Calcium/creatinine urine ratio. This is familial hypocalciuric hypercalcemia or benign familial hypercalcemia. Autosomal dominant disorder. Asymptomatic. Not cured after surgical treatment; it is due to mutation of the calcium-sensitive receptor. Difficult question since it is necessary to know data of a disease that is not usually asked in the MIR.

Calcium/creatinine urine ratio. This is familial hypocalciuric hypercalcemia or benign familial hypercalcemia. Autosomal dominant disorder. Asymptomatic. Not cured after surgical treatment; it is due to mutation of the calcium-sensitive receptor. [HIDDEN] since it is necessary to know data of a disease that is not usually asked in the MIR.

In a 30-year-old female patient a calcium level of 11 mg/dl (normal less than 10.5 mg/dl) is found during a routine company examination. PTH determination was 45 pg/ml (VN 10-55 pg/ml). The history is unremarkable except for the fact that the mother and paternal grandfather were diagnosed with hyperparathyroidism and underwent surgery, although they remained hypercalcemic. Which test is most useful in confirming the diagnosis?

Late increase in serum 1,25-dihydroxyvitamin D one month after surgery for adenomatous hyperparathyroidism.

This study was designed to follow the evolution of serum 1,25(OH)2D after surgery for primary hyperparathyroidism. Ten patients were studied before and for up to 85 d after removal of a single parathyroid adenoma. Blood and 24 h urine were obtained at various time points, for the measurement of serum or urinary phosphate and calcium indices. Before surgery, serum calcium (2.91 +/- 0.06 mmol/l; mean +/- SEM), parathyroid hormone (354 +/- 47 pg/ml) and 1,25(OH)2D (61.2 +/- 7.8 pg/ml) were elevated while serum phosphate (1.01 +/- 0.07 mmol/l) tended to be low. Relative hypoparathyroidism was evident for up to 5 d after surgery with the lowest value for serum parathyroid hormone (41 +/- 16 pg/ml) on day 1, serum calcium (2.12 +/- 0.06 mmol/l) on day 3 and highest value for serum phosphate (1.41 +/- 0.13 mmol/l) on day 5. As expected, serum 1,25(OH)2D levels decreased to 35.9 +/- 4.2 pg/ml 24 h after surgery. Stabilization of serum and urinary parameters to normal values was seen between day 5 and day 27; the only exception was serum 1,25(OH)2D, which increased again at day 27 to 57.6 +/- 5.0 pg/ml, a value as high as that before surgery. It was still elevated at day 50 (58.3 +/- 4.3 pg/ml), but returned towards normal values in three out of four patients (44 +/- 3.9 pg/ml) by day 80. No variation in 25(OH)D or 24,25(OH)2D was seen throughout the study. 1,25(OH)2D values could be related to serum parathyroid hormone values before surgery (r = 0.659, P less than 0.05) but not after. The secondary increase in serum 1,25(OH)2D could not be related to variations in serum calcium, phosphate, parathyroid hormone or diet. Further studies will be required to explain this phenomenon.

Familial hypocalciuric hypercalcemia

Diagnosis As most cases of FHH are asymptomatic and benign, the diagnosis of FHH is less likely to be made. Typically, diagnosis is made in the pursuit of uncovering the etiology of hypercalcemia. Calcium levels are often in the high normal range or slightly elevated. Commonly, the parathyroid hormone level is checked and may be slightly elevated or also on the high normal end. Normally, high calcium should cause low PTH and so this level of PTH is inappropriately high due to the decreased sensitivity of the parathyroid to calcium. This may be mistaken for primary hyperparathyroidism. However, evaluation of urine calcium level will reveal a low level of urine calcium. This too is inappropriate as high serum calcium should result in high urine calcium. If urine calcium is not checked, this may lead to parathyroidectomy for presumed primary hyperparathyroidism. Additionally as the name implies, there may be a family history of benign hypercalcemia.

Primary Hyperparathyroidism -- Evaluation -- Specific Hyperparathyroid and Hypercalcemic Disorders

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant inherited disorder that is sometimes easily confused with primary hyperparathyroidism. It is characterized by hypercalcemia, hypocalciuria, and high-normal to mildly increased parathyroid hormone secretion. [88] [112] Familial hypocalciuric hypercalcemia is caused by a mutation in the calcium-sensing receptor of the chief cells of the parathyroid gland. Histologically, the parathyroid glands appear normal. There is usually a known family history of the disorder. There are no clinical symptoms, and it requires no treatment. The diagnosis is usually made by history or the calcium/creatinine excretion ratio, although 24-hour urine testing showing severe hypocalciuria of <100 mg/24 hours is highly suggestive. The calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] in the urine of patients with familial hypocalciuric hypercalcemia is very low, typically <0.01 in 80% of cases, and FHH is more likely if hypercalcemia is detected before age 40. [88] Other causes of hypocalciuric hypercalcemia should be ruled out (vitamin D deficiency, severely calcium-deficient diet, mild renal failure, use of thiazide or lithium). A calcium infusion test can also help distinguish FHH from primary hyperparathyroidism. A calcium load will increase urinary calcium excretion in primary hyperparathyroidism but not familial hypocalciuric hypercalcemia. [88] A definitive diagnosis can be made in questionable cases by genetic testing. [88]

Evidence that calcitonin plays a role in the postnatal increase of serum 1 alpha,25-dihydroxyvitamin D.

To investigate the changes in the 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] level and the role of parathyroid hormone (PTH) and calcitonin (CT) during the early neonatal periods, we measured 1,25(OH)2D, 25-hydroxyvitamin D [25(OH)D], PTH specific for mid-regions (mPTH) and urinary cAMP (UcAMP) to evaluate the renal tubular responsiveness to intrinsic PTH and CT, as well as serum Ca and P in 28 mothers at term delivery and in their babies at birth and 5 days of age. Cord serum 1,25(OH)2D levels were low (28.8 +/- 9.2 pg/ml, mean +/- SD), while maternal serum 1,25(OH)2D levels were high (62.2 +/- 22.6 pg/ml). The low 1,25(OH)2D value increased 2.5 times (62.2 +/- 22.6 pg/ml) in 5-day-old infants, reaching a high normal adult value, concomitant with the increases in mPTH and urinary cAMP/creatinine ratio (UcAMP/Cr). The correlations between 1,25(OH)2D and UcAMP/Cr, and 1,25(OH)2D and mPTH in all paired samples of babies at birth and at 5 days of age were r = 0.456, n = 50, P less than 0.01 and r = 0.341, n = 50, P less than 0.05, respectively. These data suggest that the parathyroid activation after birth is a major factor in the rapid 1,25(OH)2D increment at that time. CT levels were high in all paired samples and in 5-day-old infants. CT vs 1,25(OH)2D showed a significant correlation (r = 0.473, P less than 0.05, n = 24) as well as the relative increase of 1,25(OH)2D (delta pg/ml) after birth vs CT at age 5 days (r = 0.537, P less than 0.01, n = 24).(ABSTRACT TRUNCATED AT 250 WORDS)

Familial Hypocalciuric Hypercalcemia -- Evaluation

The diagnosis of FHH can be easy to make in an asymptomatic hypercalcemic patient with a family history of hypercalcemia, a personal or family history of failed neck exploration, or normal serum PTH [1] [2] . More than 99% of the filtered calcium gets reabsorbed despite the presence of hypercalcemia. The 24 hours urinary calcium excretion is less than 100 mg/24 hours. The Ca/Cr excretion ratio is very low. It is calculated as follows: [UCa × SCr] / [SCa × UCr], where UCa is the urinary calcium concentration, SCr is the serum creatinine, SCa is the serum calcium concentration, and UCr is the urinary creatinine concentration, all in mg/dl. The Ca/Cr clearance ratio is less than 0.01 in 80% of cases. All patients with calcium/creatinine clearance ratio of 0.020 or less should be tested for mutations in the CaSR gene. Serum Magnesium is in the upper-normal range or mildly elevated; whereas, serum magnesium tends to be normal or low in primary hyperparathyroidism.

InternalMed_Harrison

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

[Vitamin D3 overdosage due to rashly diagnosed rachitis in a child with distal tubular acidosis].

Metabolic acidoses are diseases causing many diagnostic and therapeutic problems. Compensated metabolic acidosis can be unrecognised for a long time. This refers especially to isolated renal tubular acidosis (RTA). Unrecognised RTA causes calcium and phosphorus balance disturbances with clinical signs of improper bone mineralization. It happens that some patients with mentioned problems are "treated" as rachitic and take high doses of vitamin D. As a result, serum calcium and phosphates as well as urine calcium increase, without the satisfied influence on bone mineralization. We present a case of a 3.5 months old baby, who was "treated" as ricket in vitamin D deficiency. This baby was "cured" with high doses of cholecalciferol (0.0875 mg/24h for 2 weeks, then 0.175 mg/24h for 3 weeks) because of craniotabes. This treatment was carried on without any metabolic tests and caused the following disturbances: 25(OH)D serum level - 102.7 ng/ml (normal 11-54), 1,25(OH)2D serum level - 39.5 pg/ml (normal 15-70), calcaemia 2.7-2.85 mmol/l, phosphataemia 2.1 mmol/l. In this time the considerable hipercalciuria (second morning urine sample Ca/cr ratio 2.06 mmol/mmol) occurred. The other laboratory test showed as follows: serum albumins 4.5 g/dl, alkaline phosphatase 188 U/l, acid phosphatase 10.7 U l, Cl- 114.9 mmol/l, Na 146 mmol/l, K 4.8 mmol/l, HCO3a 16.6-20.1 mmol/l and pCO2 3.63-3.85 kPa, serum anion gap 11 mEq/l; pH of morning urine 6.5-7. These results suggested the presence of distal RTA aside from symptoms of vitamin D overdosage. The high serum levels of calcium and phosphates, craniotabes, rather low serum alkaline phosphatase activity and presence of metabolic acidosis the symptoms after the normalisation of calcium and phosphorus balance suggested that the distal RTA had been prior to calcium disturbances.

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.

[Adult-onset sex-linked familial hypophosphatemic osteomalacia].

Three patients (a grandmother, her daughter and her grandson) belonging to a 23-number-kindred of five generations suffered from adult-onset, X-linked, familiar hypophosphataemic osteomalacia. According to the familiar anecdotes the great-grandmother also had the same disease. The clinical diagnosis was documented by X-ray pictures, scintigraphic and bone histological results, the laboratory diagnosis was proven by blood and urine analyses examined after phosphate loading. The youngest, 24-year-old patient was treated with daily 3 g phosphate and high doses of calcitriol for 2 years. As a new feature of our therapy, per os treatment with 1.25 micrograms calcitriol was supplemented by daily 2-4 micrograms iv. bolus calcitriol for one week every month. The osteomalacia, causing serious symptoms and complaints, healed. Our treatment seemed to be safe, as renal functions, serum total and ionized calcium and PTH levels (including midnight values) remained in normal range. On the basis of our results this disease can be treated by administration of high doses of phosphate, provided that development of hyperparathyroidism is prevented by the coadministration of high doses of calcitriol.

Vitamin D metabolites and parathyroid hormone in Cushing's syndrome: relationship to calcium and phosphorus homeostasis.

We studied the effects of glucocorticoid excess on calcium and phosphorus homeostasis in relation to vitamin D metabolites and parathyroid hormone (PTH) in seven patients with spontaneous ACTH-dependent Cushing's syndrome. Remission of hypercortisolism resulted in a significant increase in tubular reabsorption of phosphate [from 76 +/- 4% to 89 +/- 2% (mean +/- SEM); P less than 0.01] and serum phosphorus (from 3.1 +/- 0.1 to 4.2 +/- 0.2 mg/dl; P less than 0.005). Serum calcium did not change, although there was a reduction in daily urinary calcium excretion from 0.23 +/- 0.02 to 0.107 +/- 0.02 mg calcium/mg creatinine. Serum immunoreactive PTH (iPTH) levels were normal during Cushing's syndrome (34 +/- 5 microleq/ml), but fell significantly after remission to 22 +/- 2 microleq/ml (P less than 0.05). This small decrease in iPTH did not correlate with the improvement of phosphate homeostasis. Plasma 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH2)D] concentrations in Cushing's syndrome did not differ from measurements in 97 normal subjects. After treatment, 25OHD did not change, but 1,25-(OH)2D fell in each patient from a mean of 44 to 22 pg/ml (P less than 0.02). 1,25-(OH)2D was inversely correlated with serum phosphorus (r = 0.59; P less than 0.01), but did not correlate with iPTH. The known impairment of intestinal calcium absorption in Cushing's syndrome cannot be attributed to a decrease in the circulating levels of 1,25-(OH)2D. Endogenous hypercortisolism decreases tubular phosphate reabsorption and serum phosphorus, increase tubular phosphate reabsorption and serum phosphorus, increases iPTH, and results in an increase in 1,25-(OH)2D. These events may contribute to the severe loss of bone mass in such patients and may account for the calciuria and phosphaturia of Cushing's syndrome.

[A rare cause of hypercalcemia: familial hypocalciuric hypercalcemia].

Familial hypocalciuric hypercalcemia is a rare disease with autosomal dominant transmission. Its basic defect is unknown and it requires no treatment. A 4 month-old girl was admitted for unexplained crying. She was found to have hypercalcemia (2.8 mmol/l) and later values of blood calcium were 3, 3.1 and 3 mmol/l. The serum free ionic calcium level was also elevated. The serum concentrations of protein, phosphorus, magnesium and the alkaline phosphatase activity were all normal. Serum concentrations of 25-(OH)-D3, 1.25-(OH)-2-D3 and PTH were also normal. The urinary calcium/creatinine ratio was normal and the urinary calcium excretion was 1.08 mg/kg/d. Screening of family members showed hypercalcemia in the father (2.8 mmol/l) and a brother aged 7 years (2.9 mmol/l). Short-term treatment with disodium etidronate lowered the serum calcium level to normal, but hypercalcemia reappeared once the treatment was discontinued. This asymptomatic familial hypercalcemia has the characteristics of familial hypocalciuric hypercalcemia. There was no associated endocrine disorder. Screening of family members is worthwhile.

Acromegaly as a cause of 1,25-dihydroxyvitamin D-dependent hypercalcemia: case reports and review of the literature.

Growth hormone excess has been associated with hypercalciuria and nephrolithiasis. Hypercalcemia in acromegaly is rare and usually due to coexistent primary hyperparathyroidism. To report two cases of 1,25-dihydroxyvitamin D (1,25 (OH)(2) D)-dependent hypercalcemia in cromegaly. A 50 year-old female with 2 years history of hypercalcemia presented with features of acromegaly. Serum calcium (Ca) was 10.9 mg/dl (8.6-10.2), parathyroid hormone (PTH) 20 pg/ml (10-65), PTH-related peptide undetectable, and 1,25 (OH)(2) D 119 pg/ml (15-75). Insulin-like growth factor 1 (IGF1) was 911 ng/ml (49-292) and growth hormone (GH) 14.5 ng/ml (0.03-10). MRI showed a 1.7 cm pituitary tumor. Transsphenoidal adenectomy (TSA) resulted in normalization of IGF1, GH, Ca, and 1,25 (OH)(2) D (50 pg/ml) and complete tumor resection. A 52-year-old female was diagnosed with visual field deficits on routine exam. MRI showed a 3 cm invasive pituitary macroadenoma. IGF1 was 416 ng/ml (87-238) and GH 75.8 (0-6.0) ng/ml. Incidentally, she was found with high Ca of 10.8 mg/dl (8.9-10.3) associated with PTH 19 pg/ml and 1,25 (OH)(2) D66 pg/ml. Postoperatively, IGF1 and GH remained abnormal (440 and 12.8 ng/ml, respectively), while MRI showed parasellar tumor residue. Ca remained high (10.1-11.1 mg/dl), along with elevated 1,25 (OH)(2) D level (81.3 pg/ml). In both cases, other causes of hypercalcemia were ruled out. We present 2 cases of 1,25 (OH)(2) D-dependent hypercalcemia associated with growth hormone excess. Complete resection of tumor produced biochemical remission of acromegaly and normalization of calcium and 1,25 (OH)(2) D levels, while incomplete resection was associated with persistent 1,25 (OH)(2) D-dependent hypercalcemia. Acromegaly should be considered a cause of 1,25 (OH)(2) D-dependent hypercalcemia.

Familial hypocalciuric hypercalcemia: description of a new kindred with emphasis on its difference from primary hyperparathyroidism.

In order to better understand the difference between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHP), 4 adults with this disease (FHH(+], from the same kindred, and spanning 2 generations, were compared with 6 patients with PHP, 10 normal controls (N) and 3 unaffected members of the same kindred (FHH(-]. Clinically speaking, the FHH(+) patients were asymptomatic while those with PHP had recurring renal stones. Various phosphocalcic balance elements were measured in blood and urine, in a fasting state, following oral loading of 1 g calcium, as well as in 24-hour urine specimens. Serum calcium levels were slightly higher (11.90 +/- .14 vs 11.37 +/- .24 mg/dl; p less than .05), in patients with FHH(+), but serum phosphorus (2.47 +/- .38 vs 2.88 +/- .40 mg/dl), serum parathyroid hormone (301 +/- 147 vs 291 +/- 224 pg/ml) and serum 1,25(OH)2D (52.8 +/- 6.7 vs 55.0 +/- 12.0 pg/ml) values were similar to those observed in patients with PHP. Urinary calcium present in FHH(+), while fasting (.064 +/- .043 mg/100 ml G.F.), after the calcium loading (.150 +/- .071) and in the 24-hour specimen (.089 +/- .016), was below the 95% confidence limit of values obtained in patients with PHP (.225 +/- .026, p less than .001; .413 +/- .066, p less than .001; 314 +/- .080, p less than .001), but similar to those obtained in N and FHH(-).(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized trial comparing 2.5 mEq/L calcium dialysate and calcitriol to 3.5 mEq/L calcium dialysate in patients on peritoneal dialysis.

Peritoneal dialysate containing 2.5 mEq/L of calcium has been used to prevent hypercalcemia when calcium-containing phosphate binders are given. However, worsening of hyperparathyroidism may result. Calcitriol used in conjunction with 2.5 mEq/L calcium dialysate is an attractive alternative, but has not been examined in a controlled trial. Eighteen patients were randomly assigned to either a control group (3.5 mEq/L calcium dialysate without calcitriol) or a study group (conversion to 2.5 mEq/L calcium dialysate with oral calcitriol, median dose 0.25 microgram/day). The initial mean serum calcium (9.9 vs 9.6 mg/dL), phosphate (5.4 vs 5.6 mg/dL), median n-terminal parathyroid hormone (PTH) levels (71 vs 55 pg/mL, normal < 25), and median 1,25 (OH)2 vitamin D levels (4 vs 5 pg/mL, normal 15-60 pg/mL) were not different in the two groups. After 8 weeks the serum calcium and phosphate were unchanged from baseline in both groups. The 9 patients who converted to 2.5 mEq/L calcium dialysate had an insignificant fall in the PTH level, not different from the control group. The median 1,25 (OH)2 vitamin D level rose from 4 to 23 pg/mL (p = 0.003) on calcitriol, but remained unchanged in the control group (5 pg/mL). The median doses of oral calcium (0.9 vs 1.1 g/day) and the frequency of serum calcium levels greater than 11 mg/dL (4/9 vs 3/9 patients, 10% vs 8% of all values) were similar in the study and control groups. Aluminum hydroxide was required intermittently for serum phosphate control in 3 patients on 2.5 mEq/L calcium dialysate and 4 on 3.5 mEq/L calcium dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

[Usefulness of genetic tests in familial hypocalciuric hypercalcemia with atypical clinical presentation].

Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-hour urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C>T (Pro55Leu) in exon 2 in heterozygosis. According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypical clinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs.

Surgery_Schwartz

an elevated chloride-to-phosphate ratio (>33). Urinary calcium levels need not be measured routinely, except in patients who have not had previ-ously documented normocalcemia or have a family history of hypercalcemia to rule out FHH. In patients with FHH, 24-hour urinary calcium excretion is characteristically low (<100 mg/d). Furthermore, the serum calcium-to-creatinine clearance ratio (24-hour urine calcium/plasma total calcium/24-hour urine creatinine/plasma creatinine) usually is <0.01 in patients with FHH, whereas it is typically >0.02 in patients with PHPT, although there are exceptions to this. Other biochemical features of PHPT are listed in Table 38-10. Elevated levels of alkaline phosphatase may be found in approximately 10% of patients with PHPT and are indicative of high-turnover bone disease. These patients are prone to developing postoperative hypocal-cemia due to bone hunger. Serum and urine protein electropho-resis may be necessary to exclude multiple

Hypercalcemia as an Early Finding of Opportunistic Fungal Pneumonia in Renal Transplantation: A Case Series Report.

Pneumonia caused by opportunistic fungi is a serious complication in immunocompromised patients. Hypercalcemia has been described in renal transplantation associated with Pneumocystis jirovecii (PJP) or Histoplasma capsulatum (HCP) pneumonia. We describe 5 patients who underwent kidney transplant between 2014 and 2019 and developed hypercalcemia before the diagnosis of pulmonary fungal infection: 4 patients with PJP and 1 with HCP. We assessed calcium metabolism and kidney function by total and ionized calcium, phosphorus, intact parathormone (iPTH), 25-OH vitamin D, 1,25(OH)2 vitamin D, and serum creatinine levels. Mean albumin-corrected calcium and ionized calcium were 12.56 mg/dL (range, 10.8-13.8 mg/dL) and 1.57 mmol/L (range, 1.43-1.69 mmol/L). Patients were normocalcemic, at 10.12 mg/dL (range, 9.6-10.5 mg/dL), before diagnosis and resolved hypercalcemia after antifungal treatment, at 8.86 mg/dL (range, 8.0-9.5 mg/dL). All patients had low or normal iPTH values, at 29.1 pg/mL (range, <3-44 pg/mL), with higher PTH levels 3 months before diagnosis and after treatment, at 147.3 pg/mL (range, 28.1-479 pg/mL) and 117.5 pg/mL (range, 18.2-245 pg/mL), respectively. The mean value for 25-OH vitamin D was 30.8 ng/mL (range, 14.6-62.8 ng/mL). This supports a PTH-independent mechanism, and we postulated an extrarenal production of 1,25(OH)2 vitamin D. In kidney transplant patients, hypercalcemia independent of PTH and refractory to treatment should alert for the possibility of opportunistic fungal pneumonia.

[Hypophosphatemic rickets].

Familiar hypophosphatemic rickets (X-linked hypophosphataemia) occurs very rarely, nevertheless it makes a significant medical problem because of the fact that misdiagnosed or late diagnosed leads to physical development retardation and to severe deformities of extremities. In the case of severe deformities the surgical treatment is needed. We present the case of the 5 year old girl with X-linked hypophosphataemia, who was late diagnosed, in spite of appearance of typical clinical symptoms (short stature and deformities of extremities) and typical laboratory findings (severe hypophosphataemia, serum calcium levels at the lower normal range). This girl had been "observed" (by a family doctor) for 3 years because of "varus deformity of legs". Despite considerably abnormal developmental parameters: height and weight << 3rd percentile (height >-3 s.d. for age), length of lower limbs >-3 s.d. for age and abnormalities in X-ray images of lower limbs (at the age of 3 5/12 presence of diaphysial deformations and abnormal metaphyses with zones of inadequate mineralization) the girl had not been diagnosed. After the admission to The Department of Pediatrics, Endocrinology and Disease of Adolescents: TRP 69.1%, PO4- 0.7-0.78 mmol/l, Ca 2.24-2.25 mmol/l, Mg 0.78 mmol/l, normal serum level of 25(OH)D (15.4 ng/ml [n. 11-54]), reduced serum level of 1 alpha 25(OH)2D (5.2 pg/ml [n. 15-70]), PTH 56 pg/ml [n. 10-70], ALP 401 U/l, ACP 9.5 U/l. 24-hour urine: PO4- 0.36-0.60 mmol/kg b.w., Ca 0.021 mmol/kg b.w. Probably, the girl will need surgical treatment because of severe bone deformities.

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]

Safety of megadose of vitamin D in patients with nephrolithiasis.

This article describes two patients with renal lithiasis who received a megadose of 25-hydroxy vitamin D (25[OH]D) and had a good outcome. The first case reports a 74-year-old man with a long-term history of renal lithiasis and about four episodes of renal crisis. He was treated once with extracorporeal shock wave lithotripsy. He also had a history of dyslipidemia, myocardial infarction, and stroke. Laboratory tests demonstrated 25(OH)D of 28 ng/mL (normal range (nr): >30 ng/mL), normal lipid levels, creatinine of 1.1 mg/dL, and homocysteine of 26.6 mcmol/L (nr: 5-15 mcmol/L); parathyroid hormone (PTH) was high at 67.3 pg/mL (nr: 10-65 pg/mL), serum total calcium was 8.6 mg/dL, 24-h urinary calcium was 139 mg/d (normal range 100-300 mg/d), and urinary sediment was normal. He received 50 000 IU per week of vitamin D for 3 mo, and 25(OH)D increased to 36.6 ng/mL. Urinary calcium was 142 mg/d, PTH was 46.7 pg/mL, and serum calcium was 9.6 mg/dL. No renal crisis was perceived. He asked for an alternative form of medication since he usually would forget to take drugs. Vitamin D in a single dose of 600 000 IU intramuscular was prescribed. He was asked to increase water intake to 2 to 3 L/d. After 3 mo his 25(OH)D was 75.0 ng/mL, serum calcium was 9.2 mg/dL, urinary calcium was 148 mg/d, and PTH was 38.7 pg/mL. He had no episodes of lithiasis renal crisis. Folic acid and methylcobalamin were added, and homocysteine normalized. At follow-up 3 y later, the patient was asymptomatic, cardiologic evaluation was stable without any other renal lithiasis crises, 25(OH)D continued to be normal at 62 ng/mL, and he received a megadose of vitamin D every 6 mo. Renal ultrasound revealed only microlithiasis. The second case reports a 52-year-old man with a long-term history of renal lithiasis experienced since he was 30 y old, with three renal crisis episodes. He was treated with an extracorporeal shock wave three times. Laboratory tests demonstrated 25(OH)D 18 ng/mL, normal biochemistry, total serum calcium of 10.2 mg/dL, 24-h urinary calcium of 154 mg/d, and normal urinary sediment. He received 50 000 IU per week of 25(OH)D for 3 mo, and 25(OH)D increased to 40.3 ng/mL. Urinary calcium was 167 mg/d, PTH was 35.3 pg/mL, and serum calcium was 10.1 mg/dL. No renal crisis was perceived. He asked for an alternative form of medication, and vitamin D in a single dose of 600 000 IU intramuscular was prescribed. He was asked to increase water intake to 2 to 3 L/d. After 3 mo, his 25(OH)D was 82.0 ng/mL, serum calcium was 9.6 mg/dL, urinary calcium was 175 mg/d, and PTH was 35.3 pg/mL. The renal ultrasound was unchanged. He had no episodes of lithiasis renal crisis. At follow-up 4 y later, the patient was asymptomatic without any other renal lithiasis crises, a renal ultrasound revealed a reduction of calculi size to microlithiasis, 25(OH)D continues normal, and he received a megadose of this vitamin every 4 mo. To the best of our knowledge, this is the first description of a megadose of vitamin D used in patients with nephrolithiasis. Furthermore, this shows the safety of this strategy in patients without hypercalciuria.

Parenteral nutrition for infants: effect of high versus low calcium and phosphorus content.

Calcium (Ca) and phosphorus (P) homeostasis were determined in 18 infants (birth weight, 2,810 +/- 135 g; gestational age, 37.4 +/- 0.5 weeks; mean +/- SEM) who received high or low Ca and P content (Ca, P) parenteral nutrition (PN) with a fixed, low dose of vitamin D (25 IU/dl). Nine infants were randomized into low (standard) Ca, P (20 mg Ca and 15.5 mg P/dl) and nine into high Ca, P (60-80 mg Ca and 46.5-62 mg P/dl) PN, and then were studied for up to 6 weeks. The high Ca, P group had stable serum 1,25 dihydroxyvitamin D [1,25(OH)2D], which consistently remained within the normal range (less than 116 pg/ml). Tubular reabsorption of phosphorus (TRP) also was stable and remained consistently less than 90%. The low Ca, P group had elevated and higher 1,25(OH)2D (p = 0.03) than the high Ca, P group. The mean serum 1,25(OH)2D concentration rose from 32 to 112, 115, and 133 pg/ml over a period of 6 weeks. TRP also was higher (p = 0.02) and remained consistently greater than 90%. There were no significant differences between groups in serum parathyroid hormone, calcitonin, Ca, Mg, P, alkaline phosphatase, vitamin D binding protein, and 25 hydroxyvitamin D concentrations; urine Ca/creatinine and Mg/creatinine ratios, and fractional excretion of sodium (Na). Thus, a "high" Ca (60 mg/dl) and P (46.5 mg/dl) content in PN solutions can result in stable serum 1,25(OH)2D and TRP, presumably reflecting minimal stress to Ca and P homeostatic mechanisms without further increase in urinary Ca excretion.

Secondary Hyperparathyroidism in Patients with Biliopancreatic Diversion After 10 Years of Follow-up, and Relationship with Vitamin D and Serum Calcium.

Secondary hyperparathyroidism (SHPT) is a matter of concern after biliopancreatic diversion (BPD). The aim of this study was to investigate the relationship between SHPT, 25(OH)D, and calcium after BPD. A retrospective analysis in obese patients after BPD performed between 1998 and 2016. Patients with at least 1 year of follow-up were included. SHPT was considered when PTH > 65 pg/mL in the absence of an elevated corrected calcium. 25(OH)D (ng/mL) status was defined as: deficiency < 20, insufficiency 20-29.9, and sufficiency ≥ 30. In total, 321 patients were included (76.6% women), with mean age 43.0 (10.5) years. Median follow-up was 6.0 (IQR 3.0-9.0) years. Mean body mass index was 49.8 (7.0) kg/m<sup2</sup. SHPT increased to a maximum of 81.9% in the ninth year of follow-up (95% CI: 1.5-9.1). Two years after surgery, 33.9% of patients with 25(OH)D sufficiency had SHPT (p = 0.001). Corrected calcium levels were lower in patients with PTH > 65 pg/mL when compared with PTH < 65 pg/mL; 1 year: 8.96 vs 9.1 mg/dL and 5 years: 8.75 vs 9.12 mg/dL (p < 0.01). After surgery, patients with PTH > 65 pg/mL and 25(OH)D sufficiency had lower corrected calcium levels when compared with subjects with PTH and 25(OH)D in normal range. Two years: 9.0 vs 9.2 mg/dL (p < 0.05) and 4 years: 8.9 vs 9.2 mg/dL (p < 0.01). Once 25(OH)D is sufficient, the increase in PTH persists associated with a decrease in serum corrected calcium. It is important to ensure a sufficient calcium intake in these patients in order to avoid SHPT and osteomalacia in the future.

The differentiation between FHH and primary hyperparathyroidism is more difficult in the absence of a family history of hypercalcemia if PTH levels are normal and if the Ca/Cr clearance ratio is greater than 0.01 and less than 0.02. The age at diagnosis of hypercalcemia and family history is important. Detection of asymptomatic hypercalcemia before the age of 40 years or so favors the diagnosis of FHH. Obtaining serum calcium values from first-degree relatives in the absence of family history can be helpful.

Evidence of a probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism.

1,25-Dihydroxyvitamin D [1,25-(OH)2D] is the principal mediator of the biologic effects of vitamin D. We showed previously that obese white subjects have low serum vitamin D and 25-hydroxyvitamin D (25-OHD) with increased serum-immunoreactive parathyroid hormone (PTH) and 1,25-(OH)2D, low urinary calcium, and increased urinary cyclic adenosine 3',5'-monophosphate (cyclic AMP) compared with nonobese white individuals. To determine whether 25-OHD modulates calcium metabolism, the effects of 25-OHD3, 40-100 micrograms/day for 9 days, were compared in seven obese and seven nonobese white subjects who were between the ages of 20 and 34 years. Each of them was hospitalized on a metabolic ward and given a constant daily diet that contained 400 mg calcium, 900 mg phosphate, and 18 mEq magnesium. Whereas 25-OHD3 increased mean serum 25-OHD from 7 +/- 1 to 37 +/- 5 ng/ml (P less than 0.01) and urinary calcium from 102 +/- 18 to 146 +/- 17 mg/day (P less than 0.001) and decreased mean serum 1,25-(OH)2D from 40 +/- 2 to 28 +/- 2 pg/ml (P less than 0.01) and urinary cyclic AMP from 3.23 +/- 0.57 to 2.00 +/- 0.17 nM/dl GF (P less than 0.05), it did not change mean serum calcium, ionized calcium, phosphate, magnesium, immunoreactive PTH or urinary phosphate, or creatinine clearance in the obese subjects. In contrast, 25-OHD3 increased mean serum 25-OHD from 16 +/- 1 to 46 +/- 4 pg/ml (P less than 0.001) but did not alter mean serum 1,25-(OH)2D or urinary calcium or cyclic AMP in the nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation of renal cyclic adenosine monophosphate, serum parathyroid hormone and phosphate reabsorption in recurrent calcium urolithiasis, healthy controls and hyperparathyroidism (author's transl)].

In three groups (n = 12 each) of male controls (22--43 years), patients with recurring calcium urolithiasis (21--36 years) and hyperparathyroidism (HPT; 17--71 years) proven by surgery renal cyclic adenosine monophosphate (RcAMP), fractional tubular phosphate reabsorption and serum parathyroid hormone (PTH) were measured during endogenous creatinine clearance. RcAMP (muMol/g creatinine) was: controls 1.48 +/- SEM 0.27; stone formers 2.037 +/- 0.343 (not significantly different); HPT 6.234 +/- 0.454 (p less than 0.001). There is no overlap between HPT and controls. Phosphate reabsorption is least in HPT (0.84 +/- 0.015), higher in controls (0.924 +/- 0.004) and stone formers (0.941 +/- 0.007). All differences are statistically significant. Under the conditions selected (moderate hydration of individuals) Serum PHT (pg-equiv/ml) is lowest in stome formers (less than 100--339), higher in controls (less than 100--933) and HPT (400--1150). there is no overlap in PHT between the former and the latter group but a marked one between controls and HPT. For clinical purposes the resulting diagnostic uncertainty in a given patient can be overcome by additional determinations of RcAMP and ionised serum calcium: when referring to serum PTH HPT patients fall outside, RCU patients within 2 standard deviations of either parameter in control subjects. This procedure presently appears superior to those proposed in the past (urinary cAMP etc.) but requires confirmation in larger patient populations. Moreover, since HPT prevails in middle and upper age decades, their RcAMP values and those of RCU patients should be related to a range seen in closely age- and sex-matched controls.

Evidence for alteration of the vitamin D-endocrine system in blacks.

As compared with values in white subjects, bone mass is known to be increased and urinary calcium to be diminished in black individuals. To evaluate the possibility that these changes are associated with alterations in the vitamin D-endocrine system, an investigation was performed in 12 black subjects, 7 men and 5 women, and 14 white subjects, 8 men and 6 women, ranging in age from 20 to 35 yr. All of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium, 900 mg of phosphorus, and 110 meq of sodium. Whereas mean serum calcium, ionized calcium, and phosphate were the same in the two groups, mean serum immunoreactive parathyroid hormone (350 +/- 34 vs. 225 +/- 26 pg/ml, P less than 0.01) and mean serum 1,25-dihydroxyvitamin D (1,25(OH)2D) (41 +/- 3 vs. 29 +/- 2 pg/ml, P less than 0.01) were significantly higher, and mean serum 25-hydroxy-vitamin D (25-OHD) was significantly lower in the blacks than in the whites (6 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001). Mean urinary sodium and 24-h creatinine clearance were the same in the two groups, whereas mean urinary calcium was significantly lower (101 +/- 14 vs. 166 +/- 13 mg/d, P less than 0.01) and mean urinary cyclic AMP was significantly higher (3.11 +/- 0.47 vs. 1.84 +/- 0.25 nM/dl glomerular filtrate, P less than 0.01) in the blacks. Further, the blacks excreted an intravenous calcium load, 15 mg/kg body weight, as efficiently as the whites (49 +/- 3 vs. 53 +/- 3%, NS). Mean serum Gla protein was lower in blacks than in whites (14 +/- 2 vs. 24 +/- 3 ng/ml, P less than 0.02), and increased significantly in both groups in response to 1,25(OH)2D3, 4 micrograms/d for 4 d. There was a blunted response of urinary calcium to 1,25(OH)2D3 in the blacks, and mean serum calcium did not change. The results indicate that alteration of the vitamin D-endocrine system with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D as a result of secondary hyperparathyroidism may contribute to the increased bone mass in blacks. Their low serum 25-OHD is attributed to diminished synthesis of vitamin D in the skin because of increased pigment.

Hyperparathyroidism

Diagnosis The gold standard of diagnosis is the PTH immunoassay. Once an elevated PTH has been confirmed, the goal of diagnosis is to determine whether the hyperparathyroidism is primary or secondary in origin by obtaining a serum calcium level: Tertiary hyperparathyroidism has a high PTH and high serum calcium. It is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism. Hyperparathyroidism can cause hyperchloremia and increase renal bicarbonate loss, which may result in a normal anion gap metabolic acidosis. Differential diagnosis Familial benign hypocalciuric hypercalcaemia can present with similar lab changes. In this condition, the calcium creatinine clearance ratio, however, is typically under 0.01. Blood tests

Occult Renal Calcifications in Patients with Normocalcemic Primary Hyperparathyroidism and Their Association with the Parathyroid Hormone-Vitamin D Axis.

Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by elevated serum levels of parathyroid hormone (PTH) with persistently normal serum calcium concentrations after excluding secondary causes of hyperparathyroidism. Urolithiasis and/or nephrocalcinosis may occur in hypercalcemic PHPT, but little is known about these complications in NPHPT. <iObjectives</i. To identify occult urolithiasis and nephrocalcinosis in asymptomatic patients with NPHPT and evaluate biochemical markers as risk predictors for the development of renal calcification (RC). <iMethods</i. Cross-sectional analysis of 34 patients with no history of urolithiasis and/or nephrocalcinosis. The diagnosis of NPHPT was as follows: elevated serum PTH (reference range: 15-65 pg/mL), normal albumin-corrected serum calcium, normal urinary calcium excretion, serum 25(OH)D >30 ng/mL, eGFR (CKD-EPI) > 60 mL/min/1.73 m<sup2</sup, without intestinal disease, and not on medications such as thiazide diuretics, lithium, bisphosphonates, or denosumab. Patients were categorized according to the presence or absence of RC identified by renal imaging. Their clinical and biochemical characteristics were then compared. <iResults</i. The patients had a mean age of 67.97 ± 10.45 years, predominantly postmenopausal women (88.2%); serum PTH, 119.67 ± 64.44 pg/mL; 25(OH)D, 39.00 ± 8.88 ng/dL; 1.25(OH))<sub2</subD, 74.53 ± 26.37 pg/mL; corrected serum calcium, 9.34 ± 0.62 mg/dL; and 24-hour urinary calcium, 134.87 ± 79.68 mg/day. RC was identified in 26.5% of the patients. There was no difference in anthropometric and clinical parameters, renal function, 25(OH)D, and urinary pH in patients with or without RC. Patients with RC had higher PTH values (176.22 vs. 99.32 pg/mL, <iP</i = 0.001), 1.25(OH) 2D (96.83 vs. 62.36 pg/mL, <iP</i = 0.005), and 24-hour urinary calcium (181.9 vs. 117.94 mg/day, <iP</i = 0.037). <iConclusion</i. Occult renal calcifications are common in NPHPT and are associated with increased serum PTH, 1.25(OH))<sub2</subD, and 24 h urinary calcium.

[Standard procedure and the diagnostic criteria for the Ellsworth-Howard test using human PTH-(1-34)].

The present study was undertaken to establish a standard method to perform the Ellsworth-Howard test using human PTH-1-34). For this purpose we made a survey of literature concerning the Ellsworth-Howard test and then examined the data of the Ellsworth-Howard tests performed on 178 hypoparathyroid patients using human PTH-(1-34). The main items of investigation were: (i) to determine the appropriate dose of PTH for administration to adults and children; and (ii) to define the criteria of practical usefulness for the differential diagnosis of the types of hypoparathyroidism. From the analysis of the data, the following findings and conclusions were obtained. The dose of human PTH-(1-34) appropriate for diagnostic use is 100 U per person for adults and 100 U per body surface area of one square meter (100 U/m2) for children. The criteria of positive response in the Ellsworth-Howard test are defined as follows. a) phosphaturic response: (U4 + U5) - (U2 + U3) = more than 35 mg/2 h b) cyclic AMP response: U4 - U3 = more than 1 mumol/h, and U4/U3 = more than 10 times. In the above formula, U2 - U5 represent the urine samples collected hourly in order. PTH is injected at the time between U3 and U4. For the application of the criteria in children, one should use the values corrected for body surface area of one square meter. It is necessary to confirm the following conditions before the application of the criteria: the presence of hypocalcemia and hyperphosphatemia; the lack of phosphate deficiency (basal urinary phosphate excretion more than 10 mg/2 h); the accuracy of timed urine collections (ratio of creatinine excretion during 2 hours before PTH to that after PTH administration in the range from 0.8 to 1.2); and the absence of marked diurnal variation in phosphate excretion (difference in phosphate excretion between the two basal hourly urine less than 17.5 mg/h). To ensure the above conditions, medications such as phosphate-binding antacids should be withheld for at least 1 week before the test, and the test should be performed according to the standard procedure described in this paper. The diagnosis of pseudohypoparathyroidism Type II should be done cautiously. It is necessary to take account of the high basal urinary cyclic AMP excretion and the elevated serum PTH level along with the results of the Ellsworth-Howard test (positive cyclic AMP response and negative phosphaturic response) for a definite diagnosis of this entity.

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:

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:

InternalMed_Harrison

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