Chronic Hypercalcemia Research Articles

The effect of primary hyperparathyroidism on pancreatic exocrine function.

Elastase-1 is a proteolytic enzyme secreted by pancreatic acinar cells, and measurements of the concentration this enzyme are used to evaluate pancreatic exocrine function. We aimed to determine whether pancreatic exocrine function declines due to chronic hypercalcemia by measuring fecal elastase levels. 75 patients with primary hyperparathyroidism (18 men and 47 women) and 30 healthy subjects (11 men and 19 women) participated in this study. Renal function tests, lipid parameters, bone mineral density, and serum calcium, phosphorus, vitamin D, parathormone, glucose, and thyroid stimulating hormone levels as well as fecal elastase concentrations, were determined in these patients and controls. The mean fecal elastase level was 335.3±181.4μg/g in the PHPT group and 317.4±157.3μg/g in the control group. There was no significant difference in fecal elastase levels between the two groups (p=0.5). Chronic hypercalcemia in primary hyperparathyroidism did not decrease the fecal elastase level, which is an indirect indicator of chronic pancreatitis; therefore, chronic hypercalcemia in PHPT may not cause chronic pancreatitis.

69-Year-Old Woman With Confusion and Fatigue

Resident in Internal Medicine, Mayo School of Graduate Medical Education, Rochester, MN (H.M.K.); Advisor to resident and Consultant in Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN (A.E.K.). A 69-year-old woman presented to her primary care physicianwith a 4-day history of fatigue and dizziness. She was 45 minutes late for her appointment because she had trouble driving to the office. She reported no motor or sensory deficits but had difficulty with coordination. Review of systems was positive for dysuria and urinary frequency. She did not have fever, chills, weight or appetite changes, respiratory, cardiac, or gastrointestinal symptoms, or recent head trauma. The patient’s medical history was remarkable for hypertension, hyperlipidemia, type 2 diabetes mellitus, osteoporosis, and gastroesophageal reflux disease. Medications included metoprolol tartrate, lisinopril with hydrochlorothiazide, lovastatin, cholecalciferol, and as-needed calcium carbonate. She had smoked half a pack of cigarettes per day for 40 years but had quit smoking 6 years previously. She didnot use alcohol or illicit drugs. On examination, the patient was afebrile with a blood pressure of 104/67 mm Hg, heart rate of 76 beats/min, respiratory rate of 17 breaths/min, oxygen saturation of 94% while breathing room air, and body mass index (calculated as weight in kilograms divided by height inmeters squared) of 39 kg/m. Shewas alert and oriented to person, place, and time. Her speech was dysarthric, and she had difficulty following simple commands. Her coordination was impaired with symmetric dysmetria on finger-to-nose testing, heel-kneeshin testing, and rapid alternating movements. Cranial nerves II through XII were intact. Results of motor and sensory examinations were within normal limits. Reflexes were symmetric. Lymph node, thyroid, cardiac, respiratory, gastrointestinal, musculoskeletal, and skin examinations identified no abnormalities.

Percutaneous ultrasound-guided alcohol ablation of solitary parathyroid adenoma in a patient with primary hyperparathyroidism

Parathyroidectomy is considered the definitive cure for primary hyperparathyroidism due to a single parathyroid adenoma, which represents the most common cause of chronic hypercalcemia. However, in few cases, surgery may be technically difficult or risky. We report the use of percutaneous ultrasound-guided alcohol ablation of a parathyroid adenoma as an alternative to surgery in an 88-year-old male patient with significant medical comorbidities.

Unexpected hypercalcemia in a diabetic patient with kidney disease

We report a case of a diabetic patient with progressive chronic kidney disease and unexplained hypercalcemia. This unusual presentation and the investigation of all possible causes led us to perform a renal biopsy. The systemic sarcoidosis diagnosis was confirmed by the presence of interstitial multiple granulomas composed of epithelioid and multinucleated giant cells delimited by a thin fibrous reaction, and by pulmonary computed tomography finding of numerous lumps with ground-glass appearance. Sarcoidosis most commonly involves lungs, lymph nodes, skin and eyes, whilst kidney is less frequently involved. When it affects males it is characterized by hypercalcemia, hypercalciuria, and progressive loss of renal function. Early treatment with steroids allows for a gradual improvement in renal function and normalization of calcium serum values. Otherwise, the patient would quickly progress to end stage renal disease. Finding of hypercalcemia in a patient with renal failure must alert physicians because it may be a sign of several pathological entities.

Familial hypocalciuric hypercalcemia associated with crystal deposition disease

Chondrocalcinosis is a common disease occasionally associated with hypercalcemia in case of primary hyperparathyroidism. Familial Hypocalciuric Hypercalcemia (FHH) is a rare and almost always asymptomatic condition, due to an autosomal dominant mutation of the calcium-sensing receptor gene. We report the case of a 61-year-old female with chronic hypercalcemia and joint pain. Clinical and biological data revealed chondrocalcinosis associated with FHH. Since primary hyperparathyroidism may mimic FHH, calcium to creatinine clearance ratio should be calculated in every case to avoid a wrong diagnosis and useless parathyroid surgery. The paucity of FFH complications, including chondrocalcinosis, makes their study difficult: additional studies are needed to clearly evaluate the link between FHH and chondrocalcinosis.

Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function.

Hypercalcaemia secondary to hypervitaminosis a in a patient with chronic renal failure.

Vitamin A toxicity is a well-described medical condition with a multitude of potential presenting signs and symptoms. It can be divided into acute and chronic toxicity. Serum vitamin A concentrations are raised in chronic renal failure even with ingestion of less than the usual toxic doses. Hypercalcaemia can occasionally be associated with high levels of vitamin A but it is rare. In this report, we describe a 67- year old female patient with chronic kidney disease who was taking vitamin A supplements for approximately 10 years. The patient had worsening of her chronic kidney disease over the last years and developed chronic hypercalcaemia. Her vitamin A level was elevated with a daily intake of 7000 IU. The vitamin A supplement was stopped. A few months later, vitamin A level diminished substantially and serum calcium levels returned to normal.

Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure

Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined. We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors. Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR. This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25(OH)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.

Management of the renal adverse effects of lithium

SummaryLithium is one of the most effective psychotropic drugs we have, but it is underused because of its low therapeutic index, the need for regular blood tests and perceptions about its adverse effects, including renal problems. The last include urinary concentration deficits and diabetes insipidus, chronic kidney disease (including renal failure), nephrotic syndrome, hypercalcaemia, hyperparathyroidism and distal tubular acidosis. This article reviews these adverse effects with special emphasis on their management.

Serum Calcitonin May Falsely Estimate Tumor Burden in Chronic Hypercalcemia: A Case of Prostatic and Multiple Bone Metastases from Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a calcitonin (Ct)-secreting tumor of the parafollicular or C cells of the thyroid gland. Higher serum Ct levels are associated with larger tumor size, distant metastases, and prognosis. We report herein a case of prostate and multiple bone metastases of nonfamilial MTC with mildly elevated Ct levels. A 73-year-old man who was found to have a 2.5 cm MTC in the left thyroid lobe with cervical lymph node metastases presented with confused mental status because of severe hypercalcemia (albumin-modified serum calcium concentration 15.2 mg/dL) associated with multiple bone metastases. Prostate biopsy was performed because the patient had frequent urination with mildly elevated serum prostate-specific antigen (5.297 ng/mL). Histologically, the prostate was diagnosed as MTC metastasis, forming a tissue architecture closely resembling the previously diagnosed MTC, and the cells were positive for Ct, carcinoembryonic antigen, and thyroid transcription factor 1. Although the patient had multiple MTC metastases, basal and calcium-stimulated serum Ct levels were not significantly elevated, measuring 22.7 pg/mL (normal <10 pg/mL) and 22.1 pg/mL, respectively. A chronic hypercalcemic state may exhaust Ct reserves and diminish the Ct response to an acute intravenous calcium injection. Therefore, the Ct level of a patient in a hypercalcemic state should be carefully interpreted. To our knowledge, this is the first reported case in the literature in which serum Ct levels were not significantly increased when associated with hypercalcemia, and an MTC metastasis to the prostate.

Pediatric Ovarian Dysgerminoma Presenting With Hypercalcemia and Chronic Constipation

Malignancy-associated hypercalcemia is a common finding among adult malignancies. However, the incidence of malignancy-induced hypercalcemia associated with germ cell tumor among pediatric patients is very rare. We describe a 9-year-old girl with an ovarian dysgerminoma presenting with chronic constipation and hypercalcemia. We review some of the causes of malignancy-associated hypercalcemia described in literature and treatment strategies. We also recommend considering oncological processes in the presence of hypercalcemia.

Muscle function and quality of life are not impaired in familial hypocalciuric hypercalcemia: a cross-sectional study on physiological effects of inactivating variants in the calcium-sensing receptor gene (CASR)

Familial hypocalciuric hypercalcemia (FHH) is often due to inactivating variants in the calcium-sensing receptor (CASR) gene causing chronically elevated plasma calcium levels with inappropriately normal or elevated parathyroid hormone levels. In patients with primary hyperparathyroidism, the state of hyperparathyroid hypercalcemia is associated with reduced muscle strength and impaired quality of life (QoL). To study whether FHH affects muscle function, postural stability, and QoL. In a cross-sectional study, we investigated muscle strength (handgrip, elbow flexion/extension, and knee flexion/extension), balance function, physical activity, and QoL in 50 patients with FHH and in a similar number of age- and gender-matched population-based healthy controls. All but one of the FHH cases had genetically verified inactivating variants in the CASR gene. Studied subjects (n=100, 68% females) had a mean age of 56.0 years. Muscle strength as assessed by measuring maximum force and maximum force production did not differ between the groups. Neither did groups differ in terms of QoL, physical activity, or postural stability, as assessed during normal standing with eyes open, normal standing with eyes closed, semi-tandem standing, or tandem standing. Adjustment for vitamin D status (plasma 25-hydroxyvitamin D levels) and BMI did not change results. Despite a state of chronic hypercalcemia, muscle strength, balance function, and QoL are not impaired in patients with FHH. Our findings are reassuring for patients with FHH as they should not be considered as having a severe disease.

Pancreatic Adenocarcinoma in a Patient With Multiple Endocrine Neoplasia 1 Syndrome

To the Editor We present the rare occurrence of a concurrent pancreatic neuroendocrine tumor (pNET) and pancreatic ductal adenocarcinoma (PDAC) in a patient with multiple endocrine neoplasia 1 (MEN1) syndrome. It is important for clinicians to consider the possibility of PDAC in patients with MEN1 because aggressive early surgical intervention provides the only chance of cure. Multiple endocrine neoplasia 1 is characterized by parathyroid adenomas, pNETs, and anterior pituitary tumors.1 Multiple endocrine neoplasia 1–associated pNETs are usually slowly progressive and associated with low malignant potential. In the context of MEN1, pancreatic NET size correlates with prognosis and the presence of metastases,2 and lesions of more than 2 cm are associated with greater genetic instability and malignant behaviour.3 The European Neuroendocrine Tumour Society recommendations for management of pancreatic lesions in a patient with MEN1 state that early diagnosis and surgical excision of MEN1-related pNET improve survival, preventing or delaying the development of distant metastases.4 It is mandatory to operate on MEN1-related nonfunctioning pancreatic tumors with metastases, size of more than 2 cm, or yearly increased size of more than 0.5 cm. Management of pNETs of less than 2 cm is controversial, current recommendation being intensive surveillance to avoid repeated intervention where lesions are typically multiple and behave in an indolent fashion.

Klinische aanpak van hypercalcemie bij de kat

Een verhoogde concentratie van totaal calcium is een onderkende afwijking op het bloedonderzoekvan de kat. De belangrijkste oorzaken van hypercalcemie bij de kat zijn neoplasie, chronischenierziekte en idiopathische hypercalcemie. Het diagnostisch onderzoek van een kat met persisterendehypercalcemie omvat verschillende stappen: een uitgebreid lichamelijk onderzoek, testen opfeliene leukemievirus en feliene immunodefi ciëntievirus, een volledig bloed- en urineonderzoek, hetbepalen van geïoniseerd calcium, radiografi eën van de thorax (en het abdomen), een echografi e vanhet abdomen en de hals en de bepaling van het parathyroïd hormoon en ‘parathyroid hormonerelatedprotein’. Een logische en specifi eke aanpak is nodig om tot een juiste diagnose te komen. Debehandeling richt zich vooral op de onderliggende oorzaak.

Incidence and prevalence of primary hyperparathyroidism in a racially mixed population.

The epidemiology of primary hyperparathyroidism (PHPT) has generally been studied in Caucasian populations. The aim was to examine the incidence and prevalence of PHPT within a racially mixed population. A descriptive epidemiologic study was performed. The study population included 3.5 million enrollees within Kaiser Permanente Southern California. All patients with at least one elevated serum calcium level (>10.5 mg/dL, 2.6 mmol/L) between 1995 and 2010 were included. Cases of PHPT were identified by electronic query of laboratory values using biochemical criteria, after exclusion of secondary or renal and tertiary hyperparathyroidism cases. The incidence and prevalence rates of PHPT were calculated according to sex, race, age group by decade, and year. Initial case finding identified 15,234 patients with chronic hypercalcemia, 13,327 (87%) of which had PHPT as defined by elevated or inappropriately normal parathyroid hormone levels. The incidence of PHPT fluctuated from 34 to 120 per 100,000 person-years (mean 66) among women, and from 13 to 36 (mean 25) among men. With advancing age, incidence increased and sex differences became pronounced (incidence 12-24 per 100,000 for both sexes younger than 50 y; 80 and 36 per 100,000 for women and men aged 50-59 y, respectively; and 196 and 95 for women and men aged 70-79 y, respectively). The incidence of PHPT was highest among blacks (92 women; 46 men, P < .0001), followed by whites (81 women; 29 men), with rates for Asians (52 women, 28 men), Hispanics (49 women, 17 men), and other races (25 women, 6 men) being lower than that for whites (P < .0001). The prevalence of PHPT tripled during the study period, increasing from 76 to 233 per 100,000 women and from 30 to 85 per 100 000 men. Racial differences in prevalence mirrored those found in incidence. PHPT is the predominant cause of hypercalcemia and is increasingly prevalent. Substantial differences are found in the incidence and prevalence of PHPT between races.

A Case of Isolated Small Intestinal Wall Calcification on Patient with Continuous Ambulatory Peritoneal Dialysis

The metastatic calcification is defined as the deposition of calcium salt in normal tissue with an abnormal serum biochemical environment, such as chronic kidney disease, hyperparathyroidism, and hypercalcemia related with malignancy. Although the metastatic calcification can develop in any organs and tissues, presenting its symptoms and complications are rare. Thus a few cases have been reported. This case shows the metastatic calcification of the small intestine without any peritoneal and mesenteric vascular calcification which was early diagnosed by computed tomography and mesenteric angiography in a patient with abdominal pain, receiving continuous ambulatory peritoneal dialysis due to end stage renal disease. The clinician should early consider the metastatic calcification as differential diagnosis when unidentified calcifications are noted in simple abdominal X-ray such as in the present case, and promptly confirm it by using appropriate diagnostic tests in order to prevent its complications and progression.

An unusual case of episodic quadriparesis

The natural history of untreated asymptomatic primary hyperparathyroidism (PHPT) remains incompletely understood. Increased level of parathyroid hormone produces the characteristic biochemical phenotype of hypercalcemia, hypophosphatemia and the various clinical sequelae of chronic hypercalcemia. Periodic paralysis (PP) is a group of disorders of different etiologies with episodic, short-lived and hyporeflexic skeletal muscle weakness, with or without myotonia, but without sensory deficit and without loss of consciousness. However, PHPT has rare association with episodic quadriparesis mimicking as PP.

OFF-LABEL USE OF PAMIDRONATE IN HYPER-CALCEMIC NEWBORN AFFECTED BY SUBCUTANEOUS FAT NECROSIS AFTER THERAPEUTIC HYPOTERMIA

Background: Subcutaneous fat necrosis is a dermatological disorder with characteristic subcutaneous nodules or plaques. It has a benign nature and generally runs a self-limiting course, although can cause significant and dangerous complications, including hypercalcemia. Outbreak of hypercalcemia occurs even several months after hypothermic treatment in asymptomatic or symptomatic way. Irritability, lethargy, hypotonia, emesis, polyuria, polydipsia, constipation and failure to thrive are the most common symptoms of hypercalcemia while seizures, cardiac arrest and acute or chronic renal failure are the most serious manifestations. Chronic hypercalcemia is also associated with nephrocalcinosis and metastatic calcifications of skin, heart, lever and vessels. Low calcium and vitamine D formula preparation milk, diuretics, such as furosemide, and corticosteroids are first-line treatments. In some refractory case pamidronate is used. Pamidronate is a biphosphonate which can modulate bone turnover by leading hydroxyapatite crystals, and it can inhibit osteoclastic bone resorption. Observation: A male full-term infant weighing 2,300 grams was born after an emergency cesarean section due to fetal heart rate decelerations. His initial Apgar scores were 1 at 1 minute, 4 at 5 minutes and 8 at 15 minutes. Due to hypoxicischaemic encephalopathy (stage 1 of Sarnat classification, with abnormal voltage and paroxysmal activities at electroencephalogram),a whole-body therapeutic hypothermia was initiated before sixth hour of life. It was performed to a target rectal temperature of 33,5&deg;C, for about 36 hours. In the third day of life, he developed characteristic subcutaneous fat necrosis skin lesions, such as firm, indurated plaques and red and violaceous nodules, on the upper back area and buttocks. One month after the hypotermic treatment the infant developed a rapid, asymptomatic increase of calcemia. First his milk was changed to a very low calcium and vitamin D formula preparation, without a clinical improvement. Hypercalcemia (total serum calcium 13,8 mg/dL [reference range 9-10.9 mg/dL] and ionized calcium 1,96 mmol/L [reference range 1,12-1,32 mmol/L]) was successfully treated with a 3-days therapy of intravenous pamidronate at dose of 0,5 mg/kg/die. No side effects were detected during the treatment and then serum calcium levels remained stable.

OFF-LABEL USE OF PAMIDRONATE IN HYPER-CALCEMIC NEWBORN AFFECTED BY SUBCUTANEOUS FAT NECROSIS AFTER THERAPEUTIC HYPOTERMIA

Background: Subcutaneous fat necrosis is a dermatological disorder with characteristic subcutaneous nodules or plaques. It has a benign nature and generally runs a self-limiting course, although can cause significant and dangerous complications, including hypercalcemia. Outbreak of hypercalcemia occurs even several months after hypothermic treatment in asymptomatic or symptomatic way. Irritability, lethargy, hypotonia, emesis, polyuria, polydipsia, constipation and failure to thrive are the most common symptoms of hypercalcemia while seizures, cardiac arrest and acute or chronic renal failure are the most serious manifestations. Chronic hypercalcemia is also associated with nephrocalcinosis and metastatic calcifications of skin, heart, lever and vessels. Low calcium and vitamine D formula preparation milk, diuretics, such as furosemide, and corticosteroids are first-line treatments. In some refractory case pamidronate is used. Pamidronate is a biphosphonate which can modulate bone turnover by leading hydroxyapatite crystals, and it can inhibit osteoclastic bone resorption. Observation: A male full-term infant weighing 2,300 grams was born after an emergency cesarean section due to fetal heart rate decelerations. His initial Apgar scores were 1 at 1 minute, 4 at 5 minutes and 8 at 15 minutes. Due to hypoxicischaemic encephalopathy (stage 1 of Sarnat classification, with abnormal voltage and paroxysmal activities at electroencephalogram),a whole-body therapeutic hypothermia was initiated before sixth hour of life. It was performed to a target rectal temperature of 33,5°C, for about 36 hours. In the third day of life, he developed characteristic subcutaneous fat necrosis skin lesions, such as firm, indurated plaques and red and violaceous nodules, on the upper back area and buttocks. One month after the hypotermic treatment the infant developed a rapid, asymptomatic increase of calcemia. First his milk was changed to a very low calcium and vitamin D formula preparation, without a clinical improvement. Hypercalcemia (total serum calcium 13,8 mg/dL [reference range 9-10.9 mg/dL] and ionized calcium 1,96 mmol/L [reference range 1,12-1,32 mmol/L]) was successfully treated with a 3-days therapy of intravenous pamidronate at dose of 0,5 mg/kg/die. No side effects were detected during the treatment and then serum calcium levels remained stable.

Treatment of Chronic Hypercalcemia

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .