[Diagnosis and etiology of primary adrenal insufficiency]. / Diagnostic et étiologie de l'insuffisance surrénalienne primaire.

Since its first description in 1855, our understanding of primary adrenal insufficiency has greatly evolved. However, diagnosis is often delayed, as symptoms are frequently nonspecific in the early stages of the disease. In this article, we review the classical manifestations, associated diseases, as well as the diagnostic algorithm for primary adrenal insufficiency, aiming to enable earlier diagnosis.

Depuis la première description en 1855, nos connaissances de l'insuffisance surrénalienne primaire ont beaucoup évolué. Cependant, le diagnostic est souvent retardé, les symptômes étant fréquemment aspécifiques aux premiers stades de la maladie. Dans cet article, nous rappelons les manifestations classiques, les maladies associées, ainsi que l'algorithme diagnostique de l'insuffisance surrénalienne primaire, afin de permettre un diagnostic plus précoce.

On Primary Adrenal Insufficiency with Normal Concentrations of Cortisol - Early Manifestation of Addison's Disease.

Primary adrenal insufficiency (AI) is an endocrine disorder in which hormones of the adrenal cortex are produced to an insufficient extent. Since receptors for adrenal steroids have a wide distribution, initial symptoms may be nonspecific. In particular, the lack of glucocorticoids can quickly lead to a life-threatening adrenal crisis. Therefore, current guidelines suggest applying a low threshold for testing and to rule out AI not before serum cortisol concentrations are higher than 500 nmol/l (18 µg/dl). To ease the diagnostic, determination of morning cortisol concentrations is increasingly used for making a diagnosis whereby values of>350 nmol/l are considered to safely rule out Addison's disease. Also, elevated corticotropin concentrations (>300 pg/ml) are indicative of primary AI when cortisol levels are below 140 nmol/l (5 µg/dl). However, approximately 10 percent of our patients with the final diagnosis of primary adrenal insufficiency would clearly have been missed for they presented with normal cortisol concentrations. Here, we present five such cases to support the view that normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin are indicative of primary adrenal insufficiency when the case history is suggestive of Addison's disease. In all cases, treatment with hydrocortisone had been started, after which the symptoms improved. Moreover, autoantibodies to the adrenal cortex had been present and all patients underwent a structured national education program to ensure that self-monitored dose adjustments could be made as needed.

X-linked adrenoleukodystrophy and primary adrenal insufficiency.

X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal ß-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.

Autoimmune primary adrenal insufficiency -current diagnostic approaches and future perspectives.

The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI.

A Patient with Addison Disease (Primary Adrenal Insufficiency) Presenting for Surgical Extraction of Third Molars.

The local prevalence of primary adrenal insufficiency (PAI) depends on various factors such as genetics, environment, and timely disease diagnosis. PAI is uncommon, and the prevalence is reported to be 2 per 10,000 population. PAI is commonly caused by an autoimmune process that destroys the adrenal gland, resulting in the loss of glucocorticoid and mineralocorticoid secretion from the adrenal cortex. The lack of cortisol results in impaired glucose/fat/protein metabolism, hypotension, increased adrenocorticotropic hormone secretion, impaired fluid excretion, and hyperpigmentation. PAI has a female predominance and is commonly seen in ages 20 to 50 years but can occur at any age.

Autoimmune adrenal insufficiency in children: a hint for polyglandular syndrome type 2?

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

Acute Mania in a Patient With Primary Adrenal Insufficiency Due to Autoimmune Adrenalitis: A Case Report.

We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.

An 11-year-old girl with Autoimmune Polyglandular Syndrome (APS) type 2: a case report and review of literature.

OBJECTIVES: Autoimmune polyglandular syndrome type 2 (APS2) is characterized by autoimmune adrenal insufficiency (AI) in conjunction with autoimmune thyroid disease (AITD) and/or type 1 diabetes mellitus (T1DM). The aim is to report an 11-year-old girl with concurrence of Addison disease, celiac disease and thyroid autoimmunity. CASE PRESENTATION: She initially presented at the age of 5 with vomiting, dehydration, hyponatremia, hyperkalemia and low glucose. She recovered with intravenous hydration but the diagnosis was not established. She presented again at the age of 11 with hyperpigmentation, weakness and signs of impending adrenal crisis. Diagnosis of autoimmune AI was established together with celiac disease and thyroid autoimmunity. Thus, she met criteria for APS, being the third pediatric case report of APS2 with this combination. CONCLUSIONS: This case is notable for the atypical age of onset, given that APS2 is rare in the pediatric population. Furthermore, it depicts the insidious course of Addison disease with symptoms fluctuating for years before diagnosis.

Coronary artery disease in a patient with Addison's disease: a case report and literature review.

BACKGROUND: Addison's disease which is due to dysfunction of the adrenal gland, with abnormal secretion of glucocorticoids and mineralocorticoids, is rare. By inducing inflammation and disorders of water and electrolyte metabolism, Addison's disease may accelerate progression of co-existed cardiovascular diseases. Addison's disease combined with cardiovascular disease is infrequent, only 10 cases in the literature. CASE PRESENTATION: We reported a 51-year-old male patient with unstable angina pectoris and hypotension. Changes on coronary angiography within 2 years suggested rapid progression of coronary artery disease in a patient with low cardiovascular risk. An additional clue of skin hyperpigmentation, fatigue and further examination confirmed the diagnosis of Addison's disease caused by adrenal tuberculosis. After hormone replacement treatment, the frequency and severity of the angina pectoris were alleviated significantly, as were hypotension, hyperpigmentation and fatigue. CONCLUSIONS: The combination of Addison's disease and coronary artery disease in one patient is rare. Addison's disease can induce inflammation and disorders of water and electrolyte metabolism, which may further accelerate the course of coronary artery disease. Meanwhile, the hypotension in Addison's disease may affect the coronary blood flow, which may result in an increased susceptibility to unstable angina in the presence of coronary stenosis. So, we should analyze comprehensively if the coronary artery disease progress rapidly.

Intractable vomiting as a presentation of adrenal insufficiency - a case report.

An array of pathophysiological processes can lead to chronic nausea and vomiting, including gastrointestinal and non-gastrointestinal disorders. Initial symptoms of adrenal insufficiency are usually non-specific, but intractable nausea and vomiting are infrequently associated, posing a diagnostic dilemma for clinicians. Here we present such a patient, who responded to glucocorticoid replacement with complete improvement.

Addison's disease without hyperpigmentation in pediatrics: pointing towards specific causes.

INTRODUCTION: Hyperpigmentation of skin and mucous membranes comprises a hallmark of the clinical diagnosis of Addison's disease. However, there have been reports of patients with adrenal insufficiency from diverse causes who did not develop hyperpigmentation. The pathophysiology responsible for the absence of increased pigmentation is not clearly defined in many cases. CASE PRESENTATION: We present a patient with isolated glucocorticoid deficiency due to two novel heterozygous variants in the sphingosine-1-phosphate lyase 1 (SPGL1) gene that did not develop any hyperpigmentation. DISCUSSION: We elaborate on the presumed mechanism of the absence of hyperpigmentation in adrenal insufficiency due to SPGL1 deficiency and discuss the other reported cases of Addison's disease without hyperpigmentation and the possible mechanism accounted for. CONCLUSION: Absence of hyperpigmentation, a basic component of the clinical diagnosis of Addison's disease, may lead to delay of a critical diagnosis, while causes that result in adrenal insufficiency without hyperpigmentation should explicitly be considered in pediatric cases where adrenal failure is documented by clinical symptomatology and biochemistry.

[Hyperpigmentation reveals Addison's disease in a pregnant woman].

A 31-year-old woman was admitted to the local department of endocrinology for control of known anti-TPO positive hypothyroidism during pregnancy. The clinician noticed a remarkable hyperpigmentation. Primary adrenal insufficiency was diagnosed and treatment with cortico- and mineralosteroids commenced. Diagnosis of primary adrenal insufficiency during pregnancy is challenging as many symptoms overlap with normal symptoms of pregnancy. The usual diagnostic criteria cannot be used due to the altered hormone concentrations during pregnancy.