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Endocrine and Metabolic Manifestations of Invasive Fungal Infections and Systemic Antifungal Treatment

      Systemic fungal infections are increasingly reported in immunocompromised patients with hematological malignancies, recipients of bone marrow and solid organ allografts, and patients with AIDS. Mycoses may infiltrate endocrine organs and adversely affect their function or produce metabolic complications, such as hypopituitarism, hyperthyroidism or hypothyroidism, pancreatitis, hypoadrenalism, hypogonadism, hypernatremia or hyponatremia, and hypercalcemia. Antifungal agents used for prophylaxis and/or treatment of mycoses also have adverse endocrine and metabolic effects, including hypoadrenalism, hypogonadism, hypoglycemia, dyslipidemia, hypernatremia, hypocalcemia, hyperphosphatemia, hyperkalemia or hypokalemia, and hypomagnesemia. Herein, we review how mycoses and conventional systemic antifungal treatment can affect the endocrine system and cause metabolic abnormalities. If clinicians are equipped with better knowledge of the endocrine and metabolic complications of fungal infections and antifungal therapy, they can more readily recognize them and favorably affect outcome.
      ADH (antidiuretic hormone), AMB (amphotericin B), CYP (cytochrome P), DI (diabetes insipidus), LDL-C (low-density lipoprotein cholesterol), LH (luteinizing hormone), SIADH (syndrome of inappropriate ADH production)
      The incidence of systemic fungal infections is increasing in immunocompromised patients. Because these infections frequently disseminate, they may affect the function of the pituitary, thyroid, parathyroid, and adrenal glands; the pancreas; and the reproductive organs. Metabolic complications, such as electrolytic abnormalities, can also occur. Agents used for prophylaxis and/or treatment of mycoses also have adverse endocrine and metabolic effects (Table 1). We review how mycoses affect the endocrine system and cause metabolic derangements and discuss the endocrine and metabolic complications of antifungal agents. The focus is on only systemic antifungal agents for invasive mycoses, such as the polyenes (mainly amphotericin B [AMB] and its lipid formulations), the azoles (fluconazole, itraconazole, voriconazole, posaconazole, and ketoconazole), and the echinocandins (caspofungin, micafungin, and anidulafungin). Agents that are used topically or have antifungal properties, such as pentamidine, trimethoprim-sulfamethoxazole, dapsone, and atovaquone, are not discussed.
      TABLE 1Adverse Endocrine and Metabolic Effects of Systemic Antifungal Agents
      Antifungal agentEndocrine effectsMetabolic effects
      Polyenes
       Amphotericin BOligospermia in animalsHypernatremia, hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia
       Lipid formulations of amphotericin BPancreatitisHypernatremia, hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia, hyperphosphatemia, pseudohyperphosphatemia
       NystatinOligospermia in animalsHypokalemia, hypomagnesemia, hypocalcemia
      Azoles
       KetoconazoleHypothyroidism, Addison disease. decreased libido, impotence, gynecomastia, menstrual irregularitiesHypokalemia, hypocalcemia, hypoglycemia, dyslipidemia
       FluconazolePancreatitis, Addison disease, Conn-like syndrome, menstrual irregularitiesHypokalemia, hypoglycemia
       ItraconazolePancreatitis, Addison disease, Conn-like syndrome, decreased libido, impotence, gynecomastia, menstrual irregularitiesHypokalemia, dyslipidemia
       VoriconazolePancreatitisHypokalemia, hypomagnesemia, hypoglycemia, dyslipidemia
       PosaconazoleMenstrual irregularitiesNone reported
      Echinocandins
       Caspofungin, anidulafungin, micafunginPancreatitisHypokalemia, hypomagnesemia, hypercalcemia
      Other systemic antimicrobial agents with antifungal properties
       GriseofulvinPancreatitisNone reported
       Potassium iodideThyrotoxicosis (Jod-Basedow disease), hypothyroidism (Wolff-Chaikoff effect)Hyperkalemia
      We searched the MEDLINE and PubMed databases (from 1966 to February 2008) and abstracts from major infectious disease meetings held from 1992 to 2007 for published reports pertaining to the endocrine and metabolic manifestations of invasive mycoses and their antifungal treatment using terms such as endocrine, metabolic, electrolytes, fungal, molds, yeast, aspergillosis, candida, pituitary, thyroid, pancreas, adrenal, ovaries, reproductive system, sodium, potassium, calcium, phosphorous, dyslipidemia, amphotericin B, azoles, and echinocandins. Studies were selected on the basis of the importance of data (as determined by frequency of citations by subsequent publications in the specialty) and originality. Review articles by thought leaders in mycology and endocrinology were also included in our search.

      PITUITARY INVOLVEMENT AND DYSFUNCTION

       Mycoses

      In pituitary infections, which are rare, bacteria are the most common infecting microbes, whereas fungi are much less frequent.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      Interestingly, the pituitary gland has a role in innate antifungal immunity; Breuel et al
      • Breuel KF
      • Kougias P
      • Rice PJ
      • et al.
      Anterior pituitary cells express pattern recognition receptors for fungal glucans: implications for neuroendocrine immune involvement in response to fungal infections.
      showed that pituitary receptors sense circulating Candida glucans and respond by Toll-like receptor 4 (TLR4) and CD14 gene expression.
      Pituitary involvement is also rare in patients with central nervous system fungal infections. Of 40 patients with intracranial fungal infections, only 6 (15%) had sellar distribution.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      Various mycoses can infiltrate the pituitary gland
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Yeung IY
      • Whitelaw BC
      • Hortobágyi T
      • et al.
      Phaeohyphomycosis: an unusual pituitary mass.
      • Heary RF
      • Maniker AH
      • Wolansky LJ
      Candidal pituitary abscess: case report.
      • Yu YQ
      • Jiang XX
      • Gao YJ
      MRI of a pituitary cryptococcoma simulating an adenoma.
      • Scanarini M
      • Rotilio A
      • Rigobello L
      • Pomes A
      • Parenti A
      • Alessio L
      Primary intrasellar coccidioidomycosis simulating a pituitary adenoma.
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Bartlett JA
      • Hulette C
      Central nervous system pneumocystosis in a patient with AIDS.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      (Table 2). The pathogenesis of pituitary fungal infection involves (1) hematogenous spread, typically seen with disseminated opportunistic yeast or mold infections in immunosuppressed hosts; (2) extension from adjacent anatomical sites (ie, cryptococcal meningeal infection or aspergillosis of the sphenoid sinus, cavernous sinus, and skull base); or (3) iatrogenic inoculation (eg, with Aspergillus or Candida species) during transsphenoidal adenoma resection.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      TABLE 2Mycoses Reported to Infiltrate Various Organs of the Endocrine System
      The percentages for postmortem infiltration of different endocrine organs correspond to the highest reported rate of infiltration in the literature. In cases in which infiltration is sporadic, percentages are not provided. + = sporadic infiltration; − = not reported in the literature.
      Fungal infectionPituitary glandThyroid glandPancreasAdrenal glandMale reproductive organsFemale reproductive organs
      Aspergillosis+35.0%4.7%5.0%++
      Zygomycosis3.0%+
      Fusariosis++
      Scedosporiosis++++
      Scopulariopsis infection++
      Candidiasis+8.0%2.9%5.0%+
      Cryptococcosis+12.0%3.8%15.0%++
      Histoplasmosis++82.0%++
      Blastomycosis++10.0%10.0%+
      Coccidioidomycosis+6.0%+36.0%++
      Paracoccidioidomycosis+4.0%+80.0%++
      Sporotrichosis+++
      Trichosporonosis+++
      Pneumocystosis+23.0%
      Percentages refer to cases of extrapulmonary pneumocystosis.
      9.0%15.0%
      Percentages refer to cases of extrapulmonary pneumocystosis.
      Basidiobolomycosis+++
      Chromoblastomycosis+
      Saccharomyces spp infection+
      Malassezia spp infection++
      Trichophyton spp infection+
      a The percentages for postmortem infiltration of different endocrine organs correspond to the highest reported rate of infiltration in the literature. In cases in which infiltration is sporadic, percentages are not provided. + = sporadic infiltration; − = not reported in the literature.
      b Percentages refer to cases of extrapulmonary pneumocystosis.
      Pituitary fungal infections have no specific clinical features; like any pituitary process, they may cause headache, ophthalmoplegia due to optic chiasm compression, and/orendocrine dysfunction.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      Most such infections have no overt endocrine symptoms. However, hypopituitarism occurs rarely, manifesting most often as decreased libido and menstrual abnormalities because of luteinizing hormone (LH) and follicle-stimulating hormone insufficiency.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      Moreover, diabetes insipidus (DI) presenting as polydipsia and polyuria from impaired antidiuretic hormone (ADH) release is not uncommon.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      Indeed, DI occurs more frequently with pituitary infections than with adenomas, implying that posterior pituitary function is affected early during pituitary infections.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      Hyperprolactinemia and decreases in thyrotropin-releasing hormone and corticotropin also occur; conversely, endocrine function may be normal.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Dubey A
      • Patwardhan RV
      • Sampth S
      • Santosh V
      • Kolluri S
      • Nanda A
      Intracranial fungal granuloma: analysis of 40 patients and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      Fungal pituitary infections are radiographically indistinguishable from intrasellar bacterial infections and tumors. Consequently, they are often misdiagnosed as tumors, and diagnosis is made unexpectedly after surgery or at autopsy.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Yeung IY
      • Whitelaw BC
      • Hortobágyi T
      • et al.
      Phaeohyphomycosis: an unusual pituitary mass.
      • Heary RF
      • Maniker AH
      • Wolansky LJ
      Candidal pituitary abscess: case report.
      • Yu YQ
      • Jiang XX
      • Gao YJ
      MRI of a pituitary cryptococcoma simulating an adenoma.
      • Scanarini M
      • Rotilio A
      • Rigobello L
      • Pomes A
      • Parenti A
      • Alessio L
      Primary intrasellar coccidioidomycosis simulating a pituitary adenoma.
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Bartlett JA
      • Hulette C
      Central nervous system pneumocystosis in a patient with AIDS.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      Certain magnetic resonance imaging findings are thought to be specific for pituitary infection. Therefore, when peripheral enhancement, hypointensity, or calcifications are seen on T2-weighted images, infection is favored over a tumor.
      • Yu YQ
      • Jiang XX
      • Gao YJ
      MRI of a pituitary cryptococcoma simulating an adenoma.
      Investigators have used gallium-67 imaging for postoperative follow-up of patients with pituitary abscesses caused by Aspergillus spp, but more studies are needed to establish the role of imaging modalities in these patients.
      • Parker KM
      • Nicholson JK
      • Cezayirli RC
      • Biggs PJ
      Aspergillosis of the sphenoid sinus: presentation as a pituitary mass and postoperative gallium-67 imaging.
      The mortality rate with pituitary fungal infections exceeds 70% because of delayed recognition and the typically disseminated nature of these infections.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Bartlett JA
      • Hulette C
      Central nervous system pneumocystosis in a patient with AIDS.
      Treatment comprises antifungal therapy and transsphenoidal resection, which is preferred over craniotomy to prevent intracranial dissemination.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      Fungal infections can also influence sodium homeostasis by affecting pituitary ADH release. Hypernatremia secondary to DI or hyponatremia caused by the syndrome of inappropriate ADH production (SIADH) can develop in patients with mycoses. Diabetes insipidus occurs primarily with cryptococcal basilar meningitis
      • Juffermans NP
      • Verbon A
      • Van der Poll T
      Diabetes insipidus as a complication of cryptococcal meningitis in an HIV-infected patient.
      but also with aspergillosis, candidiasis, zygomycosis, and blastomycosis.
      • Mielke B
      • Weir B
      • Oldring D
      • von Westarp C
      Fungal aneurysm: case report and review of the literature.
      • Pinzer T
      • Reiss M
      • Bourquain H
      • Krishnan KG
      • Schackert G
      Primary aspergillosis of the sphenoid sinus with pituitary invasion—a rare differential diagnosis of sellar lesions.
      • Heary RF
      • Maniker AH
      • Wolansky LJ
      Candidal pituitary abscess: case report.
      • Stalldecker G
      • Molina HA
      • Antelo N
      • Arakaki T
      • Sica RE
      • Basso A
      Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis [in Spanish].
      • Ryan M
      • Yeo S
      • Maguire A
      • et al.
      Rhinocerebral zygomycosis in childhood acute lymphoblastic leukaemia.
      • Kelly PM
      Systemic blastomycosis with associated diabetes insipidus.
      Fungal cryptococcal and coccidioidal meningitis rarely cause SIADH
      • Stockstill MT
      • Kauffman CA
      Comparison of cryptococcal and tuberculous meningitis.
      • Webb M
      • Ziauddin A
      • Okusa MD
      Coccidioidomycosis meningitis and syndrome of inappropriate antidiuretic hormone.
      ; the incidence of SIADH in patients with cryptococcal meningitis is approximately 8%.
      • Stockstill MT
      • Kauffman CA
      Comparison of cryptococcal and tuberculous meningitis.
      A well-recognized cause of SIADH is pneumonia.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      Any fungal pneumonia can be complicated by SIADH. Pneumocystis pneumonia, caused by Pneumocystis jiroveci (formerly Pneumocystis carinii), is reportedly the most common cause of SIADH in patients with AIDS; antifungal treatment often corrects hyponatremia.
      • Tang WW
      • Kaptein EM
      • Feinstein EI
      • Massry SG
      Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex.

       Antifungal Agents

      Antidiuretic hormone acts by aquaporin 2-induced increase of the water permeability of renal collecting tubules. Amphotericin B decreases aquaporin 2 expression in the kidney medulla, makes collecting tubules insensitive to ADH, and may rarely cause reversible nephrogenic DI.
      • Kim SW
      • Yeum CH
      • Kim S
      • Oh Y
      • Choi KC
      • Lee J
      Amphotericin B decreases adenylyl cyclase activity and aquaporin-2 expression in rat kidney.
      • Späth-Schwalbe EM
      • Koschuth A
      • Dietzmann A
      • Schanz J
      • Possinger K
      Successful use of liposomal amphotericin B in a case of amphotericin B-induced nephrogenic diabetes insipidus.
      It also causes hypokalemia, a well-known etiology of nephrogenic DI; however, nephrogenic DI can occur without hypokalemia.
      • Kim SW
      • Yeum CH
      • Kim S
      • Oh Y
      • Choi KC
      • Lee J
      Amphotericin B decreases adenylyl cyclase activity and aquaporin-2 expression in rat kidney.
      • Späth-Schwalbe EM
      • Koschuth A
      • Dietzmann A
      • Schanz J
      • Possinger K
      Successful use of liposomal amphotericin B in a case of amphotericin B-induced nephrogenic diabetes insipidus.
      Higher levels of prostaglandin E2 and increased apoptosis seem to contribute to AMB-mediated DI.
      • Höhler T
      • Teuber G
      • Wanitschke R
      • Meyer zum Büschenfeld KH
      Indomethacin treatment in amphotericin B induced nephrogenic diabetes insipidus.
      • Varlam DE
      • Siddiq MM
      • Parton LA
      • Rüssmann H
      Apoptosis contributes to amphotericin B-induced nephrotoxicity.
      Amelioration of DI can be achieved with amiloride plus hydrochlorothiazide, indomethacin, and replacement of AMB-deoxycholate by lipid AMB formulations, which (for reasons that are not understood) cause DI less often.
      • Späth-Schwalbe EM
      • Koschuth A
      • Dietzmann A
      • Schanz J
      • Possinger K
      Successful use of liposomal amphotericin B in a case of amphotericin B-induced nephrogenic diabetes insipidus.
      • Höhler T
      • Teuber G
      • Wanitschke R
      • Meyer zum Büschenfeld KH
      Indomethacin treatment in amphotericin B induced nephrogenic diabetes insipidus.
      • Kirchlechner V
      • Koller DY
      • Seidl R
      • Waldhauser F
      Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride.

      THYROID INVOLVEMENT AND DYSFUNCTION

       Mycoses

      The thyroid is resistant to microbial invasion because of its rich blood supply, iodine content, and capsule.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Although several fungi may infect the thyroid
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Winzelberg GG
      • Gore J
      • Yu D
      • Vagenakis AG
      • Braverman LE
      Aspergillus flavus as a cause of thyroiditis in an immunosuppressed host.
      • Kalina PH
      • Campbell RJ
      Aspergillus terreus endophthalmitis in a patient with chronic lymphocytic leukemia.
      • Iwen PC
      • Rupp ME
      • Bishop MR
      • et al.
      Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.
      • Mori T
      • Egashira M
      • Kawamata N
      • et al.
      Zygomycosis: two case reports and review of reported cases in the literature in Japan [in Japanese].
      • Riddell IV, J
      • Chenoweth CE
      • Kauffman CA
      Disseminated Scedosporium apiospermum infection in a previously healthy woman with HELLP syndrome.
      • Berenguer J
      • Rodríguez-Tudela JL
      • Richard C
      • et al.
      Deep infections caused by Scedosporium prolificans: a report on 16 cases in Spain and a review of the literature.
      • Wuyts WA
      • Molzahn H
      • Maertens J
      • et al.
      Fatal Scopulariopsis infection in a lung transplant recipient: a case report.
      • Gandhi RT
      • Tollin SR
      • Seely EW
      Diagnosis of Candida thyroiditis by fine needle aspiration.
      • Avram AM
      • Sturm CA
      • Michael CW
      • Sisson JC
      • Jaffe CA
      Cryptococcal thyroiditis and hyperthyroidism.
      • Goldani LZ
      • Klock C
      • Diehl A
      • Monteiro AC
      • Maia AL
      Histoplasmosis of the thyroid.
      • Babu A
      • Lacuesta E
      • Patel S
      Cervical blastomycosis masquerading as a thyroid mass.
      • Smilack JD
      • Argueta R
      Coccidioidal infection of the thyroid.
      • Ito T
      • Ishikawa Y
      • Fujii R
      • et al.
      Disseminated Trichosporon capitatum infection in a patient with acute leukemia.
      • Gold JW
      • Poston W
      • Mertelsmann R
      • et al.
      Systemic infection with Trichosporon cutaneum in a patient with acute leukemia: report of a case.
      • Koyanagi T
      • Nishida N
      • Osabe S
      • et al.
      Autopsy case of disseminated Trichosporon inkin infection identified with molecular biological and biochemical methods.
      • Guttler R
      • Singer PA
      • Axline SG
      • Greaves TS
      • McGill JJ
      Pneumocystis carinii thyroiditis: report of three cases and review of the literature.
      (Table 2), thyroid fungal infection occurs rarely and is clinically overt in a minority of patients.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      Of 415 previously reported cases of infectious thyroiditis (1900-1997), only 50 (12%) were fungal.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      The pathogenesis of fungal thyroiditis entails hematogenous or lymphatic spread.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Although most cases of thyroid fungal involvement occur during dissemination in immunosuppressed patients, isolated thyroid histoplasmosis, coccidioidomycosis, and pneumocystosis have been reported.
      • Goldani LZ
      • Klock C
      • Diehl A
      • Monteiro AC
      • Maia AL
      Histoplasmosis of the thyroid.
      • Smilack JD
      • Argueta R
      Coccidioidal infection of the thyroid.
      • Guttler R
      • Singer PA
      • Axline SG
      • Greaves TS
      • McGill JJ
      Pneumocystis carinii thyroiditis: report of three cases and review of the literature.
      Aspergillus spp are the predominant causative fungus for thyroiditis and asymptomatic thyroid infiltration.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Winzelberg GG
      • Gore J
      • Yu D
      • Vagenakis AG
      • Braverman LE
      Aspergillus flavus as a cause of thyroiditis in an immunosuppressed host.
      • Kalina PH
      • Campbell RJ
      Aspergillus terreus endophthalmitis in a patient with chronic lymphocytic leukemia.
      • Iwen PC
      • Rupp ME
      • Bishop MR
      • et al.
      Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.
      The literature contains 21 case reports of overt thyroiditis caused by Aspergillus spp, with thyroid infiltration found postmortem in 10% to 35% of aspergillosis cases.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Winzelberg GG
      • Gore J
      • Yu D
      • Vagenakis AG
      • Braverman LE
      Aspergillus flavus as a cause of thyroiditis in an immunosuppressed host.
      • Kalina PH
      • Campbell RJ
      Aspergillus terreus endophthalmitis in a patient with chronic lymphocytic leukemia.
      • Iwen PC
      • Rupp ME
      • Bishop MR
      • et al.
      Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.
      In contrast, thyroid infiltration is less common in other mycoses
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Winzelberg GG
      • Gore J
      • Yu D
      • Vagenakis AG
      • Braverman LE
      Aspergillus flavus as a cause of thyroiditis in an immunosuppressed host.
      • Kalina PH
      • Campbell RJ
      Aspergillus terreus endophthalmitis in a patient with chronic lymphocytic leukemia.
      • Iwen PC
      • Rupp ME
      • Bishop MR
      • et al.
      Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.
      • Mori T
      • Egashira M
      • Kawamata N
      • et al.
      Zygomycosis: two case reports and review of reported cases in the literature in Japan [in Japanese].
      • Gandhi RT
      • Tollin SR
      • Seely EW
      Diagnosis of Candida thyroiditis by fine needle aspiration.
      • Bodey G
      • Bueltmann B
      • Duguid W
      • et al.
      Fungal infections in cancer patients: an international autopsy survey.
      • Groll AH
      • Shah PM
      • Mentzel C
      • Schneider M
      • Just-Nuebling G
      • Huebner K
      Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.
      • Antinori S
      • Galimberti L
      • Magni C
      • et al.
      Cryptococcus neoformans infection in a cohort of Italian AIDS patients: natural history, early prognostic parameters, and autopsy findings.
      • Ng VL
      • Yajko DM
      • Hadley WK
      Extrapulmonary pneumocystosis.
      • Huntington RW
      • Waldmann WJ
      • Sargent JA
      • O'Connell H
      • Wybel R
      • Croll D
      Pathological and clinical observations on 142 cases of fatal coccidioidomycosis with necropsy.
      (Table 2). Unsurprisingly, P jiroveci is the most common cause of fungal thyroiditis in patients with AIDS, reflecting the high incidence of pneumocystosis in these patients.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Guttler R
      • Singer PA
      • Axline SG
      • Greaves TS
      • McGill JJ
      Pneumocystis carinii thyroiditis: report of three cases and review of the literature.
      Thyroiditis caused by P jiroveci is typically associated with aerosolized pentamidine prophylaxis, a known risk factor for extrapulmonary pneumocystosis.
      • Guttler R
      • Singer PA
      • Axline SG
      • Greaves TS
      • McGill JJ
      Pneumocystis carinii thyroiditis: report of three cases and review of the literature.
      In most cases, thyroid fungal involvement is an incidental finding at autopsy without antemortem evidence of thyroid dysfunction.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Nevertheless, it can manifest as subacute thyroiditis with local and systemic symptoms.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Neck swelling and tenderness are common because of thyroid enlargement and dysphagia from esophageal compression; in severe cases, fatal respiratory failure from tracheal obstruction has occurred.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Kishi Y
      • Negishi M
      • Kami M
      • et al.
      Fatal airway obstruction caused by invasive aspergillosis of the thyroid gland.
      Fungal thyroiditis typically begins with a brief hyperthyroid phase in which glandular destruction causes thyroid hormone release.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Transient euthyroidism ensues, followed by hypothyroidism and, ultimately, recovery to euthyroidism.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Hence, symptoms and laboratory evidence can range from those characteristic of hyperthyroidism (or even frank thyrotoxicosis) to those typical of hypothyroidism from fungal involvement, depending on the phase in which the condition is diagnosed.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      Hyperthyroidism is more common with aspergillosis and coccidioidal infection, whereas hypothyroidism is more common with thyroiditis caused by P jiroveci.
      • Aron DC
      Endocrine complications of the acquired immunodeficiency syndrome.
      • Berger SA
      • Zonszein J
      • Villamena P
      • Mittman N
      Infectious diseases of the thyroid gland.
      • Goldani LZ
      • Zavascki AP
      • Maia AL
      Fungal thyroiditis: an overview.
      • Yu EH
      • Ko WC
      • Chuang YC
      • Wu TJ
      Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.
      • Sion ML
      • Armenaka MC
      • Georgiadis I
      • Paraskevopoulos G
      • Nikolaidis I
      Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus.
      • Winzelberg GG
      • Gore J
      • Yu D
      • Vagenakis AG
      • Braverman LE
      Aspergillus flavus as a cause of thyroiditis in an immunosuppressed host.
      • Avram AM
      • Sturm CA
      • Michael CW
      • Sisson JC
      • Jaffe CA
      Cryptococcal thyroiditis and hyperthyroidism.
      • Guttler R
      • Singer PA
      • Axline SG
      • Greaves TS
      • McGill JJ
      Pneumocystis carinii thyroiditis: report of three cases and review of the literature.
      Whether this pattern reflects the degree of glandular dysregulation by the aforementioned fungi or results from differences in the timing of diagnosis remains unknown.
      Patients with acute severe fungal infections may develop euthyroid sick syndrome, characterized by decreased levels of triiodothyronine and increased levels of normal thyroxine and thyrotropin-releasing hormone, as described in cases of paracoccidioidomycosis.
      • Kiy Y
      • Machado JM
      • Mendes RP
      • Barraviera B
      • Pereira PC
      • Cury PR
      Paracoccidioidomycosis in the region of Botucatu (state of São Paulo, Brazil): evaluation of serum thyroxine (T4) and triiodothyronine (T3) levels and of the response to thyrotropin releasing hormone (TRH).
      Because such laboratory findings signify diminished peripheral conversion of thyroxine to triiodothyronine, thyroid replacement therapy is unnecessary and detrimental.
      • Brent GA
      • Hershman JM
      Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration.
      However, in one study, a decreased total triiodothyronine level was the best prognostic indicator of death from pneumonia caused by P jiroveci in patients with AIDS.
      • Fried JC
      • LoPresti JS
      • Micon M
      • Bauer M
      • Tuchschmidt JA
      • Nicoloff JT
      Serum triiodothyronine values: prognostic indicators of acute mortality due to Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome.
      Besides direct fungal invasion of the thyroid, mycotoxin secretion may influence thyroid function.
      • Selmanoglu G
      • Kockaya EA
      Investigation of the effects of patulin on thyroid and testis, and hormone levels in growing male rats.
      • Rotter BA
      • Thompson BK
      • Lessard M
      • Trenholm HL
      • Tryphonas H
      Influence of low-level exposure to Fusarium mycotoxins on selected immunological and hematological parameters in young swine.
      Specifically, at doses relevant to human exposure levels, the Aspergillus toxin patulin decreased thyroxine levels in animals, and the Fusarium toxin deoxynivalenol increased them.
      • Selmanoglu G
      • Kockaya EA
      Investigation of the effects of patulin on thyroid and testis, and hormone levels in growing male rats.
      • Rotter BA
      • Thompson BK
      • Lessard M
      • Trenholm HL
      • Tryphonas H
      Influence of low-level exposure to Fusarium mycotoxins on selected immunological and hematological parameters in young swine.
      Whether mycotoxin secretion during fungal infections affects thyroid function in humans remains unstudied.

       Antifungal Agents

      In preclinical studies, imidazoles, such as ketoconazole, have had antithyroid effects because of interference with iodine and thyroid peroxidase.
      • Comby F
      • Lagorce JF
      • Buxeraud J
      • Raby C
      Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.
      Nevertheless, administration of 200 to 600 mg/d of ketoconazole for 1 month did not affect thyroid function in euthyroid, hyperthyroid, or hypothyroid patients.
      • De Pedrini P
      • Montemurro G
      • Tommaselli A
      • Costa C
      No effect of ketoconazole on thyroid function of normals and thyrotoxic patients.
      • De Pedrini P
      • Tommaselli A
      • Montemurro G
      No effect of ketoconazole on thyroid function of normal subjects and hypothyroid patients.
      However, high-dose ketoconazole (1200 mg/d) may cause hypothyroidism.
      • Namer M
      • Khater R
      • Frenay M
      • Boublil JL
      High-dose ketoconazole in the treatment of advanced cancer of the breast [in French] [letter].
      Hypothyroidism also developed in 2 patients with chronic mucocutaneous candidiasis after prolonged (>3 months) low-dose (100-200 mg/d) treatment with ketoconazole.
      • Kitching NH
      Hypothyroidism after treatment with ketoconazole [letter].
      Because patients with chronic mucocutaneous candidiasis frequently have hypothyroidism associated with adult polyglandular autoimmune syndrome type I, it remains unclear whether ketoconazole induced hypothyroidism in these patients.
      • Kitching NH
      Hypothyroidism after treatment with ketoconazole [letter].
      No studies have implicated the triazoles in thyroid dysfunction.
      • Devenport MH
      • Crook D
      • Wynn V
      • Lees LJ
      Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives.
      Use of potassium iodide is common in treating cutaneous sporotrichosis.
      • Sterling JB
      • Heymann WR
      Potassium iodide in dermatology: a 19th century drug for the 21st century—uses, pharmacology, adverse effects, and contraindications.
      Prolonged (>1 month) potassium iodide treatment is associated with reversible thyrotoxicosis in patients with coexistent “hot” thyroid nodules (Jod-Basedow disease) and with hypothyroidism in patients with excessive autoregulation (Wolff-Chaikoff effect).
      • Sterling JB
      • Heymann WR
      Potassium iodide in dermatology: a 19th century drug for the 21st century—uses, pharmacology, adverse effects, and contraindications.

      CALCIUM AND PHOSPHORUS ABNORMALITIES AND PARATHYROID INVOLVEMENT

       Mycoses

      Hypercalcemia is a well-known complication of many granulomatous disorders, including sarcoidosis, tuberculosis, and lymphomas.
      • Barbour GL
      • Coburn JW
      • Slatopolsky E
      • Norman AW
      • Horst RL
      Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D.
      It is derived from extrarenal dysregulated production of 1,25-dihydroxyvitamin D due to interferon-γ-mediated expression of 1α-hydroxylase by activated macrophages in granulomas.
      • Adams JS
      • Sharma OP
      • Gacad MA
      • Singer FR
      Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis.
      Chronic fungal infections, including histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, candidiasis, cryptococcosis, and pneumocystosis, can also cause granulomas and reversible hypercalcemia.
      • Spindel SJ
      • Hamill RJ
      • Georghiou PR
      • Lacke CE
      • Green LK
      • Mallette LE
      Case report: vitamin D-mediated hypercalcemia in fungal infections.
      • Kantarjian HM
      • Saad MF
      • Estey EH
      • Sellin RV
      • Samaan NA
      Hypercalcemia in disseminated candidiasis.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Caldwell JW
      • Arsura EL
      • Kilgore WB
      • Reddy CM
      • Johnson RH
      Hypercalcemia in patients with disseminated coccidioidomycosis.
      • Silva LC
      • Ferrari TC
      Hypercalcaemia and paracoccidioidomycosis.
      • Ahmed B
      • Jaspan JB
      Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia.
      Reports indicate that 3% of patients with various mycoses have hypercalcemia, whereas about 10% of patients with sarcoidosis do.
      • Spindel SJ
      • Hamill RJ
      • Georghiou PR
      • Lacke CE
      • Green LK
      • Mallette LE
      Case report: vitamin D-mediated hypercalcemia in fungal infections.
      • Kantarjian HM
      • Saad MF
      • Estey EH
      • Sellin RV
      • Samaan NA
      Hypercalcemia in disseminated candidiasis.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Caldwell JW
      • Arsura EL
      • Kilgore WB
      • Reddy CM
      • Johnson RH
      Hypercalcemia in patients with disseminated coccidioidomycosis.
      • Silva LC
      • Ferrari TC
      Hypercalcaemia and paracoccidioidomycosis.
      • Ahmed B
      • Jaspan JB
      Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia.
      Whether this reflects variation in granuloma formation or subtle differences in the mechanisms of hypercalcemia between these entities is unclear.
      Studies have shown that the mechanisms of hypercalcemia differ with the various mycoses. For instance, coccidioidomycosis, the mycosis most commonly associated with hypercalcemia (incidence, 1.4%-25.0%), typically manifests late after initiation of antifungal treatment.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Caldwell JW
      • Arsura EL
      • Kilgore WB
      • Reddy CM
      • Johnson RH
      Hypercalcemia in patients with disseminated coccidioidomycosis.
      Parathyroid hormone and parathyroid hormone-related peptide levels are normal. Hypercalcemia in coccidioidomycosis is not triggered by autonomous 1,25-dihydroxyvitamin D, prostaglandin, or osteoclast-activating factor production.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Caldwell JW
      • Arsura EL
      • Kilgore WB
      • Reddy CM
      • Johnson RH
      Hypercalcemia in patients with disseminated coccidioidomycosis.
      Osseous coccidioidomycosis that causes bone resorption contributes in some cases, but hypercalcemia occurs even without bone involvement. Thus, the presence of an osteotropic substance resembling humoral hypercalcemia of malignancy has been postulated.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Caldwell JW
      • Arsura EL
      • Kilgore WB
      • Reddy CM
      • Johnson RH
      Hypercalcemia in patients with disseminated coccidioidomycosis.
      Elevated levels of nephrogenous cyclic adenosine monophosphate, low levels of 1,25-dihydroxyvitamin D, and hypercalciuria with coccidioidomycosis have also been described in patients with hypercalcemia of malignancy.
      • Stewart AF
      • Horst R
      • Deftos LJ
      • Cadman EC
      • Lang R
      • Broadus AE
      Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups.
      In contrast, studies have shown autonomous 1,25-dihydroxyvitamin D production with candidiasis, cryptococcosis, paracoccidioidomycosis, pneumocystosis, and histoplasmosis.
      • Spindel SJ
      • Hamill RJ
      • Georghiou PR
      • Lacke CE
      • Green LK
      • Mallette LE
      Case report: vitamin D-mediated hypercalcemia in fungal infections.
      • Kantarjian HM
      • Saad MF
      • Estey EH
      • Sellin RV
      • Samaan NA
      Hypercalcemia in disseminated candidiasis.
      • Ali MY
      • Gopal KV
      • Llerena LA
      • Taylor HC
      Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis.
      • Silva LC
      • Ferrari TC
      Hypercalcaemia and paracoccidioidomycosis.
      • Ahmed B
      • Jaspan JB
      Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia.
      Hypercalcemia has also been reported as part of the immune reconstitution syndrome in patients with AIDS and cryptococcosis after initiation of antiretroviral therapy.
      • Jenny-Avital ER
      • Abadi M
      Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy.
      The underlying mechanism remains unclear, but it has been postulated that hypercalcemia is caused by restoration of the granulomatous host response, resulting in autonomous 1,25-dihydroxyvitamin D production after antiretroviral therapy.
      • Lawn SD
      • Macallan DC
      Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person [letter].
      Osteopontin, a glycoprotein ligand of the αvβ3 integrin that activates macrophages and osteoclasts,
      • Reinholt FP
      • Hultenby K
      • Oldberg A
      • Heinegård D
      Osteopontin—a possible anchor of osteoclasts to bone.
      is highly expressed by histiocytes in granulomas of diverse etiologies, including histoplasmosis.
      • Carlson I
      • Tognazzi K
      • Manseau EJ
      • Dvorak HF
      • Brown LF
      Osteopontin is strongly expressed by histiocytes in granulomas of diverse etiology.
      Osteoclasts synthesize osteopontin and αvβ3 integrin, which both localize at bone resorption sites.
      • Reinholt FP
      • Hultenby K
      • Oldberg A
      • Heinegård D
      Osteopontin—a possible anchor of osteoclasts to bone.
      Hence, osteopontin may contribute to hypercalcemia via osteoclast activation and bone resorption; further studies are needed to elucidate its role in hypercalcemia associated with fungal infections. Another molecule implicated in osteoclast activation and bone resorption in hypercalcemia of malignancy is the receptor activator of nuclear factor-κβ ligand; its role in hypercalcemia of mycoses also merits investigation.
      • Li J
      • Sarosi I
      • Yan XQ
      • et al.
      RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism.
      Conversely, hypocalcemia and hyperphosphatemia caused by hypoparathyroidism have been described in a patient with pneumocystosis and parathyroid infiltration.
      • Siddiqi A
      • Goh BT
      • Brown CL
      • Hillman RJ
      • Monson JP
      Hypothyroidism and hypoparathyroidism associated with Pneumocystis carinii infection in a patient with AIDS.
      Supplementation with vitamin D and calcium was necessary to maintain eucalcemia.

       Antifungal agents

      Azoles inhibit ergosterol biosynthesis by blocking cytochrome P (CYP) 450-dependent 14α-lanosterol demethylase.
      • Sonino N
      The endocrine effects of ketoconazole.
      The reported higher frequency of endocrine complications of ketoconazole than of other azoles derives from their different selectivity for fungal vs mammalian CYP450-dependent 14α-lanosterol demethylase.
      • Sonino N
      The endocrine effects of ketoconazole.
      Ketoconazole inhibits in vitro conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by competitive inhibition of CYP450-dependent 1α-hydroxylase.
      • Henry HL
      Effect of ketoconazole and miconazole on 25-hydroxyvitamin D3 metabolism by cultured chick kidney cells.
      Administration of 600 to 900 mg/d of ketoconazole has been shown to cause a rapid, dose-dependent decrease of 40% to 45% in 1,25-dihydroxyvitamin D levels in healthy participants and in patients with hyperparathyroidism, sarcoidosis, and tuberculosis, resulting in calcium-lowering in some, but not all, patients.
      • Glass AR
      • Eil C
      Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D and total serum calcium in hypercalcemic patients.
      • Saggese G
      • Bertelloni S
      • Baroncelli GI
      • Di Nero G
      Ketoconazole decreases the serum ionized calcium and 1,25-dihydroxyvitamin D levels in tuberculosis-associated hypercalcemia.
      • Adams JS
      • Sharma OP
      • Diz MM
      • Endres DB
      Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia.
      Conversely, the triazoles do not affect calcium homeostasis.
      Polyene-induced hypomagnesemia resulting from iatrogenic Fanconi syndrome can cause hypocalcemia by adversely affecting parathyroid hormone secretion and action in the kidney.
      • Marcus N
      • Garty BZ
      Transient hypoparathyroidism due to amphotericin B-induced hypomagnesemia in a patient with beta-thalassemia.
      • Offner F
      • Krcmery V
      • Boogaerts M
      • EORTC Invasive Fungal Infections Group
      • et al.
      Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B.
      Cases of AMB- and nystatin-induced hypoparathyroidism and hypocalcemia have been reported.
      • Marcus N
      • Garty BZ
      Transient hypoparathyroidism due to amphotericin B-induced hypomagnesemia in a patient with beta-thalassemia.
      • Offner F
      • Krcmery V
      • Boogaerts M
      • EORTC Invasive Fungal Infections Group
      • et al.
      Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B.
      Conversely, caspofungin has been reported to induce hypercalcemia, but the mechanism by which it does so remains unknown.
      • Maertens J
      • Raad I
      • Petrikkos G
      • Caspofungin Salvage Aspergillosis Study Group
      • et al.
      Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy.
      Phosphate abnormalities are rarely associated with antifungal use. Specifically, because each 50-mg vial of liposomal AMB contains 37 mg of phosphorus, prolonged treatment with high-dose liposomal AMB can result in hyperphosphatemia, especially in patients with impaired renal function.
      • Jain A
      • Butani L
      Severe hyperphosphatemia resulting from high-dose liposomal amphotericin in a child with leukemia.
      Nevertheless, because liposomal AMB can interfere with the Synchron LX-20 phosphorus assay (Beckman Coulter, Fullerton, CA), pseudohyperphosphatemia can occur, and caution is required before institution of phosphate-lowering therapy.
      • Mendoza D
      • Connors S
      • Lane C
      • Stehnach S
      Liposomal amphotericin B as a cause of pseudohyperphosphatemia [letter].

      PANCREATIC INVOLVEMENT AND DYSFUNCTION

       Mycoses

      Fungi may involve the pancreas in 2 patterns. The first is hematogenous involvement during dissemination
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Berenguer J
      • Rodríguez-Tudela JL
      • Richard C
      • et al.
      Deep infections caused by Scedosporium prolificans: a report on 16 cases in Spain and a review of the literature.
      • Bodey G
      • Bueltmann B
      • Duguid W
      • et al.
      Fungal infections in cancer patients: an international autopsy survey.
      • Groll AH
      • Shah PM
      • Mentzel C
      • Schneider M
      • Just-Nuebling G
      • Huebner K
      Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.
      • Antinori S
      • Galimberti L
      • Magni C
      • et al.
      Cryptococcus neoformans infection in a cohort of Italian AIDS patients: natural history, early prognostic parameters, and autopsy findings.
      • Ng VL
      • Yajko DM
      • Hadley WK
      Extrapulmonary pneumocystosis.
      • Huntington RW
      • Waldmann WJ
      • Sargent JA
      • O'Connell H
      • Wybel R
      • Croll D
      Pathological and clinical observations on 142 cases of fatal coccidioidomycosis with necropsy.
      • Guice KS
      • Lynch M
      • Weatherbee L
      Invasive aspergillosis: an unusual cause of hemorrhagic pancreatitis.
      • Parenti DM
      • Steinberg W
      • Kang P
      Infectious causes of acute pancreatitis.
      • Ribes JA
      • Vanover-Sams CL
      • Baker DJ
      Zygomycetes in human disease.
      • Richardson SE
      • Bannatyne RM
      • Summerbell RC
      • Milliken J
      • Gold R
      • Weitzman SS
      Disseminated fusarial infection in the immunocompromised host.
      • Rippon JW
      • Zvetina JR
      • Reyes C
      Case report: miliary blastomycosis with cerebral involvement.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      • Silva-Vergara ML
      • Maneira FR
      • De Oliveira RM
      • Santos CT
      • Etchebehere RM
      • Adad SJ
      Multifocal sporotrichosis with meningeal involvement in a patient with AIDS.
      • Bigliazzi C
      • Poletti V
      • Dell'Amore D
      • Saragoni L
      • Colby TV
      Disseminated basidiobolomycosis in an immunocompetent woman.
      • Tsai CY
      • Lü YC
      • Wang LT
      • Hsu TL
      • Sung JL
      Systemic chromoblastomycosis due to Hormodendrum dermatitidis (Kano) Conant: report of the first case in Taiwan.
      • Pynka M
      • Wnuk A
      • Bander D
      • et al.
      Disseminated infection with Saccharomyces kluyveri in a patient with AIDS.
      • Shek YH
      • Tucker MC
      • Viciana AL
      • Manz HJ
      • Connor DH
      Malassezia furfur—disseminated infection in premature infants.
      (Table 2). Unless more than 80% of pancreatic tissue is affected, pancreatic insufficiency does not develop; thus, involvement is asymptomatic and usually discovered postmortem. The second pattern is seeding by Candida spp of pancreatic tissue or pseudocysts after necrotizing pancreatitis.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.
      The incidence of such infection has increased considerably from about 7% of total postpancreatic infections in the 1980s to 40% in the 2000s after routine administration of prophylactic antibiotics in patients with necrotizing pancreatitis.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.
      Besides antibiotic prophylaxis that predisposes patients to fungal superinfection, the risk factors for fungal pancreatic infection are postpancreatitis abdominal surgical manipulation and the global immune dysregulation seen with necrotizing pancreatitis, as evidenced by decreases in CD4 lymphocytes and interleukin 2.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.
      • Curley PJ
      Endotoxin, cellular immune dysfunction and acute pancreatitis.
      Most infections occur within 1 month after pancreatitis and derive from Candida spp translocated from the gut.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.
      Aspartic proteinase 6, secreted by Candida spp and regulated by the enhanced filamentous growth 1 (EFG1) transcription factor, has a role in enabling Candida spp to invade pancreatic tissue.
      • Felk A
      • Kretschmar M
      • Albrecht A
      • et al.
      Candida albicans hyphal formation and the expression of the Efg1-regulated proteinases Sap4 to Sap6 are required for the invasion of parenchymal organs.
      In most studies, pancreatic candidal infection is associated with higher mortality rates than is bacterial pancreatic infection.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      However, not all studies have shown such an association.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      Interventions proposed to prevent pancreatic seeding by fungi in high-risk patients with necrotizing pancreatitis are selective bowel decontamination and fluconazole prophylaxis.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.
      The former approach is controversial; the latter decreases the incidence of such infections, but this reduction does not translate into survival benefits and carries the risk of selecting azole-resistant Candida spp.
      • Hoerauf A
      • Hammer S
      • Müller-Myhsok B
      • Rupprecht H
      Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality.
      • De Waele JJ
      • Vogelaers D
      • Blot S
      • Colardyn F
      Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy.

       Antifungal Agents

      Pancreatitis is rarely reported after treatment with griseofulvin, liposomal AMB (0.5%-1% of patients), micafungin, fluconazole, itraconazole, and voriconazole.
      • Trivedi CD
      • Pitchumoni CS
      Drug-induced pancreatitis: an update.
      • Stuecklin-Utsch A
      • Hasan C
      • Bode U
      • Fleischhack G
      Pancreatic toxicity after liposomal amphotericin B.
      • Sato K
      • Hayashi M
      • Utsugi M
      • Ishizuka T
      • Takagi H
      • Mori M
      Acute pancreatitis in a patient treated with micafungin.
      • Vazquez JA
      • Skiest DJ
      • Nieto L
      • et al.
      A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS.
      • Boyd AE
      • Modi S
      • Howard SJ
      • Moore CB
      • Keevil BG
      • Denning DW
      Adverse reactions to voriconazole.
      Elevated levels of serum voriconazole can cause hypoglycemia, although the underlying mechanism is not understood and merits investigation.
      • Boyd AE
      • Modi S
      • Howard SJ
      • Moore CB
      • Keevil BG
      • Denning DW
      Adverse reactions to voriconazole.
      Asian patients, who frequently have the CYP2C19 sequence variation that causes increased drug concentrations, may be especially predisposed to voriconazole-induced hypoglycemia.
      • Balian JD
      • Sukhova N
      • Harris JW
      • et al.
      The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study.
      Ketoconazole and fluconazole have also been associated with development of hypoglycemia.
      • Lobo BL
      • Miwa LJ
      • Jungnickel PW
      Possible ketoconazole-induced hypoglycemia letter].
      • Niemi M
      • Backman JT
      • Neuvonen M
      • Laitila J
      • Neuvonen PJ
      • Kivistö KT
      Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.
      The mechanism for the former is unknown, whereas coadministration of fluconazole with oral hypoglycemic agents to patients with diabetes may inhibit the metabolism of the latter compounds and elevate their levels, thus predisposing patients to hypoglycemia.
      • Lobo BL
      • Miwa LJ
      • Jungnickel PW
      Possible ketoconazole-induced hypoglycemia letter].
      • Niemi M
      • Backman JT
      • Neuvonen M
      • Laitila J
      • Neuvonen PJ
      • Kivistö KT
      Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.
      This interaction appears dose-dependent and agent-specific. Therefore, coadministration of 100 mg/d of fluconazole with tolbutamide or 200 mg/d of fluconazole with glimepiride or nateglinide increased the peak plasma concentrations and the area under the curve of these compounds, hence heightening the risk of hypoglycemia.
      • Lazar JD
      • Wilner KD
      Drug interactions with fluconazole.
      • Niemi M
      • Neuvonen M
      • Juntti-Patinen L
      • Backman JT
      • Neuvonen PJ
      Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide.
      In contrast, coadministration of 50 mg/d of fluconazole with gliclazide or glibenclamide did not affect glycemic homeostasis.
      • Rowe BR
      • Thorpe J
      • Barnett A
      Safety of fluconazole in women taking oral hypoglycaemic agents [letter].
      People with CYP2C9 sequence variations have a markedly diminished capacity to metabolize CYP2C9 substrates and might be particularly at risk for hypoglycemia in the setting of azole-hypoglycemic drug coadministration.
      • Miners JO
      • Birkett DJ
      Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.
      However, more studies are needed to elucidate the frequency and relative risk of hypoglycemia as a result of different azole-hypoglycemic agent interactions.

      ADRENAL INVOLVEMENT AND DYSFUNCTION

       Mycoses

      The adrenal glands are the most common endocrine organs involved during infections, including mycoses. Frenkel
      • Frenkel JK
      Pathogenesis of infections of the adrenal gland leading to Addison's disease in man: the role of corticoids in adrenal and generalized infection.
      suggested that excessive glucocorticoid levels in adrenal circulation (ie, 20-40 times higher than in the peripheral blood) generate local cell-mediated immunosuppression that predisposes patients to glandular invasion by microorganisms.
      Isolated adrenal involvement has been reported in immunocompetent hosts with histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and pneumocystosis.
      • Lio S
      • Cibin M
      • Marcello R
      • Viviani MA
      • Ajello L
      Adrenal bilateral incidentaloma by reactivated histoplasmosis.
      • Papadopoulos KI
      • Castor B
      • Klingspor L
      • Dejmek A
      • Lorén I
      • Bramnert M
      Bilateral isolated adrenal coccidioidomycosis.
      • Torres CM
      • Duarte E
      • Guimaraes JP
      • Moreira LF
      Destructive lesion of the adrenal gland in South American blastomycosis (Lutz' disease).
      • Agarwal J
      • Agarwal G
      • Ayyagari A
      • Kar DK
      • Mishra SK
      • Bhatia E
      Isolated Pneumocystis carinii infection of adrenal glands causing Addison's disease in a non-immunocompromised adult.
      Much more often, the adrenal glands are involved in widely disseminated mycoses; at autopsy, histoplasmosis and paracoccidioidomycosis are by far the most common fungal infections found to have infiltrated the adrenal glands
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Berenguer J
      • Rodríguez-Tudela JL
      • Richard C
      • et al.
      Deep infections caused by Scedosporium prolificans: a report on 16 cases in Spain and a review of the literature.
      • Bodey G
      • Bueltmann B
      • Duguid W
      • et al.
      Fungal infections in cancer patients: an international autopsy survey.
      • Groll AH
      • Shah PM
      • Mentzel C
      • Schneider M
      • Just-Nuebling G
      • Huebner K
      Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.
      • Antinori S
      • Galimberti L
      • Magni C
      • et al.
      Cryptococcus neoformans infection in a cohort of Italian AIDS patients: natural history, early prognostic parameters, and autopsy findings.
      • Ng VL
      • Yajko DM
      • Hadley WK
      Extrapulmonary pneumocystosis.
      • Huntington RW
      • Waldmann WJ
      • Sargent JA
      • O'Connell H
      • Wybel R
      • Croll D
      Pathological and clinical observations on 142 cases of fatal coccidioidomycosis with necropsy.
      • Rippon JW
      • Zvetina JR
      • Reyes C
      Case report: miliary blastomycosis with cerebral involvement.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      • Silva-Vergara ML
      • Maneira FR
      • De Oliveira RM
      • Santos CT
      • Etchebehere RM
      • Adad SJ
      Multifocal sporotrichosis with meningeal involvement in a patient with AIDS.
      • Bigliazzi C
      • Poletti V
      • Dell'Amore D
      • Saragoni L
      • Colby TV
      Disseminated basidiobolomycosis in an immunocompetent woman.
      • Shek YH
      • Tucker MC
      • Viciana AL
      • Manz HJ
      • Connor DH
      Malassezia furfur—disseminated infection in premature infants.
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Del Negro G
      • Wajchenberg BL
      • Pereira VG
      • et al.
      Addison's disease associated with South American blastomycosis.
      • Shah B
      • Taylor HC
      • Pillay I
      • Chung-Park M
      • Dobrinich R
      Adrenal insufficiency due to cryptococcosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      (Table 2). Most such cases are asymptomatic, and antemortem diagnosis is rare. Adrenal function remains unaffected unless more than 90% of the adrenal cortex is obliterated, and so patients with disseminated mycoses may die of their infection before such destruction occurs.
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Del Negro G
      • Wajchenberg BL
      • Pereira VG
      • et al.
      Addison's disease associated with South American blastomycosis.
      • Shah B
      • Taylor HC
      • Pillay I
      • Chung-Park M
      • Dobrinich R
      Adrenal insufficiency due to cryptococcosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      Also, manifestations of adrenal insufficiency are nonspecific and may be attributed erroneously to the mycosis.
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Del Negro G
      • Wajchenberg BL
      • Pereira VG
      • et al.
      Addison's disease associated with South American blastomycosis.
      • Shah B
      • Taylor HC
      • Pillay I
      • Chung-Park M
      • Dobrinich R
      Adrenal insufficiency due to cryptococcosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      In addition to directly destroying adrenal tissue, host humoral factors generated during systemic infections, such as corticostatins/defensins, may contribute to adrenal dysfunction. Specifically, these molecules inhibit adrenal steroidogenesis by interfering with corticotropin affinity at the receptor level; their role in affecting adrenal steroidogenesis in patients with systemic mycoses should be further explored.
      • Zhu QZ
      • Hu J
      • Mulay S
      • Esch F
      • Shimasaki S
      • Solomon S
      Isolation and structure of corticostatin peptides from rabbit fetal and adult lung.
      Addison disease has been reported with histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, blastomycosis, pneumocystosis, candidiasis, and infection with Bipolaris spp.
      • Torres CM
      • Duarte E
      • Guimaraes JP
      • Moreira LF
      Destructive lesion of the adrenal gland in South American blastomycosis (Lutz' disease).
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Shah B
      • Taylor HC
      • Pillay I
      • Chung-Park M
      • Dobrinich R
      Adrenal insufficiency due to cryptococcosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      • Alteras I
      • Cojocaru I
      • Balanescu A
      Generalized candidiasis associated with Addison's disease.
      • Karim M
      • Sheikh H
      • Alam M
      • Sheikh Y
      Disseminated Bipolaris infection in an asthmatic patient: case report.
      Of these infections, histoplasmosis and paracoccidioidomycosis have the highest proclivity for the adrenal glands, and Addison disease occurs most frequently in patients with these infections (histoplasmosis, 7%-12%; paracoccidioidomycosis, 9%-14%).
      • Murray HW
      • Littman ML
      • Roberts RB
      Disseminated paracoccidioidomycosis (South American blastomycosis) in the United States.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      • Del Negro G
      • Wajchenberg BL
      • Pereira VG
      • et al.
      Addison's disease associated with South American blastomycosis.
      Prompt recognition and glucocorticoid supplementation are fundamental for survival in such patients. In patients with blastomycosis and histoplasmosis, latency periods of several years between primary infection and adrenal insufficiency are not uncommon, signifying reactivation of quiescent adrenal foci.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      • Lio S
      • Cibin M
      • Marcello R
      • Viviani MA
      • Ajello L
      Adrenal bilateral incidentaloma by reactivated histoplasmosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      Most adrenal insufficiency cases are irreversible and necessitate lifelong glucocorticoid supplementation. Nevertheless, recovery of adrenal function has been reported with antifungal treatment in histoplasmosis and paracoccidioidomycosis cases.
      • Washburn RG
      • Bennett JE
      Reversal of adrenal glucocorticoid dysfunction in a patient with disseminated histoplasmosis.
      • Osa SR
      • Peterson RE
      • Roberts RB
      Recovery of adrenal reserve following treatment of disseminated South American blastomycosis.
      Autopsy studies of paracoccidioidomycosis revealed fungal vasculitis in small arterioles, leading to tissue ischemia early during adrenal invasion.
      • Agarwal J
      • Agarwal G
      • Ayyagari A
      • Kar DK
      • Mishra SK
      • Bhatia E
      Isolated Pneumocystis carinii infection of adrenal glands causing Addison's disease in a non-immunocompromised adult.
      If left untreated, progression to glandular necrosis and irreversible endocrine impairment occur.
      • Agarwal J
      • Agarwal G
      • Ayyagari A
      • Kar DK
      • Mishra SK
      • Bhatia E
      Isolated Pneumocystis carinii infection of adrenal glands causing Addison's disease in a non-immunocompromised adult.
      Hence, prompt antifungal therapy may prevent irreversible pathological changes and salvage adrenal function.
      Adrenal reserve can also be affected by systemic mycoses, such as histoplasmosis, cryptococcosis, coccidioidomycosis, paracoccidioidomycosis, pneumocystosis, and blastomycosis.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      • Lio S
      • Cibin M
      • Marcello R
      • Viviani MA
      • Ajello L
      Adrenal bilateral incidentaloma by reactivated histoplasmosis.
      • Papadopoulos KI
      • Castor B
      • Klingspor L
      • Dejmek A
      • Lorén I
      • Bramnert M
      Bilateral isolated adrenal coccidioidomycosis.
      • Torres CM
      • Duarte E
      • Guimaraes JP
      • Moreira LF
      Destructive lesion of the adrenal gland in South American blastomycosis (Lutz' disease).
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      In particular, 50% of patients with paracoccidioidomycosis have diminished adrenal reserve, as evidenced by attenuated cortisol increments after corticotropin administration.
      • Del Negro G
      • Melo EH
      • Rodbard D
      • Melo MR
      • Layton J
      • Wachslicht-Rodbard H
      Limited adrenal reserve in paracoccidioidomycosis: cortisol and aldosterone responses to 1-24 ACTH.
      Such patients are asymptomatic, but fatal adrenal failure can occur in conditions of physiological stress. Hence, when the condition of patients with mycoses unexpectedly deteriorates, the adrenal axis should be examined thoroughly.
      Fungi might have differing affinities for infiltration of the different adrenal zones. For example, Paracoccidioides spp commonly infiltrate the zona reticularis, lowering dehydroepiandrosterone sulfate levels.
      • Del Negro G
      • Melo EH
      • Rodbard D
      • Melo MR
      • Layton J
      • Wachslicht-Rodbard H
      Limited adrenal reserve in paracoccidioidomycosis: cortisol and aldosterone responses to 1-24 ACTH.
      • Leal AM
      • Magalhães PK
      • Martinez R
      • Moreira AC
      Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.
      Such a shift in adrenal steroidogenesis away from androgens and toward the essential glucocorticoid pathway is presumably an adaptive mechanism with infections.
      • Leal AM
      • Magalhães PK
      • Martinez R
      • Moreira AC
      Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.
      Such patients may have impaired mineralocorticoid secretion with decreased aldosterone levels and elevated plasma renin activity because of zona glomerulosa infiltration. Mineralocorticoid deficiency can cause hyponatremia, hyperkalemia, and metabolic acidosis.
      • Maloney PJ
      Addison's disease due to chronic disseminated coccidioidomycosi.
      • Del Negro G
      • Wajchenberg BL
      • Pereira VG
      • et al.
      Addison's disease associated with South American blastomycosis.
      • Shah B
      • Taylor HC
      • Pillay I
      • Chung-Park M
      • Dobrinich R
      Adrenal insufficiency due to cryptococcosis.
      • Kent DC
      • Collier TM
      Addison's disease associated with North American blastomycosis: a case report.
      In contrast, in patients with histoplasmosis, sparing of the zona glomerulosa and preservation of mineralocorticoid function is the rule.
      • Goodwin Jr, RA
      • Shapiro JL
      • Thurman GH
      • Thurman SS
      • Des Prez RM
      Disseminated histoplasmosis: clinical and pathologic correlations.
      Fungal adrenal involvement manifests radiographically as glandular enlargement with peripheral enhancement, central hypoattenuation, contour preservation, and calcifications during healing.
      • Kawashima A
      • Sandler CM
      • Fishman EK
      • et al.
      Spectrum of CT findings in nonmalignant disease of the adrenal gland.
      Histoplasmosis causes bilateral symmetric adrenal enlargement, whereas paracoccidioidomycosis and blastomycosis cause asymmetric and occasionally unilateral involvement.
      • Kawashima A
      • Sandler CM
      • Fishman EK
      • et al.
      Spectrum of CT findings in nonmalignant disease of the adrenal gland.
      These characteristics help differentiate fungal adrenal infections from metastatic disease, in which the adrenal contour is distorted, and from autoimmune adrenalitis, in which the glands are atrophic.
      • Kawashima A
      • Sandler CM
      • Fishman EK
      • et al.
      Spectrum of CT findings in nonmalignant disease of the adrenal gland.

       Antifungal Agents

      Azoles affect glucocorticoid and mineralocorticoid function by inhibiting CYP450-dependent enzymes involved in adrenal steroidogenesis. Specifically, ketoconazole is a dose-dependent reversible inhibitor of cholesterol desmolase, 17,20-lyase, 11β-hydroxylase, 17α-hydroxylase, and 18-hydroxylase (Figure).
      • Lamberts SW
      • Bons EG
      • Bruining HA
      • de Jong FH
      Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells.
      • Loose DS
      • Kan PB
      • Hirst MA
      • Marcus RA
      • Feldman D
      Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes.
      • Sonino N
      The use of ketoconazole as an inhibitor of steroid production.
      Critical factors that modulate ketoconazole's endocrine effects are dosage and timing of administration because the kinetics of adrenal inhibition reflect serum ketoconazole concentrations.
      • Lamberts SW
      • Bons EG
      • Bruining HA
      • de Jong FH
      Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells.
      • Loose DS
      • Kan PB
      • Hirst MA
      • Marcus RA
      • Feldman D
      Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes.
      • Sonino N
      The use of ketoconazole as an inhibitor of steroid production.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      Thus, no effect on glucocorticoid synthesis is seen after administration of 200 mg of ketoconazole.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      • Pont A
      • Williams PL
      • Loose DS
      • et al.
      Ketoconazole blocks adrenal steroid synthesis.
      However, use of 400 or 600 mg of ketoconazole transiently blunts plasma cortisol response to corticotropin without affecting basal cortisol or pituitary corticotropin secretion.
      • Sonino N
      The use of ketoconazole as an inhibitor of steroid production.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      • Pont A
      • Williams PL
      • Loose DS
      • et al.
      Ketoconazole blocks adrenal steroid synthesis.
      • Pont A
      • Graybill JR
      • Craven PC
      • et al.
      High-dose ketoconazole therapy and adrenal and testicular function in humans.
      This effect lasts 8 hours but normalizes by 16 hours after ketoconazole administration.
      • Sonino N
      The use of ketoconazole as an inhibitor of steroid production.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      • Pont A
      • Williams PL
      • Loose DS
      • et al.
      Ketoconazole blocks adrenal steroid synthesis.
      • Pont A
      • Graybill JR
      • Craven PC
      • et al.
      High-dose ketoconazole therapy and adrenal and testicular function in humans.
      Higher doses produce more pronounced adrenal dysfunction. Nevertheless, overt adrenal insufficiency is relatively infrequent with ketoconazole, presumably because of a compensatory increase in corticotropin. However, overt adrenal insufficiency can occur with administration of 600 to 1200 mg/d of ketoconazole in divided doses; as opposed to once-daily ketoconazole use, such regimens produce sustained adrenal inhibition without allowing for compensatory normalization of adrenal steroidogenesis for a substantial part of the day.
      • Sonino N
      The use of ketoconazole as an inhibitor of steroid production.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      • Pont A
      • Williams PL
      • Loose DS
      • et al.
      Ketoconazole blocks adrenal steroid synthesis.
      • Pont A
      • Graybill JR
      • Craven PC
      • et al.
      High-dose ketoconazole therapy and adrenal and testicular function in humans.
      • Tucker Jr, WS
      • Snell BB
      • Island DP
      • Gregg CR
      Reversible adrenal insufficiency induced by ketoconazole.
      In contrast, adrenal crisis has occurred with ketoconazole dosages as low as 400 mg/d, suggesting host-specific genetic susceptibility to adrenal dysfunction.
      • Best TR
      • Jenkins JK
      • Murphy FY
      • Nicks SA
      • Bussell KL
      • Vesely DL
      Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy.
      Figure thumbnail gr1
      FIGUREThe main pathways of steroidogenesis in the adrenal glands and inhibitory effects of ketoconazole. The principal enzymes inhibited by ketoconazole are shown in yellow, and the main steroid products whose synthesis is decreased by ketoconazole are shown in red. H = hydrogen; HSD = hydroxysteroid dehydrogenase; O = oxygen; OH = hydroxylase; OHD = hydroxy dehydrogenase; SCC = cholesterol side-chain cleavage.
      Adapted from Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006, with permission of McGraw-Hill.
      In addition to inhibiting glucocorticoid synthesis, ketoconazole is a dose-dependent, reversible, competitive antagonist at the glucocorticoid receptor level.
      • Loose DS
      • Stover EP
      • Feldman D
      Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells.
      In fact, because of its antiglucocorticoid properties and rapid action onset, physicians have used ketoconazole (800-1200 mg/d) in palliative treatment of Cushing disease, adrenal tumors, and ectopic corticotropin production by small-cell lung carcinoma or carcinoid tumors.
      • Sonino N
      • Boscaro M
      • Paoletta A
      • Mantero F
      • Ziliotto D
      Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.
      • Contreras P
      • Rojas A
      • Biagini L
      • González P
      • Massardo T
      Regression of metastatic adrenal carcinoma during palliative ketoconazole treatment [letter].
      • Shepherd FA
      • Hoffert B
      • Evans WK
      • Emery G
      • Trachtenberg J
      Ketoconazole: use in the treatment of ectopic adrenocorticotropic hormone production and Cushing's syndrome in small-cell lung cancer.
      The aforementioned interaction of ketoconazole with the glucocorticoid receptor is restricted to imidazoles and does not occur with triazoles.
      • Duret C
      • Daujat-Chavanieu M
      • Pascussi JM
      • et al.
      Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor.
      Clinicians have used ketoconazole's ability to inhibit mineralocorticoid synthesis for palliative treatment of primary hyperaldosteronism due to adrenal adenomas or hyperplasia.
      • Leal-Cerro A
      • García Luna PP
      • Villar J
      • et al.
      Ketoconazole as an inhibitor of steroid production [letter].
      • Benito P
      • Corpas MS
      • Quesada JM
      • Jiménez JA
      Control of hyperaldosteronism by ketoconazole [letter].
      However, the accumulation of 11-deoxycortisol, corticosterone, and 11-deoxycorticosterone induced by inhibition of cortisol and aldosterone synthesis (Figure) can cause hypersensitivity to the mineralocorticoid properties of these compounds; indeed, hypertension develops in 14% to 27% of patients after long-term high-dose ketoconazole use; hypokalemia and edema may also develop, suggesting ketoconazole-induced Conn syndrome.
      • Aabo K
      • De Coster R
      Hypertension during high-dose ketoconazole treatment: a probable mineralocorticosteroid effect [letter].
      Fluconazole inhibits CYP450-dependent enzymes in cell cultures and animals, but concentrations required for these effects far exceed its therapeutic range. Consequently, adrenal function is unaffected in patients receiving 400 mg/d of fluconazole.
      • Albert SG
      • DeLeon MJ
      • Silverberg AB
      Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients.
      • Magill SS
      • Puthanakit T
      • Swoboda SM
      • et al.
      Impact of fluconazole prophylaxis on cortisol levels in critically ill surgical patients.
      However, the literature contains several reports of fluconazole-induced reversible Addison disease occurring within 24 to 48 hours of treatment.
      • Albert SG
      • DeLeon MJ
      • Silverberg AB
      Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients.
      • Santhana Krishnan SG
      • Cobbs RK
      Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient.
      Critically ill patients already at increased risk of adrenal insufficiency who receive high-dose fluconazole (800 mg/d) are most predisposed to developing adrenal insufficiency; however, it has been reported even with dosing of 200 mg/d.
      • Santhana Krishnan SG
      • Cobbs RK
      Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient.
      Fluconazole has reversed hypercortisolism in adrenal carcinoma-induced Cushing syndrome cases.
      • Riedl M
      • Maier C
      • Zettinig G
      • Nowotny P
      • Schima W
      • Luger A
      Long term control of hypercortisolism with fluconazole: case report and in vitro studies.
      Although itraconazole does not inhibit adrenal steroidogenesis at 100 to 400 mg/d,
      • Queiroz-Telles F
      • Purim KS
      • Boguszewski CL
      • Afonso FC
      • Graf H
      Adrenal response to corticotrophin and testosterone during long-term therapy with itraconazole in patients with chromoblastomycosis.
      reversible adrenal insufficiency has been reported at 600 mg/d.
      • Sharkey PK
      • Rinaldi MG
      • Dunn JF
      • Hardin TC
      • Fetchick RJ
      • Graybill JR
      High-dose itraconazole in the treatment of severe mycoses.
      Also, combination of itraconazole with high-potency inhaled glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis.
      • Skov M
      • Main KM
      • Sillesen IB
      • Müller J
      • Koch C
      • Lanng S
      Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide.
      Such suppression occurs because itraconazole, an inhibitor of CYP3A4, decreases glucocorticoid clearance and increases serum glucocorticoid levels.
      • Varis T
      • Kivistö KT
      • Backman JT
      • Neuvonen PJ
      Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers.
      In a study of 25 patients receiving itraconazole and inhaled budesonide, adrenal insufficiency developed in 11 patients and Cushing syndrome in 1 patient.
      • Skov M
      • Main KM
      • Sillesen IB
      • Müller J
      • Koch C
      • Lanng S
      Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide.
      Adrenal function recovered in only 1 patient, whereas the remaining 10 had persistent adrenal insufficiency 2 to 10 months after treatment discontinuation.
      • Skov M
      • Main KM
      • Sillesen IB
      • Müller J
      • Koch C
      • Lanng S
      Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide.
      Variation in CYP3A4 activity or glucocorticoid receptor sequence variations may explain such host-specific phenotypic diversity in adrenal function manifestations.
      • DeRijk RH
      • Schaaf M
      • de Kloet ER
      Glucocorticoid receptor variants: clinical implications.
      In addition, mineralocorticoid-induced edema, hypokalemia, and hypertension have been reported in 63% of patients receiving high-dose itraconazole (600 mg/d).
      • Sharkey PK
      • Rinaldi MG
      • Dunn JF
      • Hardin TC
      • Fetchick RJ
      • Graybill JR
      High-dose itraconazole in the treatment of severe mycoses.
      No adrenal effects have been reported with voriconazole or posaconazole.

      POTASSIUM AND MAGNESIUM ABNORMALITIES INDUCED BY ANTIFUNGAL AGENTS

      Hypokalemia develops in up to 90% of AMB-deoxycholate-treated patients and may occur and persist even weeks after treatment discontinuation.
      • Deray G
      Amphotericin B nephrotoxicity.
      Amphotericin B forms intramembranous pores in distal convoluted renal tubules, increasing their permeability and potassium urinary wasting.
      • Deray G
      Amphotericin B nephrotoxicity.
      Apoptosis is an important modulator of this process.
      • Varlam DE
      • Siddiq MM
      • Parton LA
      • Rüssmann H
      Apoptosis contributes to amphotericin B-induced nephrotoxicity.
      Additionally, AMB causes renal tubular acidosis type I because of a defect in distal tubule hydrogen potassium adenosine triphosphatase and promotes potassium urinary loss.
      • Deray G
      Amphotericin B nephrotoxicity.
      Moreover, AMB enhances sodium reabsorption in the distal colon, causing fecal potassium loss.
      • Deray G
      Amphotericin B nephrotoxicity.
      A recent study suggested that preexisting proteinuria may protect from AMB-deoxycholate-induced hypokalemia because binding of AMB to albumin in the tubular lumen may decrease the free drug fraction available to bind to the luminal epithelial surface.
      • Mohan S
      • Ahmed S
      • Alimohammadi B
      • Jaitly M
      • Cheng JT
      • Pogue VA
      Proteinuria lowers the risk of amphotericin B-associated hypokalaemia.
      Reversible, dose-dependent hypokalemia is more often caused by AMB-deoxycholate than by lipid AMB formulations
      • Deray G
      Amphotericin B nephrotoxicity.
      ; the latter have less affinity for mammalian cell membranes, thus reducing the incidence of nephrotoxicity. However, dose-dependent liposomal AMB-induced hypokalemia does occur; a recent study showed a 30% and 16% incidence of hypokalemia (potassium level <3 mEq/L [to convert to mmol/L, multiply by 1.0]) in patients treated with 10 vs 3 mg/kg of liposomal AMB daily, respectively.
      • Cornely OA
      • Maertens J
      • Bresnik M
      • AmBiLoad Trial Study Group
      • et al.
      Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad Trial).
      Hypokalemia can be ameliorated by administration of amiloride or spironolactone or by dilution of AMB in fat emulsion instead of dextrose.
      • Wazny LD
      • Brophy DF
      Amiloride for the prevention of amphotericin B-induced hypokalemia and hypomagnesemia.
      • Ural AU
      • Avcu F
      • Cetin T
      • et al.
      Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients?.
      • Nucci M
      • Loureiro M
      • Silveira F
      • et al.
      Comparison of the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in fat emulsion in a randomized trial with cancer patients.
      Nystatin causes hypokalemia by a similar mechanism.
      • Offner F
      • Krcmery V
      • Boogaerts M
      • EORTC Invasive Fungal Infections Group
      • et al.
      Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B.
      Fluconazole, itraconazole, and voriconazole also cause hypokalemia in up to 9%, 12%, and 16% of treated patients, respectively.
      • Glasmacher A
      • Cornely O
      • Ullmann AJ
      • Itraconazole Research Group of Germany
      • et al.
      An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia.
      • Denning DW
      • Ribaud P
      • Milpied N
      • et al.
      Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.
      Ventricular fibrillation and rhabdomyolysis have been reported with severe itraconazole-mediated hypokalemia.
      • Nelson MR
      • Smith D
      • Erskine D
      • Gazzard BG
      Ventricular fibrillation secondary to itraconazole induced hypokalaemia [letter].
      Echinocandins cause hypokalemia in 2% to 11% of patients, and studies have suggested a dose-dependent hypokalemic effect for caspofungin.
      • Maertens J
      • Raad I
      • Petrikkos G
      • Caspofungin Salvage Aspergillosis Study Group
      • et al.
      Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy.
      • Arathoon EG
      • Gotuzzo E
      • Noriega LM
      • Berman RS
      • DiNubile MJ
      • Sable CA
      Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases.
      The precise mechanisms by which azoles and echinocandins cause hypokalemia have not been elucidated.
      The AMB lipid complex and AMB-deoxycholate are also associated with hyperkalemia via intracellular potassium shift.
      • Craven PC
      • Gremillion DH
      Risk factors of ventricular fibrillation during rapid amphotericin B infusion.
      Renal insufficiency and rapid infusion (<1 hour) increase AMB serum levels and the risk of hyperkalemia and ventricular fibrillation
      • Craven PC
      • Gremillion DH
      Risk factors of ventricular fibrillation during rapid amphotericin B infusion.
      ; this increased risk can be avoided by slower infusion (4-6 hours) and AMB administration during hemodialysis.
      • Craven PC
      • Gremillion DH
      Risk factors of ventricular fibrillation during rapid amphotericin B infusion.
      Renal failure also predisposes potassium iodide-treated patients to hyperkalemia.
      • Sterling JB
      • Heymann WR
      Potassium iodide in dermatology: a 19th century drug for the 21st century—uses, pharmacology, adverse effects, and contraindications.
      Hypomagnesemia occurs in 30% to 75% of AMB-treated patients because of increased urinary magnesium secretion from AMB-induced tubular defects in distal convoluted tubules.
      • Marcus N
      • Garty BZ
      Transient hypoparathyroidism due to amphotericin B-induced hypomagnesemia in a patient with beta-thalassemia.
      • Barton CH
      • Pahl M
      • Vaziri ND
      • Cesario T
      Renal magnesium wasting associated with amphotericin B therapy.
      The incidence of hypomagnesemia increases during the second week of AMB administration, peaks by the fourth week, and then plateaus.
      • Barton CH
      • Pahl M
      • Vaziri ND
      • Cesario T
      Renal magnesium wasting associated with amphotericin B therapy.
      Hypomagnesemia, which is dose-dependent and reversible, is more common with AMB-deoxycholate than with lipid AMB formulations; it may persist for weeks after AMB discontinuation.
      • Barton CH
      • Pahl M
      • Vaziri ND
      • Cesario T
      Renal magnesium wasting associated with amphotericin B therapy.
      Amiloride ameliorated AMB-mediated hypomagnesemia in some studies.
      • Wazny LD
      • Brophy DF
      Amiloride for the prevention of amphotericin B-induced hypokalemia and hypomagnesemia.
      Up to 63% of patients treated with voriconazole and up to 3% of those treated with caspofungin have been shown to develop hypomagnesemia.
      • Maertens J
      • Raad I
      • Petrikkos G
      • Caspofungin Salvage Aspergillosis Study Group
      • et al.
      Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy.
      • Denning DW
      • Ribaud P
      • Milpied N
      • et al.
      Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.
      • Arathoon EG
      • Gotuzzo E
      • Noriega LM
      • Berman RS
      • DiNubile MJ
      • Sable CA
      Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases.