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Frank L, Brandt S, Wabitsch M. Subcutaneous fat necrosis in newborns: a systematic literature review of case reports and model of pathophysiology. Mol Cell Pediatr 2022; 9:18. [PMID: 36427118 PMCID: PMC9700527 DOI: 10.1186/s40348-022-00151-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Subcutaneous fat necrosis of the newborn (SCFN) is a rare disease occurring in the first days of life. Characteristically, the infants show hard nodules in subcutaneous tissue, purple or erythematous in color and appear on the upper back, cheeks, buttocks and limbs. In most cases, SCFN is a self-limiting disease, as the nodules disappear in up to 6 months. A severe complication associated with SCFN is hypercalcaemia. Pathophysiological mechanisms causing SCFN or associated hypercalcaemia are not fully understood yet. METHODS A systematic literature research including the six biggest databases for medical research has been used to identify all published case reports of SCFN. N = 206 publications has been identified containing n = 320 case reports. All cases have been classified into four subgroups (depending on reported serum-calcium-level): hypercalcaemia, normocalcaemia, hypocalcaemia or no information given. Reported maternal factors, birth characteristics, details about SCFN, diagnostics, therapy and long-term observations have been extracted from publications. RESULTS This is the first systematic literature research that summed up all published cases of SCFN from 1948 up to 2018. Information about serum calcium level was given in 64.3% of the cases. From those, the majority showed hypercalcaemia (70.5%) (normocalcaemia 25.1%, hypocalcemia 4.3%). 89.3% of newborns with hypercalcaemia showed suppressed levels of the parathormone. Maternal gestational diabetes, maternal hypertensive diseases during pregnancy, macrosomia (> 4000g), asphyxia and therapeutic hypothermia are risk factors for SCFN. Histological findings showed a granulomatous inflammation in 98% of cases. CONCLUSION We identified that maternal, birth characteristics and therapeutic measures are probably risk factors for SCFN. These risk factors should be taken into account within the care of neonates.
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Affiliation(s)
- Leonie Frank
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
- Department of Orthopaedics and Trauma Surgery, Oberschwaben Clinic Wangen im Allgäu, Wangen im Allgäu, Germany
| | - Stephanie Brandt
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
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Motlaghzadeh Y, Bilezikian JP, Sellmeyer DE. Rare Causes of Hypercalcemia: 2021 Update. J Clin Endocrinol Metab 2021; 106:3113-3128. [PMID: 34240162 DOI: 10.1210/clinem/dgab504] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Primary hyperparathyroidism and malignancy are the etiologies in 90% of cases of hypercalcemia. When these entities are not the etiology of hypercalcemia, uncommon conditions need to be considered. In 2005, Jacobs and Bilezikian published a clinical review of rare causes of hypercalcemia, focusing on mechanisms and pathophysiology. This review is an updated synopsis of rare causes of hypercalcemia, extending the observations of the original article. EVIDENCE ACQUISITION Articles reporting rare associations between hypercalcemia and unusual conditions were identified through a comprehensive extensive PubMed-based search using the search terms "hypercalcemia" and "etiology," as well as examining the references in the identified case reports. We categorized the reports by adults vs pediatric and further categorized the adult reports based on etiology. Some included reports lacked definitive assessment of etiology and are reported as unknown mechanism with discussion of likely etiology. EVIDENCE SYNTHESIS There is a growing understanding of the breadth of unusual causes of hypercalcemia. When the cause of hypercalcemia is elusive, a focus on mechanism and review of prior reported cases is key to successful determination of the etiology. CONCLUSIONS The ever-expanding reports of patients with rare and even unknown mechanisms of hypercalcemia illustrate the need for continued investigation into the complexities of human calcium metabolism.
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Affiliation(s)
- Yasaman Motlaghzadeh
- Stanford University School of Medicine, Division of Endocrinology, Gerontology and Metabolism, Palo Alto, CA 94305, USA
| | - John P Bilezikian
- Division of Endocrinology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Deborah E Sellmeyer
- Stanford University School of Medicine, Division of Endocrinology, Gerontology and Metabolism, Palo Alto, CA 94305, USA
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Innao V, Allegra A, Ginaldi L, Pioggia G, De Martinis M, Musolino C, Gangemi S. Reviewing the Significance of Vitamin D Substitution in Monoclonal Gammopathies. Int J Mol Sci 2021; 22:4922. [PMID: 34066482 PMCID: PMC8124934 DOI: 10.3390/ijms22094922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 11/25/2022] Open
Abstract
Vitamin D is a steroid hormone that is essential for bone mineral metabolism and it has several other effects in the body, including anti-cancer actions. Vitamin D causes a reduction in cell growth by interrupting the cell cycle. Moreover, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, exerts various effects via its interaction with the vitamin D receptor on the innate and adaptive immune system, which could be relevant in the onset of tumors. Multiple myeloma is a treatable but incurable malignancy characterized by the growth of clonal plasma cells in protective niches in the bone marrow. In patients affected by multiple myeloma, vitamin D deficiency is commonly correlated with an advanced stage of the disease, greater risk of progression, the development of pathological fractures, and a worse prognosis. Changes in the vitamin D receptor often contribute to the occurrence and progress of deficiencies, which can be overcome by supplementation with vitamin D or analogues. However, in spite of the findings available in the literature, there is no clear standard of care and clinical practice varies. Further research is needed to better understand how vitamin D influences outcomes in patients with monoclonal gammopathies.
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Affiliation(s)
- Vanessa Innao
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
| | - Alessandro Allegra
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (L.G.); (M.D.M.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 Teramo, 64100 Teramo, Italy
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy;
| | - Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (L.G.); (M.D.M.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 Teramo, 64100 Teramo, Italy
| | - Caterina Musolino
- Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, Division of Haematology, University of Messina, 98125 Messina, Italy; (V.I.); (C.M.)
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
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Makris K, Bhattoa HP, Cavalier E, Phinney K, Sempos CT, Ulmer CZ, Vasikaran SD, Vesper H, Heijboer AC. Recommendations on the measurement and the clinical use of vitamin D metabolites and vitamin D binding protein - A position paper from the IFCC Committee on bone metabolism. Clin Chim Acta 2021; 517:171-197. [PMID: 33713690 DOI: 10.1016/j.cca.2021.03.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/10/2021] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
Vitamin D, an important hormone with a central role in calcium and phosphate homeostasis, is required for bone and muscle development as well as preservation of musculoskeletal function. The most abundant vitamin D metabolite is 25-hydroxyvitamin D [25(OH)D], which is currently considered the best marker to evaluate overall vitamin D status. 25(OH)D is therefore the most commonly measured metabolite in clinical practice. However, several other metabolites, although not broadly measured, are useful in certain clinical situations. Vitamin D and all its metabolites are circulating in blood bound to vitamin D binding protein, (VDBP). This highly polymorphic protein is not only the major transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites, but also participates in the transport of the 25(OH)D into the cell via a megalin/cubilin complex. The accurate measurement of 25(OH)D has proved a difficult task. Although a reference method and standardization program are available for 25(OH)D, the other vitamin D metabolites still lack this. Interpretation of results, creation of clinical supplementation, and generation of therapeutic guidelines require not only accurate measurements of vitamin D metabolites, but also the accurate measurements of several other "molecules" related with bone metabolism. IFCC understood this priority and a committee has been established with the task to support and continue the standardization processes of vitamin D metabolites along with other bone-related biomarkers. In this review, we present the position of this IFCC Committee on Bone Metabolism on the latest developments concerning the measurement and standardization of vitamin D metabolites and its binding protein, as well as clinical indications for their measurement and interpretation of the results.
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Affiliation(s)
- Konstantinos Makris
- Clinical Biochemistry Department, KAT General Hospital, 14561 Athens, Greece; Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", Medical School, University of Athens, Athens, Greece.
| | - Harjit P Bhattoa
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Etienne Cavalier
- Department of Clinical Chemistry, University of Liège, CHU de Liège, Domaine du Sart-Tilman, B-4000 Liège, Belgium
| | - Karen Phinney
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD, USA
| | - Christopher T Sempos
- Coordinator, Vitamin D Standardization Program (VDSP), Havre de Grace, MD 21078, USA
| | - Candice Z Ulmer
- Clinical Chemistry Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Samuel D Vasikaran
- PathWest Laboratory Medicine, Fiona Stanley Hospital, Murdoch, WA, Australia
| | - Hubert Vesper
- Clinical Chemistry Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Annemieke C Heijboer
- Department of Clinical Chemistry, Endocrine Laboratory, Amsterdam Gastroenterology Endocrinology & Metabolism, Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
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Bettuzzi T, Ram-Wolff C, Hau E, de Masson A, Vignon-Pennamen MD, Beylot-Barry M, Cormier C, Bagot M. Severe hypercalcemia complicating granulomatous slack skin disease: an exceptional case. J Eur Acad Dermatol Venereol 2019; 33:e354-e356. [PMID: 31026372 DOI: 10.1111/jdv.15646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- T Bettuzzi
- Dermatology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - C Ram-Wolff
- Dermatology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - E Hau
- Dermatology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - A de Masson
- Dermatology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - M D Vignon-Pennamen
- Pathology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - M Beylot-Barry
- Dermatology Department, CHU Bordeaux, Bordeaux University, Hospital Saint-André, 1 rue Jean Burguet, 33075, Bordeaux, France
| | - C Cormier
- Rhumatology Department, Hospital Cochin, Paris 5 University, 27 rue du faubourg saint Jacques, 75014, Paris, France
| | - M Bagot
- Dermatology Department, Hospital St Louis, Paris 7 University, 1 Avenue Claude Vellefaux, 75010, Paris, France
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Wimalawansa SJ, Razzaque MS, Al-Daghri NM. Calcium and vitamin D in human health: Hype or real? J Steroid Biochem Mol Biol 2018; 180:4-14. [PMID: 29258769 DOI: 10.1016/j.jsbmb.2017.12.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/04/2017] [Accepted: 12/14/2017] [Indexed: 12/18/2022]
Abstract
The incidence and prevalence of vitamin D deficiency are increasing worldwide. It is estimated that over 50% of the world's population have low vitamin D (i.e., hypovitaminosis D; serum levels below 30 ng/mL). In vitamin D inadequacy, human physiological systems work inefficiently. In humans, 80% of the vitamin D is synthesized in the presence of ultraviolet rays from sunlight; for the rest, we rely on diet and nowadays, supplements. The latter becomes important when one is exposed to less than optimal amounts of sunlight, inability to generate vitamin D in the skin efficiently, and/or having conditions that lead to decreased intestinal absorption or increased catabolism of vitamin D. The normal serum 25-hydroxyvitamin D [25(OH)D] level is around 30 ng/mL (75 nmol/L) and the optimal range is between 30 and 60 ng/mL (75-150 nmol/L). In 2011, the Institute of Medicine (IOM) suggested that 600IU of vitamin D is adequate for people below age 71 who are not exposed to sunshine. Although this might be relevant to the ambulatory healthy white Caucasians to achieve serum 25(OH)D level of 20 ng/mL, but it is insufficient for other ethnic groups. Moreover, the IOM recommendations are not suitable for those who live outside North America. Vitamin D requirements are higher during adolescence, pregnancy and lactation, and in many other disease conditions. Most clinicians consider 30 ng/mL as the minimum serum level of 25(OH)D necessary to maintain good health. In the absence of sunlight exposure and with daily oral intake of 600IU vitamin D, very few people would reach serum 25(OH)D level above 30 ng/mL. While an additional daily intake of 1000IU of vitamin D are required for people with lighter-skin color, those with darker complexion and the elderly, require a minimum of 2000IU/day to maintain serum 25(OH)D levels over 30 ng/mL; 5000 IU/day supplement is considered as the safe daily upper limit of supplementation. Vulnerable groups such as the disabled and/or house-bound, obese, with gastrointestinal abnormalities and/or malabsorption syndromes, institutionalized people (e.g., nursing homes, prisons, etc.), and pregnant and lactating women need approximately 4000IU per day for optimal physiological activity. Vitamin D is essential for gastrointestinal calcium absorption, mineralization of osteoid tissue and maintenance of serum ionized calcium level. It is also important for other physiological functions, such as muscle strength, neuromuscular coordination, hormone release, subduing autoimmunity, and curtailing the development of certain cancers.
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Affiliation(s)
- Sunil J Wimalawansa
- Endocrinology, Metabolism & Nutrition, 661 Darmody Avenue North Brunswick, NJ, 08902, USA.
| | - Mohammed S Razzaque
- Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
| | - Nasser M Al-Daghri
- Prince Mutaib Chair for Biomarkers of Osteoporosis, Department of Biochemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
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7
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The When, What & How of Measuring Vitamin D Metabolism in Clinical Medicine. Nutrients 2018; 10:nu10040482. [PMID: 29652819 PMCID: PMC5946267 DOI: 10.3390/nu10040482] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/03/2018] [Accepted: 04/11/2018] [Indexed: 12/18/2022] Open
Abstract
We now have the ability to measure a number of different vitamin D metabolites with very accurate methods. The most abundant vitamin D metabolite, 25-hydroxyvitamin D, is currently the best marker for overall vitamin D status and is therefore most commonly measured in clinical medicine. The added value of measuring metabolites beyond 25-hydroxyvitamin D, like 1,25-, and 24,25-dihydroxyvitamin D is not broadly appreciated. Yet, in some more complicated cases, these metabolites may provide just the information needed for a legitimate diagnosis. The problem at present, is knowing when to measure, what to measure and how to measure. For 25-hydroxyvitamin D, the most frequently used automated immunoassays do not meet the requirements of today’s standards for certain patient groups and liquid chromatography-tandem mass spectrometry is the desired method of choice in these individuals. The less frequently measured 1,25-dihydroxyvitamin D metabolite enables us to identify a number of conditions, including 1α-hydroxylase deficiency, hereditary vitamin D-resistant rickets and a number of granulomatous diseases or lymphoproliferative diseases accompanied by hypercalcaemia. Furthermore, it discriminates between the FGF23-mediated and non-FGF23-mediated hypophosphatemic syndromes. The 24,25-dihydroxyvitamin D metabolite has proven its value in the diagnosis of idiopathic infantile hypercalcaemia and has the potential of having value in identifying other diseases. For both metabolites, the understanding of the origin of differences between assays is limited and requires further attention. Nonetheless, in every way, appropriate measurement of vitamin D metabolism in the clinical laboratory hinges eminently on the comprehension of the value of the different metabolites, and the importance of the choice of method.
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Bikle DD, Patzek S, Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review. Bone Rep 2018; 8:255-267. [PMID: 29963603 PMCID: PMC6021194 DOI: 10.1016/j.bonr.2018.02.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/06/2018] [Accepted: 02/23/2018] [Indexed: 01/13/2023] Open
Abstract
Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH)2D via the enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH)2D. Only in certain granulomatous diseases such as sarcoidosis does the extra renal tissue produce sufficient 1,25(OH)2D to contribute to the circulating levels, generally associated with hypercalcemia, as illustrated by the case report preceding the review. Therefore the expression of CYP27b1 outside the kidney under normal circumstances begs the question why, and in particular whether the extra renal production of 1,25(OH)2D has physiologic importance. In this chapter this question will be discussed. First we discuss the sites for extra renal 1,25(OH)2D production. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH)2D3 production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue specific deletion of CYP27b1, the role of extra renal CYP27b1 expression in normal and pathologic states can now be addressed definitively.
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Affiliation(s)
- Daniel D Bikle
- Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California San Francisco, United States
| | - Sophie Patzek
- Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California San Francisco, United States
| | - Yongmei Wang
- Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California San Francisco, United States
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9
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Kono M, Hasegawa T, Nagai S, Odani T, Akikawa K, Nomura Y, Sato H, Kikuchi K, Amizuka N, Kikuchi H. Palisaded neutrophilic and granulomatous dermatitis as a novel cause of hypercalcemia: A case report. Medicine (Baltimore) 2017; 96:e6968. [PMID: 28538395 PMCID: PMC5457875 DOI: 10.1097/md.0000000000006968] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a benign, inflammatory dermatosis with distinct histopathological features often observed in patients with systemic diseases. There were no reports of PNGD without underlying systemic diseases as an underlying cause of hypercalcemia. Herein, we report a case of a 62-year-old man with hypercalcemia due to PNGD, but with no underlying systemic diseases, including tuberculosis, sarcoidosis, or vasculitis. PATIENT CONCERNS Laboratory tests showed an elevated C-reactive protein level, an elevated corrected calcium level, a normal 25-hydroxyvitamin D level, and an elevated 1,25-dihydroxyvitamin D level. There were no other abnormalities to explain the hypercalcemia. Positron emission tomography-computed tomography showed abnormal uptake in his skin. Histopathological examination of the skin showed palisaded granulomatous infiltrate in the dermis. Neutrophils, degenerated collagen, and fibrin were present in the centers of the palisades without prominent mucin. There were no eosinophils, central necrosis, or necrotizing vasculitides. These features were consistent with PNGD. DIAGNOSES A diagnosis of PNGD with hypercalcemia was established. INTERVENTIONS Oral prednisolone was administered to the patient. OUTCOMES After treatment, his symptoms resolved, and his calcium, 1,25-dihydroxyvitamin D and CRP levels returned to normal. Skin specimens before and after treatment were assessed using immunohistochemistry for 1a-hydroxylase. Granuloma and epidermal cells were 1a-hydroxylase-positive before treatment. After treatment, the granuloma diminished in size and the 1ahydroxylase-positive areas of the epidermal cells decreased. LESSONS This case was particularly unique because increased 1a-hydroxylase expression in the granuloma and epidermal cells seemed to result in hypercalcemia due to excessive transformation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Physicians should consider PNGD as an underlying cause of hypercalcemia.
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Affiliation(s)
- Michihito Kono
- Third Department of Internal Medicine, Hokkaido P.W.F.A.C., Obihiro-Kosei General Hospital, Obihiro
| | - Tomoka Hasegawa
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo
| | - So Nagai
- Department of Diabetes and Endocrinology, Sapporo Medical Center, NTT EC, Sapporo
| | - Toshio Odani
- Third Department of Internal Medicine, Hokkaido P.W.F.A.C., Obihiro-Kosei General Hospital, Obihiro
| | - Kazumasa Akikawa
- Third Department of Internal Medicine, Hokkaido P.W.F.A.C., Obihiro-Kosei General Hospital, Obihiro
| | | | | | - Keisuke Kikuchi
- Division of Pathology, Hokkaido P.W.F.A.C., Obihiro-Kosei General Hospital, Obihiro, Japan
| | - Norio Amizuka
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo
| | - Hideaki Kikuchi
- Third Department of Internal Medicine, Hokkaido P.W.F.A.C., Obihiro-Kosei General Hospital, Obihiro
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Adashek J, Mu W, Francis J, Cohen B, Pruette C, Grossberg A, Bodurtha J. Incontinentia Pigmenti with Persistent Hypercalcemia: Case Report. Pediatr Dermatol 2016; 33:e315-7. [PMID: 27412134 DOI: 10.1111/pde.12925] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Incontinentia pigmenti (IP) is an X-linked dominant disorder that in most cases is considered lethal in males. IP affects the skin, hair, teeth, nails, eyes, and central nervous system. We report a case of persistent hypercalcemia (10.6-11.3 mg/dL) in a 19-month-old Caucasian boy with clinical IP. The proposed mechanism for his hypercalcemia is discussed.
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Affiliation(s)
- Jacob Adashek
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California.
| | - Weiyi Mu
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Jacquelyn Francis
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Bernard Cohen
- Division of Pediatric Dermatology, Johns Hopkins University, Baltimore, Maryland
| | - Cozumel Pruette
- Division of Pediatric Nephrology, Johns Hopkins University, Baltimore, Maryland
| | - Annie Grossberg
- Division of Pediatric Dermatology, Johns Hopkins University, Baltimore, Maryland
| | - Joann Bodurtha
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
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Varallo-Nunez A, Ho MY, Varikatt W. Granulomatous slack skin: a case report. Pathology 2016; 48:89-91. [PMID: 27020219 DOI: 10.1016/j.pathol.2015.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
MESH Headings
- Abdomen/pathology
- Antigens, CD/metabolism
- Gene Rearrangement, T-Lymphocyte
- Humans
- Lymphoma, T-Cell, Cutaneous/diagnosis
- Lymphoma, T-Cell, Cutaneous/genetics
- Lymphoma, T-Cell, Cutaneous/pathology
- Male
- Middle Aged
- Neoplasm Recurrence, Local/diagnosis
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Skin Neoplasms/diagnosis
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
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Affiliation(s)
| | - Man-Yuk Ho
- NSW Health, Nepean Hospital, Haematology Department, NSW, Australia
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12
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Yamada S, Uemura M, Tokumoto M, Nagara T, Noguchi H, Hirahashi M, Nakano T, Tsuruya K, Kitazono T. Hypercalcemia induced by Rosai-Dorfman disease in a hemodialysis patient: histological evidence of extrarenal calcitriol overproduction. Intern Med 2014; 53:2783-7. [PMID: 25500439 DOI: 10.2169/internalmedicine.53.3001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Rosai-Dorfman disease (RDD) is a rare disorder characterized by the proliferation of histiocytes in the sinus of the affected lymph nodes, which leads to massive lymphadenopathy. RDD usually presents as an increased inflammatory response and lymph node swelling. We herein report the case of a hemodialysis patient with a fever, hypercalcemia and increased serum calcitriol level who was histologically diagnosed to have RDD. Immunohistochemistry revealed an increased expression of 1α-hydroxylase by histiocytes in the dilated sinus, indicating the extrarenal overproduction of calcitriol. Treatment with oral prednisolone decreased the serum levels of inflammatory markers and calcitriol, normalized the serum calcium level and mitigated the systemic lymph node enlargement.
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Affiliation(s)
- Shunsuke Yamada
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan
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Moraitis AG, Hewison M, Collins M, Anaya C, Holick MF. Hypercalcemia associated with mineral oil-induced sclerosing paraffinomas. Endocr Pract 2013; 19:e50-6. [PMID: 23337133 DOI: 10.4158/ep12092.cr] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Granuloma-forming diseases such as sarcoidosis are associated with extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)₂D]. We describe a case of extensive skin lesions associated with mineral oil injections in which we provide evidence for cutaneous granuloma synthesis of 1,25(OH)₂D in the pathogenesis of the patient's hypercalcemia. METHODS Analysis of expression of the 25(OH)D-1a-hydroxylase (1-a OHase [CYP27b1]) was carried out by immunohistochemical analysis of involved skin. RESULTS In involved skin, expression of CYP27b1 was found in the dermis, where it is not normally expressed. Successful management of hypercalcemia was achieved with glucocorticoids. CONCLUSIONS Hypercalcemia associated with mineral oil induced skin lesions is likely driven by unregulated expression of CYP27b1 by inflammatory monocytes and macrophages infiltrating the dermis.
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Affiliation(s)
- Andreas G Moraitis
- Eunice Shriver Kennedy National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.
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Iwakura T, Ohashi N, Tsuji N, Naito Y, Isobe S, Ono M, Fujikura T, Tsuji T, Sakao Y, Yasuda H, Kato A, Fujiyama T, Tokura Y, Fujigaki Y. Calcitriol-induced hypercalcemia in a patient with granulomatous mycosis fungoides and end-stage renal disease. World J Nephrol 2013; 2:44-48. [PMID: 24175265 PMCID: PMC3782225 DOI: 10.5527/wjn.v2.i2.44] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Revised: 03/27/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease (ESRD) in April 2012. On admission, his corrected serum calcium level was 9.3 mg/dL, and his intact parathyroid hormone level was 121.9 pg/mL (normal range 13.9-78.5 pg/mL), indicating secondary hyperparathyroidism due to ESRD. After starting hemodialysis, urinary volume diminished rapidly. The serum calcium level increased (12.7 mg/dL), and the intact parathyroid hormone level was suppressed (< 5 pg/mL), while the 1,25-dihydroxyvitamin D3 (calcitriol) level increased (114 pg/mL, normal range: 20.0-60.0 pg/mL) in June 2012. The possibilities of sarcoidosis and tuberculosis were ruled out. Skin biopsies from tumorous lesions revealed a diagnosis of granulomatous mycosis fungoides. The serum soluble interleukin-2 receptor levels and the degrees of skin lesions went in parallel with the increased serum calcium and calcitriol levels. Therefore, the patient was diagnosed as having calcitriol-induced hypercalcemia possibly associated with granulomatous mycosis fungoides. Granulomatous mycosis fungoides is rare, and its association with calcitriol-induced hypercalcemia has not been reported. Careful attention to calcium metabolism is needed in patients with granulomatous mycosis fungoides, especially in patients with ESRD.
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Abstract
The incidence of vitamin D deficiency is rising worldwide, yet in the vast majority of patients, the condition remains undiagnosed and untreated. Current evidence overwhelmingly indicates that supplemental doses greater than 800 IU/day have beneficial effects on the musculoskeletal system, improving skeletal homeostasis, thus leading to fewer falls and fractures. Evidence is also accumulating on the beneficial effects of vitamin D on extraskeletal systems, such as improving immune health, autoimmune disorders, cancer, neuromodulation, diabetes, and metabolic syndrome. The cause-effect relationship of vitamin D deficiency with increasing incidences of nonskeletal disorders is being investigated. Published reports support the definition of sufficiency, serum levels of 25-hydroxyvitamin D [25(OH)D] greater than 30 ng/mL (75 nmol/L). To achieve this, most people need vitamin D supplementation ranging from 600 to 2000 IU/day; consumption up to of 5000 international units (IU) per day of vitamin D is reported as safe. Although light-skinned individuals need 1000 IU/day of vitamin D, elderly and dark-skinned individuals are likely to need approximately 2000 IU/day to maintain serum 25(OH)D levels greater than 30 ng/mL. Other vulnerable patients, such as the obese, those who have undergone bariatric surgery, and those with gastrointestinal malabsorption syndromes, may require higher doses of vitamin D to maintain normal serum levels and be healthy.
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Affiliation(s)
- Sunil J Wimalawansa
- Physiology & Integrative Biology, Endocrinology, Metabolism & Nutrition, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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Abstract
Interaction between vitamin D and the immune system has been recognized for many years, but its relevance to normal human physiology has only become evident in the past 5 years. Studies of innate immune responses to pathogens such as Mycobacterium tuberculosis have shown that pathogen-recognition receptor-mediated activation of localized vitamin D metabolism and signaling is a key event associated with infection. Vitamin D, acting in an intracrine fashion, is able to induce expression of antibacterial proteins and enhance the environment in which they function. The net effect of these actions is to support increased bacterial killing in a variety of cell types. The efficacy of such a response is highly dependent on vitamin D status; in other words, the availability of circulating 25-hydroxyvitamin D for intracrine conversion to active 1,25-dihydroxyvitamin D by the enzyme 25-hydroxyvitamin D-1α-hydroxylase. The potential importance of this mechanism as a determinant of human disease is underlined by increasing awareness of vitamin D insufficiency across the globe. This Review will explore the molecular and cellular systems associated with antibacterial responses to vitamin D in different tissues and possible consequences of such a response for the prevention and treatment of human immune disorders.
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Affiliation(s)
- Martin Hewison
- Department of Orthopaedic Surgery, Room 410D, Orthopaedic Hospital Research Center, 615 Charles E. Young Drive South, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab 2010; 95:3111-7. [PMID: 20427501 DOI: 10.1210/jc.2009-2673] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
CONTEXT Calcitriol-mediated hypercalcemia resulting from elevated extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase) activity has not previously been described in giant cell polymyositis. CASE We report an unusual case of hypercalcemia due to disseminated granulomatous disease in a 62-yr-old woman with profound proximal muscle weakness and weight loss. She was initially diagnosed with vitamin D deficiency myopathy with a low serum 25-hydroxyvitamin D; serum calcium at this time was low-normal. Vitamin D(3) 3000 IU daily was prescribed. One month later, blood work showed new hypercalcemia and hypercalciuria with normalized 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D was high-normal, despite a suppressed PTH, undetectable PTHrP, and essentially normal renal function. Her hypercalcemia resolved, and her strength improved only after prednisone was added to bisphosphonate therapy. Two weeks later, she died from acute congestive heart failure. METHODS AND RESULTS Autopsy revealed a disseminated giant cell myositis affecting skeletal, cardiac, and gastrointestinal smooth muscle. Immunohistochemistry localized 1alpha-hydroxylase to the inflammatory infiltrates in skeletal and cardiac muscle. EVIDENCE A review of English publications in Medline and Embase, including a reference search of retrieved articles, revealed that calcitriol-mediated hypercalcemia has been described in over 30 conditions, most of which are granulomatous in nature, ranging from inflammatory conditions and foreign body exposures to infections and neoplasms. CONCLUSIONS Hypercalcemia resulting from autonomous 1alpha-hydroxylase activity may be unmasked by low-dose vitamin D supplementation and should not be excluded from the differential diagnosis of nonparathyroid causes if the serum calcitriol is inappropriately normal, rather than frankly elevated.
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Affiliation(s)
- Melissa Kallas
- Department of Medicine, University of Calgary, 1403 29 Street NW, Calgary, Alberta, Canada T2N 4J8
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Ho ACH, Hasson N, Singh-Grewal D. Sarcoidosis or scleroderma? An unusual case of sarcoidosis in a 3-year-old Caucasian girl. Rheumatology (Oxford) 2009; 48:1172-3. [PMID: 19581383 DOI: 10.1093/rheumatology/kep160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Hypercalcemia and overexpression of CYP27B1 in a patient with nephrogenic systemic fibrosis: clinical vignette and literature review. J Bone Miner Res 2009; 24:1135-9. [PMID: 19113910 PMCID: PMC6956690 DOI: 10.1359/jbmr.081261] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Nephrogenic systemic fibrosis (NSF) is a disease of thickened, hard, hyperpigmented skin lesions with or without systemic fibrosis occurring in patients with renal insufficiency and associated with the administration of gadolinium-containing contrast. The pathogenesis of this disease is unclear, and there is no definitive treatment. We describe a 71-yr-old patient with stable chronic lymphocytic leukemia (CLL), end-stage renal disease (ESRD), and NSF who presented with hypercalcemia in 2006. Before onset of renal insufficiency in 2002, serum calcium, phosphorus, and PTH levels were normal. In 2004, the patient began hemodialysis, and he was diagnosed with NSF in 2005, shortly after undergoing an MRI with gadolinium contrast administration. Over the next 6 mo, albumin-corrected serum total calcium levels rose from 9.9 to 13.1 mg/dl (normal range, 8.5-10.5 mg/dl) with normal serum phosphorus levels. On admission in September 2006, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were elevated at 130.7 pg/ml (normal range, 25.1-66.1 pg/ml). Biopsy of an NSF lesion showed increased 25-hydroxyvitamin D(3)-1-alpha hydroxylase (CYP27B1) immunostaining compared with the biopsy from a normal control. This is the first reported association of NSF with hypercalcemia caused by elevated 1,25(OH)(2)D levels. This metabolic disturbance should be sought in future cases to determine a connection between NSF, 1,25(OH)(2)D metabolism, and CYP27B1 activation in the skin, which may shed light on the pathogenesis of this unusual local and systemic fibrosing disorder.
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Farooque A, Moss C, Zehnder D, Hewison M, Shaw NJ. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in subcutaneous fat necrosis. Br J Dermatol 2008; 160:423-5. [PMID: 18811689 DOI: 10.1111/j.1365-2133.2008.08844.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The most serious complication of subcutaneous fat necrosis (SCFN), a rare condition of the newborn characterized by indurated purple nodules, is hypercalcaemia. However, the mechanism for this hypercalcaemia remains unclear. OBJECTIVES To determine whether the hypercalcaemia associated with SCFN involves expression of the vitamin D-activating enzyme 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase) in affected tissue. METHODS Skin biopsies from two male patients with SCFN and hypercalcaemia were taken. The histological specimens were assessed using a polyclonal antibody against 1alpha-hydroxylase. RESULTS Histology in both cases showed strong expression of 1alpha-hydroxylase protein (brown staining) within the inflammatory infiltrate associated with SCFN. This was consistent with similar experiments in other granulomatous conditions. CONCLUSIONS Hypercalcaemia in SCFN appears to be due to abundant levels of 1alpha-hydroxylase in immune infiltrates associated with tissue lesions. This is consistent with previous observations of extrarenal 1alpha-hydroxylase in skin from other granulomatous conditions such as sarcoidosis and slack skin disease.
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Affiliation(s)
- A Farooque
- Department of Endocrinology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
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Current World Literature. Curr Opin Nephrol Hypertens 2007; 16:388-93. [PMID: 17565283 DOI: 10.1097/mnh.0b013e3282472fd5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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