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Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

ABSTRACT: A 13-year-old Labrador retriever was diagnosed with Cushing's syndrome (CS) caused by primary bilateral nodular adrenocortical hyperplasia with adrenocorticotropic hormone (ACTH) expression. The pituitary origin of CS was ruled out by suppression of plasma ACTH concentration and absence of a proliferative lesion on histological evaluation of the pituitary gland using periodic acid-Schiff (PAS) staining, reticulin staining, and immunostaining for ACTH. A pheochromocytoma also was found at necropsy examination. On histological evaluation of both adrenal glands, at the junction of the fascicular and glomerular zones, multiple cell clusters distributed in both hyperplastic adrenal cortices expressed ACTH, whereas the pheochromocytoma cells did not. These results indicate that a disease similar to primary bilateral macronodular adrenocortical hyperplasia in humans also occurs in dogs, with intra-adrenocortical expression of ACTH, glucocorticoids excess, and clinical signs of CS. Therefore, the term ACTH-independent could be inappropriate in some cases of bilateral adrenocortical hyperplasia and suppressed plasma ACTH concentration in dogs.

SUBMITTER: Soler Arias EA

PROVIDER: S-EPMC8783325 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

Soler Arias Elber A EA Castillo Víctor A VA Louiset Estelle E Lefebvre Herve H

Journal of veterinary internal medicine 20211203 1

A 13-year-old Labrador retriever was diagnosed with Cushing's syndrome (CS) caused by primary bilateral nodular adrenocortical hyperplasia with adrenocorticotropic hormone (ACTH) expression. The pituitary origin of CS was ruled out by suppression of plasma ACTH concentration and absence of a proliferative lesion on histological evaluation of the pituitary gland using periodic acid-Schiff (PAS) staining, reticulin staining, and immunostaining for ACTH. A pheochromocytoma also was found at necrops ...[more]

PMID: 34859494

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Project description:BackgroundProlonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown.MethodsA patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient's serum was examined.ResultsImmunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient's serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient's serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3β, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin.ConclusionACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases.

Project description:BackgroundCurrent first-line anti-proteinuric treatments do not produce a satisfactory therapeutic effect in a considerable number of patients with nephrotic syndrome (NS). Interest in adrenocorticotropic hormone (ACTH) for the treatment of NS has recently been revived. The present study investigated the efficacy and safety of ACTH treatment in children with frequent relapsing NS (FRNS), steroid-dependent NS (SDNS), and steroid-resistant NS (SRNS).MethodThe ACTH treatment group was comprised of NS patients receiving ACTH treatment. Patients with serum cortisol concentrations <85.3 nmol/L and who had not received ACTH treatment previously were enrolled in the control group from January 2018 to January 2021. The maintenance dose of prednisone, the number of disease recurrences, the time of first disease relapse, immunosuppressant use, serum cortisol levels, and adverse events were recorded in both groups.ResultsFifty-one patients were included in the ACTH group, and twenty-one patients were enrolled in the control group. Concurrent treatment with one or more immunosuppressive and/or cytotoxic treatments occurred in 92.2% and 85.7% of patients in the ACTH and control groups, respectively, throughout the study period. A greater reduction in the prednisone maintenance dose was observed in the ACTH group compared with the control group after 1 year of follow up (0.603 ± 0.445 mg/kg vs. 0.267 ± 0.500 mg/kg, p = 0.006). During the one-year study period, fewer participants experienced one or more disease relapses in the ACTH group (45.1%) compared to the control group (76.2%, odds ratio = 3.896, p = 0.016). The number of disease recurrences per patient in the ACTH group was less than that in the control group (median difference = -1, p = 0.006). The mean length of remission was 8.902 m and 7.905 m in the ACTH group and control group, respectively. A log-rank test showed a longer relapse free survival for patients in the ACTH group (p = 0.046), but the Breslow test showed no significant difference between groups (p = 0.104). Ten patients in the ACTH group successfully discontinued all drug therapies. No patients in the control group were able to discontinue drug therapy as of February 2022.ConclusionACTH, combined with multiple drugs, is effective at reducing the prednisone maintenance dose and may effectively prevent disease relapses in childhood NS.

Project description:Background and objectivesThere is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial.Design, setting, participants, & measurementsParticipants aged 2-20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects.ResultsThe trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9-32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14-51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids.ConclusionsACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.

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Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

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Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

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