Urinary hydroxyproline: Urinary hydroxyproline excretion reflects the degradation of bone collagen, but is also influenced by the metabolism of other tissues (cartilage, skin) and by the absorption of products rich in collagen, such as meat or gelatins. Due to its diverse tissue origin and metabolic pattern, it correlates poorly with bone resorption.

In a routine workup of a 59-year-old woman, a smoker of 20 cigarettes/day for 25 years, hypercalcemia of 11.3 mg/dL with a phosphorus of 3.4 mg/dL is detected. It would NOT be efficient at the outset:

Hypercalcemia -- Evaluation

Most cases of hypercalcemia are detected on routine testing. Work up for etiology includes obtaining serum PTH, calcitonin, Vitamin D, ionized calcium, phosphorus, magnesium, alkaline phosphatase levels, renal functions, and urinary calcium-creatinine ratio. Sensitive and specific immunochemiluminometric assays should be used to measure parathyroid hormone (PTH) (i-PTH). Hyperparathyroidism is characterized by high calcium, high i-PTH levels with low phosphorous levels. Familial hypocalciuric hypercalcemia has inappropriately normal PTH levels with high magnesium and low calcium creatinine clearance. Other causes of hypercalcemia typically have low PTH levels. Patients with hypercalcemia and hypervitaminosis D have high serum concentrations of calcidiol, whereas, patients with a granulomatous disease have high levels of calcitriol. In patients with hypercalcemia associated with malignancy, the PTH-related peptide levels are elevated. Imaging is indicated to identify nephrolithiasis and nephrocalcinosis. Neonates and infants who are found to be hypercalcemic in the presence of dysmorphic features should prompt evaluation for Williams or Murk Jansen syndrome. [1] [7]

Milk-alkali syndrome

Serum calcium levels: high serum calcium levels. PTH: low serum PTH levels are indicative of MAS. Low serum PTH levels also exclude primary hyperthyroidism. Phosphorus: low serum phosphorus levels due to low PTH. Creatinine and BUN: high levels can indicate severity of renal damage. Magnesium: serum magnesium levels are low as hypercalcemia inhibits mg^2+ reabsorption in the renal tubules. Vitamin D levels: low vitamin D levels are found. Normal vitamin D levels eliminate primary hypercalcemia. Electrocardiograms (ECG): An ECG can also be used to diagnose MAS. The following findings related to hypercalcemia could appear on an ECG: Short QT interval: most commonly seen as short OoT or OaT changes. Prolongation of PR and QRS intervals. Increased Amplitude of QRS complex. Osborn wave Short ST segment. Radiology: Chest x-rays can help exclude any malignancy or sarcoidosis when evaluating for hypercalcemia.

Hypocalcemia -- Evaluation

Confirmation of hypocalcemia: The first part of the evaluation should focus on confirming the hypocalcemia by checking a serum albumin level to correct the total calcium or directly measuring the ionized calcium level. For each 1 g/dL decrease in albumin below 4 g/dl, 0.8 mg/dL should be added to the total serum calcium level. Checking cardiac stability: An ECG should be obtained to look for QTc prolongation, which, if present, is a risk factor for torsades de pointes. This is often treated with IV magnesium. [31] Determining the etiology of hypocalcemia: Once hypocalcemia is confirmed, further testing should be done to determine the etiology. This entails checking other electrolytes, such as serum magnesium and phosphorus levels, intact PTH, and vitamin D levels. Some causes are apparent, as in patients post-thyroidectomy or parathyroidectomy. Other biomarkers may be obtained as indicated by history and physical exam (eg, serum lipase in suspected pancreatitis.)

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In addition to measuring serum calcium, it is useful to determine albumin, phosphorus, and magnesium levels. As for the evaluation of hypercalcemia, determining the PTH level is central to the evaluation of hypocalcemia. A suppressed (or “inappropriately low”) PTH level in the setting of hypocalcemia establishes absent or reduced PTH secretion (hypoparathyroidism) as the cause of the hypocalcemia. Further history will often elicit the underlying cause (i.e., parathyroid agenesis vs. destruction). By contrast, an elevated PTH level (secondary hyperparathyroidism) should direct attention to the vitamin D axis as the cause of the hypocalcemia. Nutritional vitamin D deficiency is best assessed by obtaining serum 25-hydroxyvitamin D levels, which reflect vitamin D stores. In the setting of renal insufficiency or suspected vitamin D resistance, serum 1,25(OH)2D levels are informative.

Physiology, Calcium -- Clinical Significance -- Diagnosis

The diagnosis of hypocalcemia is first achieved by measuring serum albumin, which distinguishes true hypocalcemia from factitious hypocalcemia due to hypoalbuminemia. If albumin is normal, PTH levels should be checked to determine if the hypocalcemia is due to a disorder of PTH such as hypoparathyroidism leading to rapid hypocalcemia known as a hungry bone syndrome. If PTH levels are normal, then magnesium, vitamin D, and phosphate levels can be checked to determine if calcium levels are being affected by other electrolyte abnormalities. It is always a good idea to check kidney and liver function to determine an end-organ cause of hypocalcemia. Equally, an electrocardiogram should be ordered to assess for the effect of hypocalcemia on the heart. Radiography is often indicated to determine the etiology of chronic hypocalcemia due to disorders such as rickets or osteomalacia.

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Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases in PTH are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/ serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when

Prevalence of hypercalcemia related to hypervitaminosis D in clinical practice.

Recent interest in vitamin D has led to a substantial increase in the use of vitamin D supplements. Vitamin D intoxication may be a concern as hypervitaminosis D can result in irreversible calcification of soft tissues so that it is important to detect early markers of vitamin D intoxication. Our aim was to assess the simultaneous presence of biochemical markers of vitamin D toxicity (i.e. hypervitaminosis D, hypercalcemia) and determine the concentrations of 25-OH-vitamin D at which the risk of hypercalcemia, and thus toxicity, might begin. We evaluated retrospectively a 6-year period during which 25.567 samples were assessed for 25-OH-vitamin D status by UHPLC. Hypervitaminosis D was defined at serum 25-OH-vitamin D >160 nmol/L. Serum and urine calcium, phosphorus and iPTH were also recorded, if available. Medical history revision was performed in subjects displaying simultaneously hypervitaminosis D and hypercalcemia. Overall, hypervitaminosis D was found in 475 samples (1.86%) of which 51 displayed hypercalcemia (11.1%). A total of 382 samples were identified as the first record of hypervitaminosis D and 39 presented hypercalcemia (10.2%), most of them at 25-OH-vitamin D levels between 161 and 375 nmol/L. Only in 15 subjects, hypercalcemia could be directly attributed to vitamin D and serum 25-OH-vitamin D ranged between 164 and 1139 nmol/l. In no case, serum calcium achieved concentrations considered as critical values (>13 mg/dl). Hypercalcemia due to vitamin D represented <4% of the total hypervitaminosis D detected and <0.1% of the tests performed. However, a highly variable response was observed and most subjects presented hypercalcemia at serum concentrations of 25-OH-vitamin D < 375 nmol/L.

Hypoparathyroidism -- Evaluation

Evaluation should include the following tests: Total calcium Albumin Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin, and only the free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin) (calcium measured in mg/dL; albumin measured in g/L) Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium Parathyroid hormone level Phosphorus Blood urea nitrogen (BUN) and creatinine Alkaline phosphatase 25-hydroxyvitamin D Urine calcium and creatinine Electrocardiogram [2] [3]

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Diagnosis of Vitamin D Deficiency, Rickets, and Osteomalacia The most specific screening test for vitamin D deficiency in otherwise healthy individuals is a serum 25(OH)D level. Although the normal ranges vary, levels of 25(OH)D <37 nmol/L (<15 ng/mL) are associated with increasing PTH levels and lower bone density. The Institute of Medicine has defined vitamin D sufficiency as a vitamin D level >50 nmol/L (>20 ng/mL), although higher levels may be required to 2466 optimize intestinal calcium absorption in the elderly and those with underlying disease states. Vitamin D deficiency leads to impaired intestinal absorption of calcium, resulting in decreased serum total and ionized calcium values. This hypocalcemia results in secondary hyperparathyroidism, a homeostatic response that initially maintains serum calcium levels at the expense of the skeleton. Due to the PTH-induced increase in bone turnover, alkaline phosphatase levels are often increased. In addition to increasing bone

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Laboratory Evaluation If not recently measured, the following serum levels should be determined: electrolytes (to uncover hypokalemia or renal tubular acidosis), creatinine, calcium, and uric acid. The PTH level should be measured if indicated by high-normal or elevated serum and urine calcium concentrations. Often, 25-hydroxy vitamin D is measured in concert with PTH to investigate the possible role of secondarily elevated PTH levels in the setting of vitamin D insufficiency. The urinalysis, including examination of the sediment, can provide useful information. In individuals with asymptomatic residual renal stones, red and white blood cells are frequently present in urine. If there is concern about the possibility of an infection, a urine culture should be performed. The sediment may also reveal crystals (Fig. 342-1), which may help identify the stone type and also provide prognostic information, as crystalluria is a strong risk factor for new stone formation.

X-linked hypophosphatemia

Diagnosis Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range. Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with that for adults (2.7-4.5 mg/dL). Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range. The renal tubular reabsorption of phosphate (TRP) in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula:

Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is an inherited condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day. Signs and symptoms Most cases of familial hypocalciuric hypercalcemia are asymptomatic. Laboratory signs of FHH include: High blood levels of calcium (hypercalcemia) A low amount of calcium excreted in the urine ( Ca excretion rate < 0.02 mmol/L) High blood levels of magnesium (hypermagnesemia) High normal to mildly elevated parathyroid hormone Causes Types include:

Persistent Primary Hyperparathyroidism, Severe Vitamin D Deficiency, and Multiple Pathological Fractures.

Persistent primary hyperparathyroidism (PHPT) refers to the sustained hypercalcemia state detected within the first six months following parathyroidectomy. When it coexists with severe vitamin D deficiency, the effects on bone can be devastating. We report the case of a 56-year-old woman who was sent to this center because of persistent hyperparathyroidism. Her disease had over 3 years of evolution with nephrolithiasis and hip fracture. Parathyroidectomy was performed in her local unit; however, she continued with hypercalcemia, bone pain, and pathological fractures. On admission, the patient was bedridden with multiple deformations by fractures in thoracic and pelvic members. Blood pressure was 100/80, heart rate was 86 per minute, and body mass index was 19 kg/m(2). Calcium was 14 mg/dL, parathormone 1648 pg/mL, phosphorus 2.3 mg/dL, creatinine 2.4 mg/dL, urea 59 mg/dL, alkaline phosphatase 1580 U/L, and vitamin D 4 ng/mL. She received parenteral treatment of hypercalcemia and replenishment of vitamin D. The second surgical exploration was radioguided by gamma probe. A retroesophageal adenoma of 4 cm was resected. Conclusion. Persistent hyperparathyroidism with severe vitamin D deficiency can cause catastrophic skeletal bone softening and fractures.

Primary Hyperparathyroidism -- Evaluation

Patients on known hypercalcemic drugs, such as lithium and thiazide, should have these medications stopped for 3 to 6 months, if possible, and their serum calcium & parathyroid hormone levels retested. Patients with low vitamin D levels should receive supplements to maintain at least 30 mg/mL. If parathyroid hormone levels are still elevated, this suggests hyperparathyroidism. Familial hypocalciuric hypercalcemia can be excluded by a 24-hour urine calcium determination (<100 mg calcium/24  hours) or by a low calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] typically <0.02. [88] It may present as early as age 30 and virtually never after age 50. [88] [89]

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patients have suppressed 1,25(OH)2D. Measurement of 1,25(OH)2D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis and certain lymphomas. A useful general approach is outlined in Fig. 424-6. If the patient is asymptomatic and there is evidence of chronicity to the hypercalcemia, hyperparathyroidism is almost certainly the cause. If PTH levels (usually measured at least twice) are elevated, the clinical impression is confirmed and little additional evaluation is necessary. If there is only a short history or no data as to the duration of the hypercalcemia, occult malignancy must be considered; if the PTH levels are not elevated, then a thorough workup must be undertaken for malignancy, including chest x-ray, CT of chest and abdomen, and bone scan. Immunoassays for PTHrP may be especially useful in such situations. Attention should also be paid to clues for underlying hematologic disorders such as anemia, increased plasma globulin, and abnormal

Vitamin D deficiency

Diagnosis The serum concentration of calcifediol, also called 25-hydroxyvitamin D (abbreviated 25(OH)D), is typically used to determine vitamin D status. Most vitamin D is converted to 25(OH)D in the serum, giving an accurate picture of vitamin D status. The level of serum 1,25(OH)D is not usually used to determine vitamin D status because it often is regulated by other hormones in the body such as parathyroid hormone. The levels of 1,25(OH)D can remain normal even when a person may be vitamin D deficient. Serum level of 25(OH)D is the laboratory test ordered to indicate whether or not a person has vitamin D deficiency or insufficiency. It is also considered reasonable to treat at-risk persons with vitamin D supplementation without checking the level of 25(OH)D in the serum, as vitamin D toxicity has only been rarely reported to occur.

[Cervical macroadenoma causing hyperparathyroidism: Report of one case].

We report a 59-year-old man with a history of hypertension, recurrent renal stones and a severe hypercalcemia of 14.9 mg/dl with a serum phosphorus of 2.4 mg/dl and a serum albumin of 3.6 g/dl. Physical examination showed a 4 cm left cervical nodule, consistent with the diagnosis of thyroid nodule. Parathyroid hormone (PTH) levels were 844 pg/mL (normal 15-65 pg/ml) and a cervical ultrasound examination disclosed a solid nodule in the lower left lobe of 40 x 30 x 25 mm, adjacent to the thyroid parenchyma. Abdominal ultrasound revealed bilateral renal stones. Parathyroid scintigraphy showed a high uptake of the left lower parathyroid mass and a bone densitometry showed bone density t scores of -1.2 in the spine, -2.0 in the right femoral neck and -3.5 in the distal radius. A review of his medical record revealed the presence of hypercalcemia for at least 4 years. He was admitted for hydration and administration of 4 mg zoledronic acid iv. At 24 hours, serum calcium dropped to 11.0 mg/dl, and a left thyroid lobectomy was performed including the lower left parathyroid gland. The pathology report showed a 22.6 g parathyroid adenoma. Intraoperatory PTH descended > 50%, consistent with successful parathyroidectomy. At 7 days after surgery serum calcium was 8.8 mg/dl, phosphorus 2.1 mg/dl, alkaline phosphatase 166 U/L, albumin 3.9 g/dL, PTH 230 pg/ml and 25-OH vitamin D 12.4 ng/ml. This finding was interpreted as secondary hyperparathyroidism due to vitamin D deficiency and "hungry bone", being less likely the presence of residual or metastatic parathyroid tissue. A cholecalciferol load was administered, with significant descent of PTH.

[Diagnostic evaluation and differential diagnosis of primary hyperparathyroidism].

Primary hyperparathyroidism (PHPT) is characterized by the autonomous production of parathyroid hormone (PTH), in which there is hypercalcemia or normal-high serum calcium levels, in the presence of elevated or inappropriately normal serum PTH concentrations. Exceptionally, in symptomatic patients, a diagnosis can be established on the basis of clinical data. PHPT must always be evaluated in patients with clinical histories of nephrolithiasis, nephrocalcinosis, osseous pain, subperiosteal resorption, and pathologic fractures, as well as in those with osteoporosis-osteopenia on dual-energy X-ray absorptiometry (DEXA), a personal history of neck irradiation, or a family history of multiple endocrine neoplasia syndrome (types 1 or 2). Diagnosis of PHPT is biochemical. Asymptomatic hypercalcemia (total serum calcium corrected by albumin), without guiding signs or symptoms, is the most frequent manifestation of the disease. For the differential diagnosis, PTH(1-84) must be measured, as well as phosphate, chloride, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and calcium-to-creatinine clearance. Suppressed or inappropriately low PTH1-84 guides the diagnose toward tumoral hypercalcemia and less frequently to granulomatous disease (sarcoidosis, tuberculosis, etc.), inadequate intake of 1alpha-hydroxyvitamin D or calcitriol, vitamin D or A intoxication, lithium intake, endocrinopathies (hyperthyroidism, Addison's disease, etc.) or treatment with thiazides, among other possibilities. Diagnosis of PHPT is confirmed by demonstrating persistent hypercalcemia (or normal-high serum calcium levels) in the presence of inappropriately normal or elevated serum PTH(1-84) concentrations, unless the urinary calcium-to-creatinine clearance ratio is lower than 0.01. In these cases, in the absence of thiazide intake or severe vitamin D deficiency, diagnosis should focus on benign familial hypercalcemic hypocalciuria. Parathyroid gland imaging is useful for localization of PHPT, but not for diagnosis of this entity.

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There is no established algorithm for the evaluation of women who present with osteoporosis. A general evaluation that includes complete blood count, serum and 24-h urine calcium, renal and hepatic function tests, and a 25(OH)D level is useful for identifying selected secondary causes of low bone mass, particularly for women with fractures or very low Z-scores. An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum calcium level may reflect malnutrition and osteomalacia. In the presence of hypercalcemia, a serum PTH level differentiates between hyperparathyroidism (PTH↑) and malignancy (PTH↓), and a high PTHrP level can help document the presence of humoral hypercalcemia of malignancy (Chap. 424). A low urine calcium (<50 mg/24 h) suggests osteomalacia, malnutrition, or malabsorption; a high urine calcium (>300 mg/24 h) is indicative of hypercalciuria and must be investigated further. Hypercalciuria occurs primarily in three situations: (1)

[Changes in mineral metabolism in stage 3, 4, and 5 chronic kidney disease (not on dialysis)].

With progression of chronic kidney disease (CKD), disorders of mineral metabolism appear. The classic sequence of events begins with a deficit of calcitriol synthesis and retention of phosphorus. As a result of this, serum calcium decreases and parathyroid hormone (PTH) is stimulated, producing in the bone the high turnover (HT) bone disease known as osteitis fibrosa while on the other extreme we find the forms of low turnover (LT) bone disease. Described later and initially associated with aluminum intoxication, these diseases are now seen primarily in older and/or diabetic patients, who in a uremic setting have relatively low levels of PTH to maintain normal bone turnover. Osteomalacia is also included in this group, which after the disappearance of aluminum intoxication is rarely observed. LT forms of hyperparathyroidism facilitate the exit of calcium (Ca) and phosphorus (P) from bone, whereas the adynamic bone limits the incorporation of Ca and P into bone tissue. Therefore, both forms facilitate the availability of Ca and P, which ends up being deposited in soft tissues such as arteries. The link between bone disease and vascular calcifications in CKD is now a well-established phenomenon. 2. Diagnostic strategies Calcium, Phosphorus They have little capacity to predict underlying bone disease, but their regular measurement is decisive for therapeutic management of the patient, especially in the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics. Ideally, Ca++ should be used, but total Ca is routinely used. It is recommended to adjust albumin levels in the event of hypoalbuminemia (for each g/dL of decrease in albumin, total serum Ca decreases 0.9 mg/dL). The following formula facilitates rapid calculation of corrected total calcium: Corrected total Ca (mg/dL) = total Ca (mg/dL) + 0.8 [4-albumina (g/dL)]. Parathyroid hormone "Intact" PTH is the biochemical parameter that best correlates with bone histology (levels measured with the Allegro assay from Nichols Institute Diagnostics, no longer available). Various assays are currently available that use antibodies against different fragments of the molecule, but they have significant intermethod variability and have not been validated. A whole PT assay (1-84) is currently unavailable. A consensus to establish uniform criteria for PTH measurement remains to be established. During the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics, more frequent measurement may be required based on clinical judgment. Calcifediol (25(OH)D3) It is important to maintain adequate levels of 25(OH)D3 (> 30 ng/mL), since they will be the substrate for production of 1- 25(OH)2 D3, and their deficiency aggravates hyperthyroidism. Determining 25(OH)D3 levels every 6-12 months is a recommended guideline. Other markers of bone turnover (osteocalcin, total and bone alkaline phosphate, free pyridolines in serum, and C-terminal telopeptide of collagen) do not improve the predictive power of PTH and therefore their systematic use is not justified. Radiologic studies Radiologic studies are of little diagnostic utility, because biochemical changes precede radiologic changes. Systematic radiologic evaluation of the skeleton in asymptomatic patients is not justified at present. They are useful as the first step in the study to detect vascular calcifications and amyloidosis due to b2-microglobulin and in symptomatic and at risk patients to detect vertebral fractures. Bone densitometry: Dual energy x-ray absorptiometry (DEXA) is the standard method to determine bone mineral density (usually in the femoral neck and vertebrae). It provides information on changes in bone mineral content, but not on the type of underlying bone disease. It is useful for follow-up of bone mass or for the study of bone mass changes in the same patient. Its value as a predictor of the risk of fracture has not been demonstrated in patients on kidney replacement therapy or with advanced chronic kidney disease. It is indicated in patients with fractures or risk factors for osteoporosis. Bone biopsy: The "gold standard" for diagnosis of bone disease. With improved knowledge of the value of noninvasive parameters, its use is infrequent. Pathological fractures in the presence or absence of minor trauma. Symptomatic patients in the presence of incongruent clinical parameters. A typical case is the presence of unexplained hypercalcemia from systemic disease, with inconclusive serum PTH values (between 120-450 pg/mL as an estimated range). Evaluation and follow-up of cardiovascular calcifications There are no consensuated clinical practice guidelines for the evaluation and follow-up of extraosseal calcifications in CKD. The clinical tools for evaluation and follow-up of cardiovascular disease are used based on clinical judgment. The periodicity of follow-up has not been established . 3. Recommended biochemical values The biochemical values recommended in clinical practice guidelines for the evaluation of bone mineral metabolism are summarized in Figure 3. The recommended PTH values do not fully coincide with the K/DOQI guidelines. The wide variability in PTH values depending on the assays used has led us to expand the recommended PTH range in stage 3 and 4 CKD. 4. Treatment 4.1. Diet. The recommended diet for the patient with CKD is traditionally based on protein restriction and phosphorus restriction for control of mineral metabolism. A favorable circumstance is that there is a close relationship between protein and phosphorus intake. In CKD stages 3, 4 and 5, it is recommended to restrict phosphorus intake to between 0.8-1 g/day when serum levels of phosphorus and PTH are above the recommended range. This is approximately equivalent to a diet of 50-60 g of protein. This reasonable antiproteinuric strategy that also restricts phosphorus intake is nutritionally safe. What should we tell them to eat? In a practical and oversimplified way, we recommend the following daily intake: Animal proteins: 1 serving (100-120 g), dairy products: 1 serving (equivalent to 200-240 mL of milk or 2 yoghourts), bread, cereals, pastas (1 cup of pasta, rice or legumes + some bread or cookies), vegetables and fruits relatively freely, but with moderation. 4.2. Medication Vitamin D supplements should be provided if serum levels are less than 30 ng/mL. In Spain, vitamin D3 (cholecalciferol) is marketed as Vitamin D3 Berenguer 2,000 IU/mL of solution. Combinations of calcium with cholecalciferol are also available. Most of the dosage forms contain approximately 500 mg of Ca+ and 400 IU of cholecalciferol. Alternatively, calcifediol (25(OH)D3), as Hidroferol 100 mcg/mL, has been used, although the dose range is very variable and has not been established. 4.3. Phosphorus binders. Use if hyperphosphatemia occurs. Start with calcium-containing phosphorus binders (calcium carbonate or calcium acetate), which also provide calcium if dietary intake is inadequate. Do not exceed 1.5 g of Ca++ per day. The most used are calcium carbonate and calcium acetate. Calcium acetate shows a similar binding potency to calcium carbonate but with a lesser calcium overload, and thus would have certain advantages as well as its greater effect at different pH ranges. However, gastric intolerance is more frequent with this dosage form. Aluminum hydroxide may sometimes be required to control phosphoremia or the occurrence of hypercalcemia. Serum aluminum values should be maintained below 30 mcg/L. Avoid use for longer than 6 months and daily doses greater than 1.5 g. Sevelamer is associated with an increased risk of acidosis and has not been approved for use in predialysis stages. Lanthanum carbonate has been recently marketed in Spain, although its indication for use in the predialysis stage of CKD is still not approved. 4.4. Vitamin D derivatives. Indicated when PTH levels are elevated. A prerequisite for their use is that Ca and P serum levels are adequately controlled. Vitamin D derivates available in Spain are 1,25(OH)2D3 (Calcitriol)and 1a(OH)D3 (a-Calcidiol). Doses should be titrated until PTH levels are normalized. Phosphate binder doses often need to be increased because these vitamin D derivatives increase intestinal absorption of calcium and phosphorus. Low doses do not cause hypercalcemia or hyperphosphatemia and do not worsen the course of renal function. Recommended doses: Calcitriol 0.25 mcg every 48 hours and alpha-Calcidiol 0.50 mcg every 48 hours. Soon to be available on the Spanish market is the oral dosage form of paricalcitol (recommended initial dose of 1 mcg/24 h), with a lesser hypercalcemic and hyperphosphoremic effect. Clinical use of calcimimetics in the predialysis state is not yet recommended and is currently under investigation.

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based on the double-antibody method for PTH exhibit very high sensitivity (especially if serum calcium is simultaneously evaluated) and specificity for the diagnosis of primary hyperparathyroidism (Fig. 424-4). In summary, PTH values are elevated in >90% of parathyroid-related causes of hypercalcemia, undetectable or low in malignancy-related hypercalcemia, and undetectable or normal in vitamin D– related and high-bone-turnover causes of hypercalcemia. In view of the specificity of the PTH immunoassay and the high frequency of hyperparathyroidism in hypercalcemic patients, it is cost-effective to measure the PTH level in all hypercalcemic patients unless malignancy or a specific nonparathyroid disease is obvious. False-positive PTH assay results are rare. Immunoassays for PTHrP are helpful in diagnosing certain types of malignancy-associated hypercalcemia. Although FHH is parathyroid-related, the disease should be managed distinctively from hyperparathyroidism. Clinical features and

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include 1.5–2 g/d of elemental calcium. Normocalcemia is usually observed within 1 week of the institution of therapy, although increases in PTH and alkaline phosphatase levels may persist for 3–6 months. The most efficacious methods to monitor treatment and resolution of vitamin D deficiency are serum and urinary calcium measurements. In patients who are vitamin D replete and are taking adequate calcium supplementation, the 24-h urinary calcium excretion should be in the range of 100–250 mg/24 h. Lower levels suggest problems with adherence to the treatment regimen or with absorption of calcium or vitamin D supplements. Levels >250 mg/24 h predispose to nephrolithiasis and should lead to a reduction in vitamin D dosage and/or calcium supplementation.

Renal Papillary Necrosis Associated With Normocalcemic Primary Hyperparathyroidism.

Renal papillary necrosis (RPN) occurring in primary hyperparathyroidism (PHPT) has not been reported. We present a 50-year-old woman who manifested RPN associated with hypercalciuria and normocalcemic PHPT. The diagnosis of RPN was based on imaging studies (ultrasound and computed tomography [CT] scan). PHPT was diagnosed with high parathyroid hormone (PTH) and high/normal serum calcium. A 38-year-old woman was evaluated for hypercalcemia (serum calcium, 11.8 mg/dL; ionized calcium, 6.3 mg/dL; phosphorus, 1.8 mg/dL; intact PTH, 98 pg/mL; and 24-hour urine calcium, 543 mg). Renal ultrasound showed no nephrocalcinosis or nephrolithiasis. A parathyroid scan revealed a left parathyroid adenoma. The patient underwent parathyroidectomy, and she became normocalcemic with normal serum PTH levels postoperatively. One year later, she was diagnosed with a left-sided bronchial carcinoid tumor. Following surgery, a surveillance gallium<sup68</sup positron emission tomography/CT scan performed 2 years later was negative for metastases. Twelve years later (aged 50 years), she presented for follow-up and reported no symptoms of hypercalcemia, fractures, nephrolithiasis, history of pyelonephritis, diabetes mellitus, analgesic drug use, or hypertension. Her serum calcium level was 9.1 mg/dL, PTH level was 82 pg/mL, 25-OH vitamin D level was 34 ng/mL, and 24-hour urine calcium level was 410 mg. However, renal ultrasound showed bilateral RPN that was confirmed by a CT scan. RPN may be associated with hypercalciuria and normocalcemic PHPT. Additional studies with a large number of patients are needed.

[Clinical value of assays of parathyroid hormone and 25-hydroxyvitamin D in internal medicine].

Over a 3 years period, PTH, 25 OHD, calcium and phosphate levels were measured in all patients admitted to a department of Internal Medicine with abnormal phospho-calcic metabolism or bone disease. The diagnostic value of iPTH was analysed, especially in cases of hyper- and hypocalcaemia. In hypercalcaemia, the iPTH did not differentiate between the two main differential diagnoses: hyperparathyroidism and cancer. In patients with a negative calcium balance, the iPTH level is often raised and many help towards diagnosis. However, it should first of all orientate the clinician towards the detection of renal failure which is a common cause of this condition.

Normocalcemic Hyperparathyroidism  -- Evaluation -- Biochemistry

A diagnosis of nPHPT in most cases is made when patients presenting with osteoporosis or renal stones are investigated proactively. In such presentations, reasonable initial investigations would include serum ionized calcium (if available otherwise, total corrected calcium), P, PTH, eGFR, 25 OH vitamin D, and urinary calcium excretion. The results from these and a thorough review of the patient's medications would suffice to exclude nSHPT and diagnose nPHPT. The clinical situation dictates other investigations like liver function tests and serum Mg. Some have proposed that an increased serum calcium/phosphate ratio might help identify independent parathyroid activity, but this has yet to be validated by prospective studies. [19] Two studies looking at this found very high negative predictive values for the albumin-adjusted calcium/phosphorus ratio of 88% and 95% suggesting that this calculation may be of more use to exclude nPHPT than to diagnose it. [19] [20]

Suboptimal health

Another criterion for diagnosis of subhealth was defined as the presence of ≥ 1 of the following abnormalities: body mass index ≥ 25 kg/m2 or waist circumference ≥ 102 cm in men and 88 cm in women; systolic pressure 120-139 mmHg and/or diastolic pressure 80-89 mmHg; serum triglyceride level ≥ 150 mg/dL and/or total cholesterol level ≥ 200 mg/dL and/or high-density lipoprotein cholesterol level < 40 mg/dL in men and 50 mg/dL in women; serum glucose level 110–125 mg/dL; estimated glomerular filtration rate 60-89 ml/min/1.73 m2; levels of liver enzymes in liver function tests between 41-59 U/L, or with fatty liver disease but < 33% of affected hepatocytes; levels of oxidative stress biomarkers beyond the reference range of 95%; or problems with both sleep quality and psychological state. Population Health Status

Jaundice

Risk factors Risk factors associated with high serum bilirubin levels include male gender, white ethnicities, and active smoking. Mean serum total bilirubin levels in adults were found to be higher in men (0.72 ± 0.004 mg/dl) than women (0.52 ± 0.003 mg/dl). Higher bilirubin levels in adults are found also in non-Hispanic white population (0.63 ± 0.004 mg/dl) and Mexican American population (0.61 ± 0.005 mg/dl) while lower in non-Hispanic black population (0.55 ± 0.005 mg/dl). Bilirubin levels are higher in active smokers. Special populations Neonatal jaundice

Humoral hypercalcemia of pregnancy treated with bisphosphonates.

Hypercalcemia can be hazardous during pregnancy, most cases being due to primary hyperparathyroidism. We report a case of hypercalcemia with suppressed PTH levels necessitating treatment with bisphosphonates during pregnancy. A 38-year-old woman at the 26th week gestation was admitted because of symptomatic hypercalcemia. She did not take any medication that could influence her calcium levels. Physical examination was unremarkable. Laboratory tests on admission were: calcium 12.7 mg/dL (8.5-10.5 mg/dL), phosphorus 1.8 mg/dL (2.5-4.5 mg/dL) and PTH on 3 consecutive tests 1.2, 1.3 and 1.2 pg/mL (15-65 pg/mL). Her 24h urine calcium was 900 mg, 25-OH-D 40 ng/mL (30-58 ng/mL) and 1,25-OH-D 99 pg/mL (80-146 for women in the third trimester). Abdominal ultrasound revealed multiple hypervascular liver lesions consistent with hemangiomas by MRI. Breast and neck ultrasound were normal, and chest CT revealed few non-significant 0.3-0.7 cm pulmonary nodules with no change after an interval of 3 months. She was treated with isotonic saline, loop diuretics and calcitonin. Despite this treatment, calcium levels remained high (14.1 mg/dL), and pamidronate was initiated. On 35th week gestation, she underwent a cesarean section complicated by hypocalcemia of the newborn. Eight weeks after delivery, her calcium levels are 9.4 mg/dL and PTH 18 mg/dL. According to the extensive workup and the post-partum normalization of PTH and calcium levels, we conclude that excessive secretion of placental PTHrP was the cause of hypercalcemia in this patient. No significant adverse effect of bisphosphonate on the mother or baby were seen at the short term follow up.

[Stages of the etiological diagnosis of hypercalcemia].

After confirming hypercalcemia by 3 successive measurements of the total plasma calcium corrected for a plasma protein concentration of 72 g/l, which excludes spurious hypercalcemia due to dehydration, the physician orientates the aetiological diagnosis bearing in mind that primary hyperparathyroidism PHPT is the cause of 85 p. 100 of all asymptomatic forms of hypercalcaemia whilst overt or occult malignancy is the main cause (60 p. 100) of symptomatic forms of hypercalcaemia with PHPT responsible for 20 p. 100 of cases. Other causes, including drug toxicity with Vit D, calcium, Vit A, lithium, thiazide and aluminium hydroxide, sarcoidosis, hyperthyroidism, Addison's disease, pheochromocytoma and familial endocrine disorders are much rarer. Nevertheless, these rarer causes must be excluded on the clinical history and examination followed by radiological (chest X ray, plain abdomen X ray, bone X rays) and simple biological tests. The latter and/or scans tests should also help in a rapid diagnosis of metastatic carcinoma and multiple myeloma, so that the major diagnostic problem is to distinguish primary HPT from occult malignancy. This problem is greatly facilitated by reliable assays of C terminal or medium PTH rather than renal CAMP which is increased in 80 p. 100 of occult malignancies. When PTH assays is unavailable or unreliable Dent's hydrocortisone suppression test may be useful as a fall in'serum calcium is associated with occult malignancy in 70 p. 100 of cases and non-suppression is associated with PHPT in 91 p. 100 of cases. Discriminant analysis of the usual biochemical parameters may be helpful in this differential diagnosis and is accurate in about 90 p. 100 of cases. However, the association of PHPT and malignancy is also possible and not fortuitous.

The role of rapid PACU parathyroid hormone in reducing post-thyroidectomy hypocalcemia.

Post-thyroidectomy parathyroid hormone (PTH) levels have been used to predict hypocalcemia. The goal of this study was to determine whether selective supplementation for post anesthesia care unit (PACU) PTH < 15 mg/dL reduced hypocalcemia compared to observation or routine supplementation. Controlled cohort study of thyroidectomy patients, with chart review. Chart review of total or completion thyroidectomy patients in an academic setting. The control group consisted of 124 subjects. The selective supplementation group consisted of 169 subjects with routine PACU PTH testing. The routine supplementation group consisted of 155 subjects with immediate postoperative calcium and vitamin D supplementation. The control group received supplementation for hypocalcemia (calcium < 8.0 mg/dL). The selective PTH group received calcium and vitamin D supplementation for PACU PTH < 15 mg/dL or hypocalcemia. The routine supplementation group received oral calcium and calcitriol supplementation immediately after surgery. Four separate postoperative day 1 (POD1) outcome measures were evaluated: 1) mean serum calcium; 2) rate of hypocalcemia < 8 mg/dL; 3) rate of significant hypocalcemia < 7.5 mg/dL; and 4) rate of hypercalcemia > 10 mg/dL. Mean serum calcium was lower and the rate of hypocalcemia was higher in the control group than the selective PACU PTH group on POD1 (8.2 vs 8.6 mg/dL, P < 0.0001, and 35% vs 14%, P < 0.0001, respectively). Mean serum calcium was higher (8.9 vs 8.6 mg/dL, P < 0.0001) and the rate of hypocalcemia lower in the routine supplementation group than in the selective group. However, the rate of hypercalcemia was higher in the routine supplementation group than in the selective group (4.5% vs 0%, P = 0.006). Routine PTH testing and supplementation for patients with hypoparathyroidism reduced the proportion of patients experiencing hypocalcemia. However, supplementation for intraoperative PTH < 15 mg/dL had a higher rate of hypocalcemia than routine supplementation, but with a lower rate of hypercalcemia.

Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).

Hyperphosphatemia underlies development of hyperparathyroidism, osteodystrophy, extraosseous calcification, and is associated with increased mortality in hemodialysis patients. To determine whether calcium acetate or sevelamer hydrochloride best achieves recently recommended treatment goals of phosphorus </=5.5 mg/dL and Ca x P product </=55 mg(2)/dL(2), we conducted an 8-week randomized, double-blind study in 100 hemodialysis patients. Comparisons of time-averaged concentrations (weeks 1 to 8) demonstrated that calcium acetate recipients had lower serum phosphorus (1.08 mg/dL difference, P= 0.0006), higher serum calcium (0.63 mg/dL difference, P < 0.0001), and lower Ca x P (6.1 mg(2)/dL(2) difference, P= 0.022) than sevelamer recipients. At each week, calcium acetate recipients were 20% to 24% more likely to attain goal phosphorus [odds ratio (OR) 2.37, 95% CI 1.28-4.37, P= 0.0058], and 15% to 20% more likely to attain goal Ca x P (OR 2.16, 95% CI 1.20-3.86, P= 0.0097). Transient hypercalcemia occurred in 8 of 48 (16.7%) calcium acetate recipients, all of whom received concomitant intravenous vitamin D. By regression analysis hypercalcemia was more likely with calcium acetate (OR 6.1, 95% CI 2.8-13.3, P < 0.0001). Week 8 intact PTH levels were not significantly different. Serum bicarbonate levels were significantly lower with sevelamer hydrochloride treatment (P < 0.0001). Calcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients.

[Asymptomatic primary hyperparathyroidism : Operation or observation?]

In many cases primary hyperparathyroidism (PHPT) remains asymptomatic for years and is only detected by abnormalities in routine diagnostics. While symptomatic disease almost always requires surgical treatment, in symptom-free patients the question of whether and in what form treatment should be carried out is particularly important. The aim of this review is to summarize the current recommendations regarding the diagnostics and treatment of asymptomatic PHPT, taking the existing evidence into account. The diagnostics of asymptomatic PHPT is the same as for symptomatic disease. The diagnosis is made in the presence of elevated parathyroid hormone and balanced vitamin D levels when a combination of hypercalcemia, hypophosphatemia and hypercalciuria is present. Borderline laboratory findings occur especially in asymptomatic PHPT and the differential diagnosis of familial hypocalciuric hypercalcemia must be considered. Once the diagnosis is made sonography, radiography or computed tomography (CT) is used to search for nephrolithiasis or nephrocalcinosis. Regarding bone mineral density (BMD) measurements, in addition to routine measurements at the lumbar spine and femur, measurement at the distal radius is important as it is the most sensitive site for detecting osteoporosis in PHPT. An indication for parathyroidectomy is confirmed in the case of hypercalcemia > 1.0 mg/dl (>0.25 mmol/l) above the upper limit of normal, hypercalciuria > 400 mg/day (>10 mmol/day), renal insufficiency, proven osteoporosis or age < 50 years. If none of these criteria are fulfilled and surgery is not desired by the patient, annual laboratory check-ups and assessment of BMD every 1-2 years are recommended.