RARE DISEASE
Addison disease
Addison disease
Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Synonyms: Autoimmune Addison disease, Autoimmune adrenalitis, Classic Addison disease, Primary Addison disease
Drug discovery
0
drugs
With orphan designations
Overview
Addison disease is a primary adrenal insufficiency typically caused by autoimmune adrenal destruction, leading to cortisol and aldosterone deficiency. Key features include progressive fatigue, hyperpigmentation, hypotension, and gastrointestinal symptoms. Diagnosis requires elevated ACTH with low cortisol and abnormal ACTH stimulation testing. Treatment involves lifelong glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) replacement, stress-dose adjustments during physiologic stress, and prompt IV hydrocortisone/fluids for adrenal crises [1][2][3].
Burden
40% experience ≥1 adrenal crisis (5–10 episodes/100 patient-years), with 8% requiring emergency treatment [11][17]
Mortality risk 2–4× higher than general population, driven by cardiovascular events and infections [6][17]
Chronic complications include osteoporosis, diabetes from over-replacement, and reduced quality of life [5][6][17]
Therapies
Glucocorticoids: Hydrocortisone (15–25 mg/day in divided doses) or prednisone (3–5 mg/day) [2][3][16]
Mineralocorticoids: Fludrocortisone (0.05–0.2 mg/day), titrated to normalize plasma renin activity [2][3][16]
Emergency protocols: Stress-dose steroid adjustments during illness/surgery; mandatory emergency hydrocortisone injection kits [2][16][19]
Categories: rare endocrine diseases
Research Papers
465 drug discovery papers about Addison disease, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
465 drug discovery papers about Addison disease, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-26 | NR0B1 Gene Variants as Rare Forms of Primary Adrenal Insufficiency in Children: Case Report and Narrative Review.
Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.
2026-06-01 | Successful Therapeutic Approach to Facial Hyperpigmentation Secondary to Addison's Disease: A Case Report and Literature Review.
Addison's disease, or primary adrenal insufficiency, is a rare endocrine disorder characterized by deficient glucocorticoid and mineralocorticoid production, frequently associated with cutaneous hyperpigmentation due to chronic elevation of adrenocorticotropic hormone. Facial hyperpigmentation may persist despite adequate hormonal replacement, representing a therapeutic challenge with limited evidence to guide dermatologic management. We report the case of a 41-year-old female patient with an eight-year history of progressive hyperpigmentation affecting the face, hands, and oral mucosa. Physical examination revealed severe facial involvement with brown-violaceous macules and associated telangiectasias. The patient had a prior diagnosis of autoimmune ovarian failure in 2017 and was diagnosed with Addison's disease in 2020, receiving stable glucocorticoid replacement therapy. Histopathological evaluation demonstrated basal layer hyperpigmentation without interface dermatitis, consistent with endocrine-related pigmentation and overlapping melasma features. A multimodal therapeutic approach was implemented, including picosecond Nd:YAG laser therapy (approximately seven sessions at six- to eight-week intervals), oral tranexamic acid (250 mg twice daily), and a topical depigmenting regimen containing tranexamic acid, niacinamide, retinoids, and antioxidants. The patient demonstrated a significant reduction in modified Melasma Area and Severity Index score from 19.8 to 7.8 (60.6% reduction), along with a marked improvement in quality of life, as evidenced by a posttreatment Melasma Quality of Life Scale score of 20/70. This case highlights that persistent hyperpigmentation in Addison's disease may not fully resolve with endocrine treatment alone and may require adjunctive dermatologic interventions. A personalized, multimodal strategy targeting multiple pathogenic pathways, including melanogenesis, plasmin-mediated signaling, vascular factors, and dermal pigment deposition, can achieve significant improvement, even in patients with darker phototypes and long-standing disease. These findings underscore the importance of a multidisciplinary approach and suggest a potential role for combination therapies, including laser-based modalities, in managing complex pigmentary disorders associated with systemic conditions. Further studies are needed to establish standardized treatment protocols and evaluate long-term outcomes.
2026-03-24 | Prednisolone Once Daily vs Hydrocortisone Thrice Daily in Hypoadrenalism: A Randomized Clinical Trial.
Adrenal insufficiency is conventionally treated with daily multiple-dose hydrocortisone, and once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. Clinical trials comparing once-daily low-dose prednisolone with thrice-daily hydrocortisone are lacking. To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency. This double-blind, crossover randomized clinical trial of multiple-daily standard-dose hydrocortisone vs once-daily low-dose prednisolone (2-5 mg), performed from September 3, 2019, to December 14, 2023, involved adults with adrenal insufficiency. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at days 1, 30, and 120 of each study period for both medications. Individuals were randomized to receive 4 months of once-daily prednisolone in the morning (with placebos at noon and afternoon) or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for an additional 4 months. The primary outcome was assessment of bone turnover, detected by change in carboxylated and undercarboxylated osteocalcin between days 1 and 120 in each treatment period. Secondary outcomes included change in weight, body mass index, waist circumference, glycated hemoglobin, and subjective heath survey responses. Forty-seven participants were randomized, with 46 participants included in the analysis (median [IQR] age, 55.0 [46.5-62.8] years; 24 [52.2%] male). Twenty-four received prednisolone first and 22 received hydrocortisone first. Bone turnover was significantly slowed with prednisolone compared with hydrocortisone as evidenced by a significantly lower level of multiple bone markers, including carboxylated osteocalcin (mean treatment difference, -1.22 ng/mL; 95% CI, -2.35 to -0.10 ng/mL; P = .04), undercarboxylated osteocalcin (mean treatment difference, -1.38 ng/mL; 95% CI, -2.32 to -0.44 ng/mL; P = .005) (to convert osteocalcin to micrograms per liter, multiply by 1), urinary N-terminal telopeptide (mean treatment difference, -9.34 nmol/mmol; 95% CI, -15.4 to -3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (mean treatment difference, -13.8 ng/mL; 95% CI, -22.2 to -5.49 ng/mL; P < .001). The mean treatment group difference in weight reduction from baseline was -1.87 kg (95% CI, -3.02 to -0.72 kg; P = .002) for prednisolone treatment compared with hydrocortisone, and this was associated with concordant significantly greater reductions in body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters; treatment difference, -0.522; 95% CI, -1.01 to -0.04; P = .04), waist circumference (treatment difference, -2.26 cm; 95% CI, -3.97 to -0.56 cm; P = .01), and HbA1c (treatment difference, -0.12% [-1.23 mmol/mol; 95% CI, -1.95 to -0.51 mmol/mol]; P = .001). There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison's Disease-Specific Quality of Life Questionnaire. In this randomized clinical trial, once-daily low-dose prednisolone was associated with slower bone turnover and improvements in cardiometabolic health markers compared with multiple-dose hydrocortisone without compromising well-being. Studies assessing longer-term mortality and morbidity outcomes are needed. ClinicalTrials.gov Identifier: NCT03936517.
2026-06-26 | NR0B1 Gene Variants as Rare Forms of Primary Adrenal Insufficiency in Children: Case Report and Narrative Review.
Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.
2026-06-01 | Successful Therapeutic Approach to Facial Hyperpigmentation Secondary to Addison's Disease: A Case Report and Literature Review.
Addison's disease, or primary adrenal insufficiency, is a rare endocrine disorder characterized by deficient glucocorticoid and mineralocorticoid production, frequently associated with cutaneous hyperpigmentation due to chronic elevation of adrenocorticotropic hormone. Facial hyperpigmentation may persist despite adequate hormonal replacement, representing a therapeutic challenge with limited evidence to guide dermatologic management. We report the case of a 41-year-old female patient with an eight-year history of progressive hyperpigmentation affecting the face, hands, and oral mucosa. Physical examination revealed severe facial involvement with brown-violaceous macules and associated telangiectasias. The patient had a prior diagnosis of autoimmune ovarian failure in 2017 and was diagnosed with Addison's disease in 2020, receiving stable glucocorticoid replacement therapy. Histopathological evaluation demonstrated basal layer hyperpigmentation without interface dermatitis, consistent with endocrine-related pigmentation and overlapping melasma features. A multimodal therapeutic approach was implemented, including picosecond Nd:YAG laser therapy (approximately seven sessions at six- to eight-week intervals), oral tranexamic acid (250 mg twice daily), and a topical depigmenting regimen containing tranexamic acid, niacinamide, retinoids, and antioxidants. The patient demonstrated a significant reduction in modified Melasma Area and Severity Index score from 19.8 to 7.8 (60.6% reduction), along with a marked improvement in quality of life, as evidenced by a posttreatment Melasma Quality of Life Scale score of 20/70. This case highlights that persistent hyperpigmentation in Addison's disease may not fully resolve with endocrine treatment alone and may require adjunctive dermatologic interventions. A personalized, multimodal strategy targeting multiple pathogenic pathways, including melanogenesis, plasmin-mediated signaling, vascular factors, and dermal pigment deposition, can achieve significant improvement, even in patients with darker phototypes and long-standing disease. These findings underscore the importance of a multidisciplinary approach and suggest a potential role for combination therapies, including laser-based modalities, in managing complex pigmentary disorders associated with systemic conditions. Further studies are needed to establish standardized treatment protocols and evaluate long-term outcomes.
2026-03-24 | Prednisolone Once Daily vs Hydrocortisone Thrice Daily in Hypoadrenalism: A Randomized Clinical Trial.
Adrenal insufficiency is conventionally treated with daily multiple-dose hydrocortisone, and once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. Clinical trials comparing once-daily low-dose prednisolone with thrice-daily hydrocortisone are lacking. To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency. This double-blind, crossover randomized clinical trial of multiple-daily standard-dose hydrocortisone vs once-daily low-dose prednisolone (2-5 mg), performed from September 3, 2019, to December 14, 2023, involved adults with adrenal insufficiency. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at days 1, 30, and 120 of each study period for both medications. Individuals were randomized to receive 4 months of once-daily prednisolone in the morning (with placebos at noon and afternoon) or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for an additional 4 months. The primary outcome was assessment of bone turnover, detected by change in carboxylated and undercarboxylated osteocalcin between days 1 and 120 in each treatment period. Secondary outcomes included change in weight, body mass index, waist circumference, glycated hemoglobin, and subjective heath survey responses. Forty-seven participants were randomized, with 46 participants included in the analysis (median [IQR] age, 55.0 [46.5-62.8] years; 24 [52.2%] male). Twenty-four received prednisolone first and 22 received hydrocortisone first. Bone turnover was significantly slowed with prednisolone compared with hydrocortisone as evidenced by a significantly lower level of multiple bone markers, including carboxylated osteocalcin (mean treatment difference, -1.22 ng/mL; 95% CI, -2.35 to -0.10 ng/mL; P = .04), undercarboxylated osteocalcin (mean treatment difference, -1.38 ng/mL; 95% CI, -2.32 to -0.44 ng/mL; P = .005) (to convert osteocalcin to micrograms per liter, multiply by 1), urinary N-terminal telopeptide (mean treatment difference, -9.34 nmol/mmol; 95% CI, -15.4 to -3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (mean treatment difference, -13.8 ng/mL; 95% CI, -22.2 to -5.49 ng/mL; P < .001). The mean treatment group difference in weight reduction from baseline was -1.87 kg (95% CI, -3.02 to -0.72 kg; P = .002) for prednisolone treatment compared with hydrocortisone, and this was associated with concordant significantly greater reductions in body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters; treatment difference, -0.522; 95% CI, -1.01 to -0.04; P = .04), waist circumference (treatment difference, -2.26 cm; 95% CI, -3.97 to -0.56 cm; P = .01), and HbA1c (treatment difference, -0.12% [-1.23 mmol/mol; 95% CI, -1.95 to -0.51 mmol/mol]; P = .001). There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison's Disease-Specific Quality of Life Questionnaire. In this randomized clinical trial, once-daily low-dose prednisolone was associated with slower bone turnover and improvements in cardiometabolic health markers compared with multiple-dose hydrocortisone without compromising well-being. Studies assessing longer-term mortality and morbidity outcomes are needed. ClinicalTrials.gov Identifier: NCT03936517.
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