyperparathyroidism in whom the magnitude of hypercalcemia&#44; hypophosphatemia and serum alkaline phosphatase elevation was greater in patients with bone disease than with stone disease<span class="elsevierStyleSup">35</span>&#46; In contradiction to the hypothesis advanced by Albright&#44; the patients with bone disease had a shorter duration of symptoms before presentation&#46; In 1956&#44; Dent also reported that patients with bone disease had a shorter duration of symptoms<span class="elsevierStyleSup">36</span>&#46; Subsequently&#44; Dent reported that there was no difference in dietary intake of calcium between patients with bone or stone disease<span class="elsevierStyleSup">37</span>&#46;</p><p class="elsevierStylePara">In 1968&#44; Lloyd reviewed 138 consecutive cases of primary hyperparathyroidism accumulated by Dent in London from 1950 to 1965<span class="elsevierStyleSup">38</span>&#46; Patients were divided into overt bone disease without kidney stones &#40;Type 1&#44; n &#61; 44&#41; and kidney stones without overt bone disease &#40;Type 2&#44; n &#61; 88&#41;&#46; The remaining six patients had neither overt bone disease nor kidney stones&#46; As shown in table 2&#44; the adenoma weight was greater&#44; the growth rate of the parathyroid tissue more rapid&#44; and the duration of symptoms was shorter in patients with bone disease&#46; These results contradicted Albright&#8217;s hypothesis that patients with bone disease have a longer duration of disease&#46;</p><p class="elsevierStylePara">One explanation for the shorter duration of disease together with more severe hypercalcemia and larger adenomas in patients with bone disease is simply a more rapid growth rate of the parathyroid adenomas in patients with bone disease&#46; In the early 1970s&#44; both Woodhouse et al<span class="elsevierStyleSup">39</span> and Lumb and Stanbury<span class="elsevierStyleSup">40</span> suggested that the more rapid growth of adenomas in patients with bone disease might be from a lack of vitamin D&#46; In 1987&#44; one of the authors &#40;CRK&#41; wrote an editorial in support of this possibility<span class="elsevierStyleSup">41</span>&#46; Also in 1987&#44; Paillard and associates reported that patients with bone disease had lower values of the stored form of vitamin D&#44; 25-hydroxyvitamin D &#40;25&#91;OH&#93;D&#41;&#44; 3&#46;4 &#177; 2&#46;0 vs 17&#46;6 &#177; 13&#46;6 ng&#47;ml &#40;P &#60;0&#46;001&#41; and three-fold greater PTH values than patients with stone disease<span class="elsevierStyleSup">42</span>&#46; In more recent studies&#44; Silverberg et al in a longitudinal study of patients with mild hyperparathyroidism&#44; found that patients in the lowest tertile of 25&#40;OH&#41;D measurements &#40;12 &#177; 3 ng&#47;ml&#41; had the highest PTH values<span class="elsevierStyleSup">43</span>&#46; Rao&#44; et al&#46;&#44; in a study of 148 consecutive patients operated for primary hyperparathyroidism with a mean resected parathyroid gland weight of 1&#46;27 grams&#44; reported an inverse correlation between 25&#40;OH&#41;D and parathyroid gland weight while the correlation between the active form of vitamin D&#44; calcitriol&#44; and parathyroid gland weight was not significant<span class="elsevierStyleSup">44</span>&#46; These results suggest that a suboptimal vitamin D status may stimulate parathyroid adenoma growth&#46; The presence of 1 alpha-hydroxylase&#44; the enzyme responsible for conversion of 25&#40;OH&#41;D to calcitriol&#44; in parathyroid cells suggests the possibility that 25&#40;OH&#41;D may directly affect PTH secretion and parathyroid gland growth<span class="elsevierStyleSup">45&#44;46</span>&#46; Also contributing to the lowering of 25&#40;OH&#41;D levels in primary hyperparathyroidism is that high PTH levels decrease 25&#40;OH&#41;D levels by increasing conversion of 25&#40;OH&#41;D to calcitriol<span class="elsevierStyleSup">47</span>&#46; In summary&#44; even in the studies of Silverberg and Rao in which the increased weight of the parathyroid adenoma was modest and the diagnosis of primary hyperparathyroidism was made relatively early in the course of the disease&#44; vitamin D status seemed to play a role<span class="elsevierStyleSup">43&#44;44</span>&#46;</p><p class="elsevierStylePara">Since the 1970s&#44; the clear demarcation between patients with bone and stone disease previously seen in patients with primary hyperparathyroidism starting with the report of Albright in 1934 and continuing through the 1960s has been lost<span class="elsevierStyleSup">32</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">35</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">38</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">48-</span><span class="elsevierStyleSup">51</span>&#46; Beginning in the 1930s and continuing for the next three decades&#44; the sequence of events in diagnosing bone disease in primary hyperparathyroidism often was as described by Albright&#44; &#34;appearance of a bone tumor&#44; biopsy&#44; diagnosis of benign giant cell tumor&#44; local treatment&#44; and finally recognition of generalized disease only years later&#34;<span class="elsevierStyleSup">2</span>&#46; However&#44; the introduction of multichannel analyzers in which serum calcium and phosphorus values were routinely measured resulted in the detection of many asymptomatic hyperparathyroid patients with mild hypercalcemia&#46;</p><p class="elsevierStylePara">In a recent review of primary hyperparathyroidism&#44; the average weight of the removed adenoma was 400 to 600 mg&#44; values which are only three to four times greater than the combined weight of four normal parathyroid glands<span class="elsevierStyleSup">52</span>&#46; In contrast&#44; the mean weight of the removed parathyroid adenomas in the Albright study from 1934 was approximately 11 grams<span class="elsevierStyleSup">32</span>&#46; In 1947&#44; Norris reviewed 322 cases from the existing world literature and reported that the average weight of a removed parathyroid adenoma was 8 grams<span class="elsevierStyleSup">48</span>&#46; In 1963&#44; Hodgkinson reported that the mean weight of the removed adenoma was 5&#46;1 grams in patients with bone disease and 1&#46;4 grams in patients with stone disease<span class="elsevierStyleSup">49</span>&#46; Similar differences in the weight of parathyroid adenomas between patients with bone and those with stone disease were reported by Lloyd in his analysis of Dent&#8217;s patients<span class="elsevierStyleSup">38</span> and by O&#8217;Riordan<span class="elsevierStyleSup">51</span>&#46; The mean weight of the parathyroid adenoma in patients with bone disease was 5&#46;9 grams in the former and 4&#46;2 grams in the latter series&#46;</p><p class="elsevierStylePara">In areas of the world with limited access to medical care&#44; vitamin D insufficiency&#47;deficiency appears to be more common and the duration of primary hyperparathyroidism much longer before diagnosis and treatment&#46; In recent studies of primary hyperparathyroidism from India and China&#44; the presence of large parathyroid adenomas and bone disease has been associated with vitamin D insufficiency&#47;deficiency &#40;figure 7&#41;<span class="elsevierStyleSup">53-</span><span class="elsevierStyleSup">57</span>&#46; In a study from China&#44; the presenting PTH value was 21 times greater than normal<span class="elsevierStyleSup">55</span>&#46; Similarly&#44; in a study from India&#44; the mean weight of the removed parathyroid adenoma was 10&#46;75 g in hypercalcemic patients and 3&#46;9 g in normocalcemic patients<span class="elsevierStyleSup">54</span>&#46; In another study from India&#44; the mean weight of the removed parathyroid adenoma was 7&#46;9 g<span class="elsevierStyleSup">56</span>&#46; Moreover&#44; the 25&#40;OH&#41;D value was less than 10 ng&#47;ml in the majority of these patients&#46; In the cited studies&#44; pathologic bone fractures&#44; bone cysts&#44; and brown tumors were commonly encountered<span class="elsevierStyleSup">54-</span><span class="elsevierStyleSup">56</span>&#46; In summary&#44; the severe form of primary hyperparathyroidism characterized by large adenomas and disabling bone disease&#44; first described by Albright in the 1930s&#44; is still commonly encountered in areas of the world with limited access to medical care&#46; Furthermore&#44; the severe form of primary hyperparathyroidism seen in these patients is often associated with vitamin D insufficiency&#47;deficiency&#46; &#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">VIGNETTES IN WICH OBSERVATIONS BY ALBRIGHT HAVE HAD CONTINUED CLINICAL RELEVANCE</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">1937&#46; Prelude to the &#34;Trade-Off Hypothesis&#34; of Slatopolsky and Bricker</span><span class="elsevierStyleSup">10</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">58</span><span class="elsevierStyleBold"> which was Advanced to Explain the Development of Secondary Hyperparathyroidism</span></p><p class="elsevierStylePara">Albright made the following statement in a 1937 publication<span class="elsevierStyleSup">59</span>&#58; &#34;It has been suggested above that the parathyroid hyperplasia is a compensation for the disturbed equilibrium occasioned by phosphate retention resulting from the renal insufficiency&#46; In the absence of the hyperplasia there would probably be greater phosphate retention in the blood with a lowering of the blood calcium level and severe tetany&#46; If these concepts are correct&#44; the hyperplasia would have to be considered beneficial&#46; The one reservation might have to be made that&#44; while helping homeostasis&#44; the parathyroid hyperplasia may lead to bone disease&#34;&#46; Confirmation of the Albright hypothesis has been shown in many animal and clinical studies of phosphate loading&#46; Also in studies of patients with stage 3 and 4 CKD treated with the calcimimetic&#44; cinacalcet&#44; the reduction in PTH values has increased the serum phosphorus concentration<span class="elsevierStyleSup">60</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">1941&#46; Hypothesis that Hypercalcemia in Malignancy could be from Ectopic Hormone Production </span></p><p class="elsevierStylePara">At a clinicopathological conference&#44; a 51 year old male presenting with hypercalcemia and hypophosphatemia was discussed<span class="elsevierStyleSup">61</span>&#46; A neck exploration for presumed hyperparathyroidism was performed&#44; but no abnormality was found&#46; Bone x-rays showed a destructive lesion in the right ilium&#44; which on biopsy was reported to originate from a renal cell carcinoma&#46; The comment of Albright at the end of the conference was &#34;Why a person should have high serum calcium and low serum phosphorus when the cause of the disturbance is a tumor destroying bone is an interesting theoretical question&#46; We treated this case by radiation of the tumor masses&#59; the serum calcium went down to normal&#44; and the serum phosphorus went up to normal&#46; Gradually&#44; both values became abnormal again&#46; I suspected that the tumor might be producing parathyroid hormone&#46; I therefore had it assayed by Dr&#46; J&#46; B&#46; Collip&#44; but no hormone was found&#34;&#46; In essence&#44; Albright was the first to suggest the possibility of ectopic hormone production by a tumor&#46; Today we know the causal agent responsible for the hypercalcemia and hypophosphatemia to be PTH-related protein and not PTH&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">1941&#46; Pseudohypoparathyroidism in Vitamin D Deficiency</span></p><p class="elsevierStylePara">A year before Albright reported the clinical entity of pseudohypoparathyroidism in which there was a failure to respond to PTE in patients with characteristic body features<span class="elsevierStyleSup">18</span>&#44; he recognized a subset of patients with vitamin D deficiency in whom the serum calcium was low and the serum phosphorus was normal&#46; Albright logically but incorrectly thought that the problem was because the necessary compensatory increase in parathyroid function had not taken place<span class="elsevierStyleSup">62</span>&#46; Subsequently&#44; there continued to be reports of patients with vitamin D deficiency in whom hypocalcemia was accompanied by normal or even high serum phosphorus values<span class="elsevierStyleSup">40</span><span class="elsevierStyleSup">&#44;</span><span class="elsevierStyleSup">63-</span><span class="elsevierStyleSup">65</span>&#46; In 1985&#44; Rao et al established that the hypocalcemia associated with vitamin D depletion can impair the phosphaturic response to PTH despite an appropriately increased nephrogenous cyclic AMP response<span class="elsevierStyleSup">66</span>&#46; Correction of hypocalcemia with vitamin D and calcium treatment restored the phosphaturic response to PTH despite a reduction in nephrogenous cyclic AMP&#46; Thus&#44; these patients had an acquired form of pseudohypoparathyroidism type II&#44; which was subsequently shown to be from a postreceptor G protein defect<span class="elsevierStyleSup">67</span>&#46; In the opinion of the authors&#44; another possibility which should be evaluated is that the vitamin D deficiency and the hypocalcemia combine to impair FGF23 production<span class="elsevierStyleSup">22-25</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">1941&#46; Immobilization and Hypercalcemia</span></p><p class="elsevierStylePara">Albright reported the case of a 14 year old boy who in an athletic injury&#44; fractured his right femur at the site of a bone cyst<span class="elsevierStyleSup">68</span>&#46; After an open reduction&#44; the boy was placed in a spica cast immobilizing him from the waist down&#46; Shortly thereafter anorexia and vomiting developed&#46; Because the presence of the bone cyst raised the possibility of primary hyperparathyroidism&#44; serum calcium was measured and found to be 14&#46;6 mg&#47;dl with a serum phosphorus of 4&#46;5 mg&#47;dl&#46; Mild renal insufficiency also developed&#46; Because of the persistent hypercalcemia&#44; the boy underwent a parathyroid exploration at which only normal parathyroid glands were identified&#46; Six weeks later because of persistent hypercalemia&#44; the anterior mediastinum was explored but no parathyroid tissue was identified&#46; Once the patient was mobilized&#44; the serum calcium decreased to normal values&#46; Albright concluded that the sequence of events was&#58; <span class="elsevierStyleItalic">a&#41;</span> solitary bone cyst&#59; <span class="elsevierStyleItalic">b&#41;</span> fracture through cyst&#59; <span class="elsevierStyleItalic">c&#41;</span> immobilization of a large part of a previously active skeleton&#59; <span class="elsevierStyleItalic">d&#41;</span> osteoporosis from disuse with an excess of calcium from bone being presented to the kidney&#59; <span class="elsevierStyleItalic">e&#41;</span> an inability of the kidney to excrete promptly all the calcium&#59; <span class="elsevierStyleItalic">f&#41;</span> resulting in hypercalcemia&#59; and <span class="elsevierStyleItalic">g&#41;</span> kidney damage from excess of calcium being excreted through the kidney&#46; Albright further added that once renal insufficiency developed&#44; it probably increased the tendency to hypercalcemia&#46; From this case&#44; Albright learned that immobilization of an individual with active skeletal remodeling increases calcium efflux from bone and he also recognized that a decreased glomerular filtration rate reduces the capacity to excrete calcium&#44; which in turn&#44; exacerbates hypercalcemia&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara">In the late 1920s&#44; Albright joined Joseph Aub and Walter Bauer to pursue studies of calcium and phosphorus metabolism&#46; First Aub and then Bauer were appointed to academic positions in other subspecialties at Harvard&#44; which by 1930 left the young Albright as the primary investigator of calcium and phosphorus metabolism in Boston&#46; Through inductive reasoning&#44; which has been defined by the late Jacob Bronowski as that unpredictable blend of speculation and insight&#44; Albright came to recognize in normal volunteers and in hypo- and hyperparathyroid patients&#44; the presence of consistent patterns of response for calcium and phosphorus metabolism&#46; Fuller Albright was truly the first person to establish a sense of order out of the existing chaos in the new field of calcium and phosphorus metabolism&#46; As one of the 20<span class="elsevierStyleSup">th</span> century&#8217;s preeminent philosophers of science&#44; Karl Popper has stated&#44; &#34;Science does not rest upon rock-bottom&#46; The bold structure of its theories rises&#44; as it were&#44; above a swamp&#44; but not down to any natural or given base&#59; and when we cease our attempts to drive our piles into a deeper layer&#44; it is not because we have reached firm ground&#46; We simply stop when we are satisfied that they are firm enough to carry the structure&#44; at least for the time being&#34;&#46; Albright was the first to establish a functional system which explained calcium and phosphorus metabolism&#46; His classic book&#44; <span class="elsevierStyleItalic">The Parathyroid Glands and Metabolic Bone Disease</span>&#44; published in 1948&#44; became the standard reference for a generation of students of calcium and phosphorus metabolism&#46; Albright trained many future investigators and became an inspiration for the next generation of clinical investigators studying calcium and phosphorus disorders&#46; As the importance of translational research is again rightfully being emphasized&#44; the contributions of Fuller Albright should be recognized and he should be celebrated as a role model for a new generation of young clinical investigators&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11836&#95;en&#95;10774&#95;t1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11836_en_10774_t1.jpg" alt="A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before and after the development of renal impairment "></img></a></p><p class="elsevierStylePara">Table 1&#46; A comparison of the calcium and phosphorus metabolism of a patient with hyperparathyroidism before and after the development of renal impairment </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11837&#95;en&#95;10774&#95;t2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11837_en_10774_t2.jpg" alt="Comparison of two types of primary hyperparathyroidism based on a series analyzed by Lloyd"></img></a></p><p class="elsevierStylePara">Table 2&#46; Comparison of two types of primary hyperparathyroidism based on a series analyzed by Lloyd</p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11838&#95;en&#95;10774&#95;f1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11838_en_10774_f1.jpg" alt="Graphic representation of balance data&#46; "></img></a></p><p class="elsevierStylePara">Figure 1&#46; Graphic representation of balance data&#46; </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11839&#95;en&#95;10774&#95;f2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11839_en_10774_f2.jpg" alt="Effect of parathyroid extract on urinary calcium and phosphorus excretion in a patient with idiopathic hypoparathyroidism&#46; "></img></a></p><p class="elsevierStylePara">Figure 2&#46; Effect of parathyroid extract on urinary calcium and phosphorus excretion in a patient with idiopathic hypoparathyroidism&#46; </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11840&#95;en&#95;10774&#95;f3&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11840_en_10774_f3.jpg" alt="Effect of a 48 hour calcium infusion with normalization of the serum calcium concentration on phosphate excretion in hypoparathyroid patients&#46; "></img></a></p><p class="elsevierStylePara">Figure 3&#46; Effect of a 48 hour calcium infusion with normalization of the serum calcium concentration on phosphate excretion in hypoparathyroid patients&#46; </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11841&#95;en&#95;10774&#95;f4&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11841_en_10774_f4.jpg" alt="The same patient before and after parathyroidectomy from original series of Albright&#46;"></img></a></p><p class="elsevierStylePara">Figure 4&#46; The same patient before and after parathyroidectomy from original series of Albright&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11842&#95;en&#95;10774&#95;f5&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11842_en_10774_f5.jpg" alt="Average preoperative serum calcium values of the first 35 patients with primary hyperparathyroidism from the Massachusetts General Hospital series&#46; "></img></a></p><p class="elsevierStylePara">Figure 5&#46; Average preoperative serum calcium values of the first 35 patients with primary hyperparathyroidism from the Massachusetts General Hospital series&#46; </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11843&#95;en&#95;10774&#95;f6&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11843_en_10774_f6.jpg" alt="Fall in serum calcium values after parathyroidectomy in 35 cases of primary hyperparathyroidism &#40;first demonstration of hungry bone syndrome&#41;&#46; "></img></a></p><p class="elsevierStylePara">Figure 6&#46; Fall in serum calcium values after parathyroidectomy in 35 cases of primary hyperparathyroidism &#40;first demonstration of hungry bone syndrome&#41;&#46; </p><p class="elsevierStylePara"><a href="grande&#47;10774&#95;108&#95;11844&#95;en&#95;10774&#95;f7&#46;jpg" class="elsevierStyleCrossRefs"><img src="10774_108_11844_en_10774_f7.jpg" alt="A global view of vitamin D levels and the magnitude of hyperparathyroidism as determined by the elevation in PTH&#46; "></img></a></p><p class="elsevierStylePara">Figure 7&#46; A global view of vitamin D levels and the magnitude of hyperparathyroidism as determined by the elevation in PTH&#46; </p>"
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        "resumen" => "<p class="elsevierStylePara">The major contributions of Fuller Albright to our understanding of calcium and phosphorus regulation and primary hyperparathyroidism are highlighted&#46; Albright was the first investigator to initiate a systematic study of mineral metabolism&#46; With resources limited to the measurement of serum calcium and phosphorus and the infusion of parathyroid extract&#44; Albright used balance studies to establish a framework for our understanding of calcium and phosphorus regulation and primary hyperparathyroidism&#46; Albright was the first to show that the etiology of primary hyperparathyroidism could be from either an adenoma or hyperplasia of the parathyroid glands and stone disease was a separate manifestation of primary hyperparathyroidism&#46; Albright also showed that&#58; <span class="elsevierStyleItalic">1&#41;</span> a renal threshold for calcium excretion was present in hypoparathyroid patients&#59; <span class="elsevierStyleItalic">2&#41;</span> correction of hypocalcemia in hypoparathyroid patients with vitamin D had a phosphaturic action&#59; <span class="elsevierStyleItalic">3&#41;</span> renal failure reduced the intestinal absorption of calcium in primary hyperparathyroidism&#59; <span class="elsevierStyleItalic">4&#41;</span> the &#171;hungry bone&#187; syndrome developed after parathyroidectomy in severe primary hyperparathyroidism&#59; and <span class="elsevierStyleItalic">5&#41;</span> a target organ can fail to respond to a hormone&#46; He also suggested that a malignant tumor could be responsible for ectopic hormone production&#46; Finally&#44; our review integrates the observations of Albright with our current knowledge of calcium regulation and disorders&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2011.Mar.10774

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Year/Month	Html	Pdf	Total

2024 October	63	32	95
2024 September	80	35	115
2024 August	84	65	149
2024 July	80	39	119
2024 June	99	46	145
2024 May	92	45	137
2024 April	87	34	121
2024 March	77	24	101
2024 February	71	40	111
2024 January	60	27	87
2023 December	70	33	103
2023 November	64	36	100
2023 October	55	39	94
2023 September	78	35	113
2023 August	65	24	89
2023 July	90	24	114
2023 June	62	20	82
2023 May	82	38	120
2023 April	51	15	66
2023 March	72	27	99
2023 February	75	17	92
2023 January	69	29	98
2022 December	89	35	124
2022 November	80	36	116
2022 October	83	46	129
2022 September	68	39	107
2022 August	76	46	122
2022 July	74	51	125
2022 June	61	40	101
2022 May	96	30	126
2022 April	157	50	207
2022 March	141	64	205
2022 February	62	49	111
2022 January	94	34	128
2021 December	80	44	124
2021 November	88	39	127
2021 October	51	47	98
2021 September	42	39	81
2021 August	91	31	122
2021 July	88	39	127
2021 June	99	23	122
2021 May	93	39	132
2021 April	232	101	333
2021 March	138	42	180
2021 February	109	29	138
2021 January	80	20	100
2020 December	76	22	98
2020 November	68	20	88
2020 October	53	15	68
2020 September	52	15	67
2020 August	50	16	66
2020 July	58	10	68
2020 June	61	14	75
2020 May	58	14	72
2020 April	38	20	58
2020 March	67	13	80
2020 February	63	30	93
2020 January	69	17	86
2019 December	80	15	95
2019 November	69	20	89
2019 October	56	25	81
2019 September	88	24	112
2019 August	65	8	73
2019 July	61	19	80
2019 June	64	18	82
2019 May	73	4	77
2019 April	73	32	105
2019 March	53	24	77
2019 February	41	14	55
2019 January	63	27	90
2018 December	142	30	172
2018 November	128	16	144
2018 October	119	13	132
2018 September	118	15	133
2018 August	93	15	108
2018 July	93	14	107
2018 June	77	12	89
2018 May	89	14	103
2018 April	68	10	78
2018 March	88	14	102
2018 February	55	10	65
2018 January	74	7	81
2017 December	70	9	79
2017 November	73	5	78
2017 October	72	9	81
2017 September	64	12	76
2017 August	42	11	53
2017 July	55	19	74
2017 June	59	13	72
2017 May	62	9	71
2017 April	60	13	73
2017 March	64	19	83
2017 February	92	11	103
2017 January	33	6	39
2016 December	64	4	68
2016 November	70	13	83
2016 October	145	7	152
2016 September	194	10	204
2016 August	210	12	222
2016 July	189	12	201
2016 June	163	0	163
2016 May	132	0	132
2016 April	103	0	103
2016 March	84	0	84
2016 February	103	0	103
2016 January	108	0	108
2015 December	109	0	109
2015 November	97	0	97
2015 October	81	0	81
2015 September	121	0	121
2015 August	85	0	85
2015 July	69	0	69
2015 June	35	0	35
2015 May	53	0	53
2015 April	6	0	6

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