Vitamin D, Calcium, and Sarcoidosis

doi:10.1378/chest.109.2.535

Chest

Volume 109, Issue 2, February 1996, Pages 535-539

https://doi.org/10.1378/chest.109.2.535 Get rights and content

Hypercalcemia occurs in about 10% of the patients with sarcoidosis; hypercalciuria is about three times more frequent. These abnormalities of calcium metabolism are due to dysregulated production of 1,25-(OH)₂-D₃ (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation. Undetected hypercalcemia and hypercalciuria can cause nephrocalcinosis, renal stones, and renal failure. Corticosteroids cause prompt reversal of the metabolic defect. Chloroquine, hydroxychloroqune, and ketoconazole are the drugs that should be used if the patient fails to respond or develops dangerous side effects to corticosteroid therapy.

Section snippets

VITAMIN D AND SARCOIDOSIS

The relationship between vitamin D and sarcoidosis was first recognized by Harrell and Fisher¹¹ in 1939. They described the occurrence of hypercalcemia in 6 of 11 patients with sarcoidosis. In one of their patients, the serum calcium level rose from a value of 9.6 to 14.2 mg/dL after the consumption of cod-liver oil. Almost 6 decades ago, these authors made three pertinent clinical observations: (1) hypercalcemia is a feature of sarcoidosis; (2) hypercalcemia can be aggravated by consuming a

SYNTHESIS AND SOURCE OF 1,25-(OH)₂-D₃ IN SARCOIDOSIS

The most active metabolite of vitamin D, 1,25-(OH)₂-D₃ is produced in the kidney from 25-hydroxycholecalciferol (25-[OH]-D3) which is produced in the liver.²⁰ Bell et al²¹ reported that in three sarcoidosis patients with hypercalcemia, the plasma levels of l,25-(OH)₂-D₃ were high when calcium levels were raised and fell when calcium levels returned to normal either spontaneously or after prednisone treatment. Further evidence that abnormal levels of 1,25-(OH)₂-D₃ occur in hypercalcemia

ROLE OF 1,25-(OH)₂-D₃

Recent studies have pointed the way toward an immune regulator role for l,25-(OH)₂-D₃.26, 27 Evidence supporting its immunologic role consists of the following: (1) the presence of specific high-affinity intracellular Vitamin D receptors (VDR) for calcitriol in activated lymphocytes, macrophages, and dendritic cells;28, 29, 30 (2) l,25-(OH)₂-D₃ inhibits mitogen-induced lymphocyte proliferation and immunoglobulin production;31, 32, 33; (3) l,25-(OH)₂-D₃ reduces in lymphocyte interleukin-2 (IL-2)

HYPERCALCEMIA

The reported incidence of hypercalcemia in sarcoidosis varies from 2 to 63%. The frequency, with a few exceptions, tends to be higher in the North American series. The highest incidence of 63% was reported by McCort et al.⁴² Cummings⁴³ found calcium levels above 11 mg (100 mL)⁻¹ (2.7 mmol.⁻¹) in 35% of his patients. Mayock et al,⁴⁴ in their review of 509 patients, recorded a frequency of 17%. Similar results were obtained by Taylor et al¹³ in their study of 345 patients with sarcoidosis. Only

HYPERCALCIURIA

Although hypercalcemia has long been recognized as a complication of sarcoidosis, the importance of hypercalciuria has been less thoroughly appreciated. Nevertheless, hypercalciuria is three times more common than hypercalcemia.⁵² In some studies, its frequency seems to have reached 60% of the cases.⁵³ Hypercalciuria is slightly more common in men than women and, in London, in whites than in West Indian patients. In patients with renal function, hypercalciuria is always present when the patient

SERUM PHOSPHATE

Much less attention has been paid to serum phosphate levels in sarcoidosis. Longcope and Frieman⁶¹ found levels ranging from 2.4 to 4.8 mg (100 mL)⁻¹ (0.78 to 1.55 mmol·L⁻¹). Putkonen et al⁴⁷ found significantly low serum phosphate levels in 8 of their 57 patients; the abnormality was more marked in patients with chronic disease. Twelve of 53 patients investigated by Selroos⁶² had phosphate levels under 2.8 mg (100 mL)⁻¹ (0.9 mmol·L⁻¹; 6 of the 12 patients had stage I disease, four had stage II

WHO NEEDS TREATMENT

The magnitude and persistence of the hypercalcemia are key indications for therapy.⁶³ Severe hypercalcemia, defined as serum calcium concentration greater than 14 mg/dL, is unusual in sarcoidosis, hence aggressive treatment is rarely indicated; whereas, chronically high urinary calcium excretion always needs correcting.64, 65, 66 The goals of therapy include the following: (1) to reduce oral and IV intake of vitamin D, calcium supplement, and diet rich in calcium; (2) to maintain an expanded

DRUGS

Prednisone, 20 to 40 mg/d, is the drug of choice to reduce the endogenous production of l,25-(OH)₂-D₃.10, 67, 68 Institution of corticosteroid therapy causes a relatively swift decrease in circulating l,25-(OH)₂-D₃ and serum calcium level within 3 to 5 days. A decrease in urinary calcium excretion rate soon follows, within 7 to 10 days. Failure to normalize the serum calcium level after 2 weeks should lead the clinician to exclude the possibility of a coexisting disorder, including

DRUGS NOT RECOMMENDED

Calcitonin, indomethacin, biphosphonates, gallium nitrate, plicamycin, phosphate (oral or intravenous), and thiazide diuretics are not indicated.

ROLE OF SURGERY

Urinary stones due to untreated, persistent hypercalciuria can be pulverized by extracorporeal lithotripsy before resorting to surgery.74, 75

DIETARY RESTRICTION

Since sarcoidosis patients exhibit abnormal regulation of vitamin D metabolism, it is desirable to monitor serum calcium levels frequently. The patient should be instructed to avoid high-calcium diet, calcium supplement, and exposure to sunlight. These precautions should be strictly adhered because even normocalcemic patients with sarcoidosis may develop hypercalcemia, renal stones, and renal failure.74, 75

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Epidemiological studies on sarcoidosis in Colombia are scarce, and although recent reports from the north of the country have been published, clinical-epidemiological associations are not clear. Our aim was to characterize patients with sarcoidosis diagnosed at Fundación Valle del Lili in Cali, Colombia.
A retrospective study of a series of sarcoidosis cases was conducted between 2011 and 2019. Demographic, clinical, laboratory, imaging, histopathological, and treatment variables were analyzed.
A total of 34 patients with a diagnosis of sarcoidosis were found. The majority were women (n = 25; 73%), and the mean age was 50 years. The main symptoms of onset were erythema nodosum (n = 11; 33%), arthritis (n = 10; 30%), and cough (n = 9; 27%). In 64% of the cases, there was pulmonary involvement, with pulmonary nodules, mediastinal adenopathy, and interstitial lung disease found in 54%, 50%, and 36% of cases, respectively. In 85% of cases, there were extrapulmonary manifestations, mainly cutaneous (50%). Angiotensin-converting enzyme (ACE) was elevated in 62% of the cases in which it was measured (n = 16; 47%). During the diagnostic process, 23 biopsies were performed, of which 95% showed granulomas with noncaseating necrosis. Most of the patients (76%) were controlled with prednisolone, at an average dose of 20 mg (7.5–50 mg) per day.
Sarcoidosis was more frequent in women and mestizos, and it presented earlier in men. Elevated ACE was not associated with extrapulmonary involvement. Calcium-phosphorus profile and antinuclear antibodies were not useful to establish the diagnosis.
En Colombia son escasos los estudios epidemiológicos sobre la sarcoidosis; aunque recientemente se han publicado reportes del norte del país, son grupos muestrales pequeños, por lo que no quedan claras las asociaciones clínico-epidemiológicas. Nuestro objetivo fue caracterizar pacientes con sarcoidosis en la Fundación Valle del Lili, en Cali, Colombia.
Se realizó un estudio retrospectivo de una serie de casos de sarcoidosis entre el 2011 y el 2019. Se analizaron variables demográficas, clínicas, de laboratorio, imagenológicas, histopatológicas y de tratamiento.
Se encontraron 34 pacientes con diagnóstico de sarcoidosis, la mayoría fueron mujeres (n = 25; 73%), y la edad promedio fue 50 años. Los principales síntomas de inicio fueron eritema nudoso (n = 11; 33%), artritis (n = 10; 30%) y tos (n = 9; 27%). En el 64% de los casos hubo compromiso pulmonar, y se encontraron nódulos pulmonares, adenopatías mediastinales y enfermedad pulmonar intersticial en un 54, 50 y 36% de los casos, respectivamente. En el 85% de los casos hubo manifestaciones extrapulmonares, principalmente cutáneas (50%). Los niveles de enzima conversora de angiotensina estuvieron elevados en el 62% de los casos en los que fue medida (n = 16; 47%). Durante el proceso diagnóstico se realizaron 23 biopsias, de las cuales el 95% evidenció granulomas con necrosis no caseificante. La mayoría de los pacientes (76%) fueron controlados con prednisolona, a una dosis promedio de 20 mg (7,5-50 mg) por día.
La sarcoidosis fue más frecuente en mujeres y mestizos. La presentación fue más temprana en hombres. La enzima conversora de angiotensina no se relacionó con compromiso extrapulmonar. Ni el perfil fósforo-calcio ni los anticuerpos antinucleares fueron útiles para establecer el diagnóstico.
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Side effects of nutritional supplements, Edited by F. Anselmo, M.S. Driscoll. Vitamin and mineral supplement consumption is widespread. They are taken for a variety of conditions, including dermatologic disorders. Although consumers often assume these supplements are safe, excessive consumption of supplements may have deleterious effects. Such vitamin supplements include vitamin A, niacin, biotin, vitamin D, and vitamin E, and specific mineral supplements include zinc, copper, and iron. These supplements may have a number of potential adverse effects.
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Las enfermedades infiltrativas sistémicas son un grupo de enfermedades relativamente raras que consisten en la infiltración de células o depósito de sustancias en múltiples órganos y sistemas, entre los que se encuentran las glándulas endocrinas. En este artículo se revisan las alteraciones endocrinológicas de las cuatro más importantes a nivel epidemiológico, como son la sarcoidosis, la histiocitosis de células de Langerhans, la hemocromatosis hereditaria y la amiloidosis sistémica. En cada una de ellas se aportarán recomendaciones al endocrinólogo para el estudio hormonal de estos pacientes.
Systemic infiltrative diseases are relatively rare conditions consisting of cell infiltration or substance deposition in multiple organs and systems, including endocrine glands. This article reviews endocrine changes in the main four diseases at epidemiological level: sarcoidosis, Langerhans cell histiocytosis, hereditary hemochromatosis, and systemic amyloidosis. Recommendations to endocrinologists for hormone work-up and management of patients with each of these conditions are provided.
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Vitamin D status is involved in the risk of many chronic diseases including cancer, inflammatory and autoimmune disease. The RANK/RANKL/OPG system is also implicated in the orchestration of immune functions.
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The expression of CYP27B1 was lower in subjects with 25(OH)D3 levels below 50 nmol/L (deficiency) than subjects with both insufficient and sufficient levels of 25(OH)D3. In subjects with deficiency, we observed the up-regulation of RANKL, TNF-α, IFN-γ, ICAM and LFA-1, and a reduction of the anti-inflammatory cytokines IL-13 and IL-4 in comparison to other subjects. Finally, we found a negative correlation between RANKL mRNA levels and 25(OH)D3 and between 25(OH)D3 and ICAM mRNA levels. A positive correlation between ICAM and RANKL was observed.
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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.
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Chest

ReviewsVitamin D, Calcium, and Sarcoidosis

Section snippets

VITAMIN D AND SARCOIDOSIS

SYNTHESIS AND SOURCE OF 1,25-(OH)2-D3 IN SARCOIDOSIS

ROLE OF 1,25-(OH)2-D3

HYPERCALCEMIA

HYPERCALCIURIA

SERUM PHOSPHATE

WHO NEEDS TREATMENT

DRUGS

DRUGS NOT RECOMMENDED

ROLE OF SURGERY

DIETARY RESTRICTION

Endocrinol Metab Clin North Am

Lancet

Am J Med

Am J Med

Vitamin D-solar rays, the milky way or both

N Engl J Med

Vitamin D metabolism and biological function

Vitamin D-biosynthesis, metabolism and mode of action

Regulation of the metabolism of vitamin D

Physiol Rev

The importance of phosphate in regulating plasma l,25-(OH)2-D levels in human: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism

J Clin Endocrinol Metab

The steroid and thyroid hormone receptor superfamily

Science

Regulation of bone formation (parts I and II)

N Engl J Med

Bone mineral mobilization activity of 1-25-dihydroxy cholecalciferol, a metabolite of vitamin D

Arch Biochem Biophys

Hypercalcemia and hypercalciuria

Semin Respir Med

Blood chemical changes in Boeck's sarcoid with particular reference to protein, calcium and phosphotase values

J Clin Invest

The causes of hypercalcemia in sarcoidosis and its treatment with cortisone and sodium phytate

J Clin Invest

Seasonal influence of sunlight on the hypercalcemia of sarcoidosis

Am J Med

Calcium metabolism in sarcoidosis

Postgrad Med J

The remission of hypercalcemia and hypercalciuria in systemic sarcoidosis by vitamin D depletion

Clin Res

Studies of the hypercalcemia of sarcoidosis: effects of steroids and exogenous vitamin D3 on the circulating cencentrations of 1,25-dihydroxyvitamin D3

Q J Med

Pathogenetic role of 1,25 dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria: different response to therapy

J Clin Endocrinol Metab

Metabolism of 25-hydroxy vitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis

J Clin Invest

Metabolism of 1,25-dihydroxyvitamin D

Physiol Rev

Evidence that increase circulating 25-dihydroxy vitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis

J Clin Invest

Hypercalcemic sarcoidosis in hypoparathyroidism

BMJ

Normocalcemia in a hypothyroid patient with sarcoidosis,: evidence for parathyroid hormone independent synthesis of 1,25 dihydroxy vitamin D

Ann Intern Med

Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25 dihydroxy vitamin D

N Engl J Med

Vitamin D conversion by sarcoid lymphnode homogenate

Ann Intern Med

Vitamin D and the immune system

J Endocrinol

The immunobiology of vitamin D

Immunol Today

1,25-dihydroxy vitamin D3, a novel immunoregulatory hormone

Science

Vitamin D, endocrine and paracrine mediator in cases of pulmonary granulomatosis

Rev Mal Respir

Specific high-affinity receptors for 1,25-dihydroxy vitamin D3 in human peripheral blood mononuclear cells, presence in monocytes and induction in T lymphocytes following activation

J Clin Endocrinol Metab

Immunomodulating properties of 1,25-dihydroxy vitamin D

Kidney Int

Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxy vitamin D3 (calcitriol)

J Clin Invest

Signal dependent pleitropic regulation of lymphocyte proliferation and cytokine production by 1,25-dihydroxy vitamin D3: potent modulation of the hormonal effects by phorbol esters

Immunology

Potentiation of the macrophage 25-hydroxy vitamin D-1 hydroxylation reaction by human pleural effusion fluid

J Clin Endocrinol Metab

Reviews
Vitamin D, Calcium, and Sarcoidosis

SYNTHESIS AND SOURCE OF 1,25-(OH)₂-D₃ IN SARCOIDOSIS

ROLE OF 1,25-(OH)₂-D₃