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PERSISTENT hypercalcemia is frequently associated with widespread metastatic calcification, most commonly in the kidneys, lungs, gastric mucosa, and blood vessels. This selective localization is believed to be due to unique physiological factors. Major pathological alterations in the function of these tissues may be expected to alter the distribution of calcium salt deposition. We are reporting a case in which nephrocalcinosis was largely confined to one kidney. It is our opinion that differences in the state of tubular glomerular function are responsible for this differential localization of calcium. Report of a Case A 51-year-old man was admitted to the New York Veterans Administration Hospital in August 1973 because of weight loss and pain in the lower back and left thigh, of several months' duration. Transurethral resections on two occasions and finally a partial cystectomy in September 1972 were performed for a transitional cell carcinoma of the urinary bladder diagnosed by cystoscopic

Vascular calcification in chronic renal failure and dialysis patients is well-documented and generally considered to be a consequence of decreased phosphorus excretion, secondary hyperparathyroidism, and increased calcium-phosphorus product. Following renal transplantation or parathyroidectomy, gradual resolution of metastatic calcification in the affected areas occurs. The case presented documents the consequence of secondary hyperparathyroidism with calcification of mammary vessels leading to severe breast pain with resolution of the pain and vessel calcification after renal transplantation. (Arch Intern Med137:375-377, 1977)

Two patients who had hypercalcemia, one from multiple myeloma and the other from metastatic carcinoma, showed striking concentrations of bone-seeking radiopharmaceuticals in the lungs on routine bone scans. Neither patient had roentgenographic evidence of intrapulmonary calcification. Histologic examination in one patient showed extensive interstitial pulmonary calcification. These cases dramatically illustrate the capability of radionuclides to detect interstitial pulmonary calcification when radiographic demonstration is lacking. The early detection of extraskeletal calcification by bone-seeking radionuclides provides a unique opportunity, not previously available, to study metastatic calcification and the effects of treatment. (JAMA230:992-995, 1974)

Diffuse interstitial pulmonary calcification (DIPC)—an unusual complication of several diseases including sarcoidosis, varicella, carcinomatosis, multiple myeloma, primary hyperparathyroidism, chronic renal disease with uremia, the "milk-alkali" syndrome—develops by either metastatic or dystrophic calcification. Metastatic calcification occurs in most hypercalcemic states, and the calcium deposits in normal visceral tissues, such as the lungs, kidneys, stomach, heart, and blood vessels. Dystrophic calcification, on the other hand, develops at normal serum calcium concentrations, and the calcium deposits in pathologic tissues, possibly by the phenomenon of calciphylaxis. The symptoms and signs of DIPC are completely nonspecific and vary depending on the stage and progression of the disease. Once induced, the calcium continues to deposit in the alveolar septa of the lung and frequently incites the development of interstitial fibrosis. This may lead to restrictive lung dysfunction and mechanically stiff lungs. The clinical expressions of DIPC are frequently masked by the manifestations of the primary disease

THE PRESENCE of calcification in soft tissues and its radiological appearance may aid in the diagnosis and treatment of certain systemic disorders. When the soft-tissue calcification occurs with an elevated serum calcium-phosphorus ion product, it is termedmetastatic calcification. In these patients, amorphous calcium phosphate and calcium hydroxyapatite crystals are deposited in multiple locations. The appearance of metastatic calcification is typical but not disease specific. Microscopically, the deposition of calcium salts may be observed in the lung, stomach, and kidney. Vascular calcification is also present, as are large, periarticular soft-tissue masses. When soft-tissue calcification occurs in altered, necrotic, or dead tissue in patients whose serum calcium and phosphorus levels are normal, it is calleddystrophic calcification, which is influenced by multiple physiological factors. These include serum calcium, phosphorus and alkaline phosphatase,pH of the tissue, vitamin D, hormonal balance, blood supply, and injury of soft tissues.1 Metastatic Calcification

In Reply.— Whether or not hypertension and an elevated calcium-phosphate product are truly independent risk factors for cardiovascular disease in hemodialysis patients is a point fairly made. It is apparent that patients who are hypertensive are also more likely to have an elevated calcium-phosphate product, because they are noncompliant. That these factors are otherwise connected is unlikely. Even if hypertension in azotemic patients is controlled by drug therapy, failure to take unpalatable and constipating phosphate binders could still permit a sustained elevated product and metastatic calcification. When present together in the same patient, the negative effect on the cardiovascular system may be synergistic. Related to hypertension or not, an elevated calcium-phosphate product is certainly abnormal, and the lack of any statistical correlation with pathological damage should not preempt vigorous attempts at controlling this abnormality or any others when nontoxic therapy is available. Nephrologists are aware that the control of these

Several instances of high potency vitamin D ("ertron") intoxication have been published lately in the medical literature; all patients recovered except 1 infant, who died and whose postmortem findings showed calcification in the renal tubules. 1 To our knowledge the case which we report is the first in which death followed the long-continued use of this preparation by an adult and in which autopsy confirmed the diagnosis of vitamin D intoxication. The case is reported because it further proves the danger of high doses of vitamin D and of the regrettable practice of noncontrolled self medication with some of the vitamins, and because it disproves the unwarranted claim of harmlessness made by some of the manufacturers of high potency vitamin D preparations. REPORT OF A CASE First Admission.— A woman aged 63 was admitted to Goldwater Memorial Hospital Dec. 28, 1942. She was badly crippled by a rheumatoid arthritis of thirteen

METASTATIC calcification may be defined as a deposition of calcium or calcium salts in abnormal locations in the body. This manifestation is quite uncommon in children and is especially unusual in the newborn. The occurrence of the condition in a young infant, in association with congenital anomalies of the gastrointestinal and urinary systems, makes it worthy of presentation. REPORT OF A CASE B. K., a white boy, was born on Aug. 17, 1949, to a 35-yr.-old mother and a 38-yr.-old father. Both parents had always been in good health. The mother was pentagravida, tetrapara, and had had no miscarriages. Her Mazzini reaction was negative. All previous pregnancies and deliveries were normal. The present pregnancy was uneventful. The delivery was normal and spontaneous, and the infant weighed 8 lb. 6 oz. (3,800 gm.) at birth. Shortly after admission to the nursery it was noted that he had an atresia of the

Since Mandl's dramatic demonstration1that osteitis fibrosa can be relieved by the removal of a parathyroid adenoma, an extensive literature has appeared on hyperparathyroidism. The concept that in some cases hypertrophy of the parathyroid glands and osteitis fibrosa are secondary to chronic renal insufficiency is well established.2The close similarity between adult renal hyperparathyroidism and the renal rickets of late childhood and adolescence has been appreciated more recently.3Both diseases are characterized by prolonged severe renal insufficiency, alterations in the calcium and phosphorus content of the blood and an increase in the urinary excretion of both substances, hypertrophy of the parathyroid glands, metastatic calcification and abnormalities in the bones. Renal rickets differs from adult renal hyperparathyroidism in the age at which it occurs, the fact that the renal insufficiency is usually due to a congenital anomaly and the greater variation in the appearance of the osseous lesions.

We have recently suggested that inorganic pyrophosphate may be a physiological inhibitor of calcification in soft tissues and a physiological regulator of calcium homeostasis through its effect on the formation and destruction of mineralized tissues.1-6This communication is concerned with the possible role of pyrophosphate in the metastatic calcification and bone disease associated with renal failure. Mineralization in General Very little is known of the mechanisms responsible for the deposition of calcium salts at normal or abnormal sites within the body. In recent years some clarification has come from studies on the mechanism of precipitation in vitro. It is now established that the concentrations of calcium and phosphate in plasma, extracellular fluid, and even in fluid withdrawn from calcifying cartilage7are much lower than those required to form crystals in vitro.1,8The formation of apatite crystals in vivo therefore requires some local promoting mechanism at the site

The condition in which calcium salts are deposited in the skin and subcutaneous tissue is referred to as calcinosis cutis. This article contains a report of two cases of the idiopathic form of that disease plus the conclusions drawn from a study of sixteen additional cases taken for the most part from the available English and American literature. 1 The first of the two patients whose cases are reported was observed by Piersall in 1929, and his findings at that time were recorded. 1a In preparing this paper, every attempt was made to exclude cases of myositis ossificans, osteoma of the skin, phlebolith, calcified tumor, atheroma, cyst, hematoma or tuberculous lesion and cases in which parasites (Trichinella, Filaria, etc.) were present in the tissues. Examples of metastatic calcification, as in osteomyelitis, metastatic malignant growth and parathyroid adenoma, were also omitted. Cases in which the disease was associated with scleroderma

To the Editor.— Metastatic calcification occurs in patients with hypercalcemia of diverse etiologies. Ectopic calcification has been documented in patients with long-standing hypercalcemia without specific treatment and in patients with hypercalcemia who have been receiving prolonged phosphate therapy. However, the exact mechanism of pathogenesis of metastatic calcification is not yet clear. A working hypothesis has been proposed based on animal and human data (Lancet 1:590,1972; Chest 61:190, 1972). The hypothesis in essence tells that under normal conditions, the body keeps the serum calcium and phosphorus level in homeostasis so that their solubility product does not exceed the point beyond which they exist in solid phase. Whenever there is imbalance of serum calcium or phosphorus, or both, the solubility product of calcium phosphate is exceeded beyond the normal value (about 2.6 × 10-30) resulting in formation of colloidal particles of calcium phosphate in the blood (J Nucl Med 12:347,1971). These

The association between soft-tissue calcification (STC) and uremia has been recognized for more than 100 years, 1 but it is only since the widespread use of regular dialysis and transplantation that this has become an important problem. 2 Virchow 1 surmised that calcium salts dissolved from bone were carried in the blood and deposited at some distant site to form "calcium metastases," a process analogous to the dissemination of cells from a primary neoplasm. In a review of 88 patients, " the underlying cause of metastatic calcification was nonmetabolic bone disease in 35, uremia in 23, primary hyperparathyroidism in 21, and vitamin D intoxication in 9. The lesions typically occur in the kidneys, stomach, lungs, and the left side of the heart, supposedly because of relative local alkalinity. 4 The essential feature of metastatic calcification is its occurrence in previously normal tissue exposed to an abnormal chemical environment, in contrast to dystrophic calcification which occurs in

Multiple miliary osteomas of the skin are seldom clinically diagnosed, but are usually identified only after histologic examination. Because they are rare, another case is reported. A 67-year-old woman had multiple flesh-colored papular lesions scattered over her face. Histologic examination disclosed some areas of mature bone with no direct connection with skin appendages. No systemic disease associated with metastatic calcification was detected. There was no history or evidence of any skin disease prior to the development of the osteomas. A short discussion of the pathogenesis is given. The mechanism of extraskeletal bone formation is unknown. It is hard to decide if these osteomas are primary heterotopic or secondary metaplastic ossifications.

There have been many excellent reports on the demineralization of bone in association with chronic diffuse nephritis (renal rickets), but the condition is still imperfectly understood. To quote Hunter,1"the theory that phosphate retention, due to the renal defect, is primarily responsible for the changes in the bones is clearly unsatisfactory." The dwarfing, polyuria and polydipsia, which are not infrequent and which strongly suggest an endocrine factor, are likewise unexplained. A lemon yellow tint to the skin, anemia and weakness of the musculature are commonly associated with chronic nephritis, but these conditions are also found in hyperparathyroidism. The case summarized in the following report is of interest because of the opportunity it afforded to study some of the metabolic and pathologic factors in detail. REPORT OF A CASE History.—D. R., a boy aged 14 years, was referred to the pediatric service in April 1932 with the following history

Although hypercalcemia is a frequent complication of neoplastic disease, 1-4 extensive extraskeletal calcification has been described only rarely. 5 Recently, inorganic phosphate therapy has been reported to lower serum calcium levels effectively and rapidly in hypercalcemic patients; its mechanism of action has not been well established. We have studied a patient with disseminated carcinoma and hypercalcemia who was treated with inorganic phosphate and who at postmortem examination demonstrated extensive soft tissue calcification. Because the degree of metastatic calcification was extreme and occurred following repeated phosphate administration, we are reporting this case. Patient Summary A 40-year-old white restaurant owner was admitted to the Massachusetts General Hospital on Oct 2, 1966, because of an enlarging painless leftsided neck mass first noted a month previously. In the week prior to admission, he had developed weakness, malaise, and occasional feverishness. Three days prior to admission, the patient had a serum calcium of 10.7 mg/

Skin necrosis occurred in a patient with osteolytic metastatic breast cancer and hypercalcemia. Metastatic calcification of the media of dermal and subcutaneous arterioles was demonstrated histopathologically. Sixteen cases of metastatic calcification with skin necrosis reported in other publications were reviewed. The present case appears to be the first in which metastatic calcification with skin necrosis occurred in the absence of chronic renal disease or hyperparathyroidism.