Hyperpigmentation and hyponatremia in a life-threatening case report of autoimmune polyglandular syndrome (APS)

Introduction

Primary adrenal insufficiency (PAI) is a rare disease that occurs in 1/5,000–1/7,000 individuals in the general population when the adrenal glands fail to produce cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, despite a normal or increased corticotropin [adrenocorticotropic hormone (ACTH)] level (1,2).

Addison’s disease is the most common cause of PAI with progressive destruction of the adrenal cortex, and it accounts for 68% to 94% of cases of PAI in developed nations (3). Anti-adrenal gland antibodies and 21-hydroxylase antibodies (21OHAb) are associated with the autoimmune aggression of the adrenal cortex. In particular, 21OHAb identifies subjects with ongoing clinical or pre-clinical adrenal autoimmunity. Autoimmune Addison’s disease (AAD) represents 80–90% of cases of Addison’s disease (3-5).

Most people with AAD experience fatigue, generalized weakness, loss of appetite, and weight loss. Other common symptoms include darkening of the skin and gastrointestinal symptoms such as nausea, vomiting, and abdominal pain that may be a sign of an adrenal crisis (6).

Adrenal crisis refers to overwhelming and life-threatening adrenal insufficiency. The most common signs of adrenal crisis are shock, dehydration, and an imbalance of sodium and potassium levels in the body. In some cases, shock is preceded by fever, nausea, vomiting, abdominal pain, weakness or fatigue, and confusion. Adrenal crisis usually occurs after an infection, trauma, or another stressor (4).

The most crucial diagnostic consideration is to confirm adrenal insufficiency by measuring serum cortisol, which is generally low; in PAI, ACTH levels will be elevated.

One of the manifestations of an adrenal crisis that may compromise the patient’s life is severe acute symptomatic hyponatremia, which complicates differential diagnosis due to the heterogeneity of the clinical presentation.

The treatment of adrenal crisis in the emergency department (ED)/intensive care unit (ICU) setting requires immediate administration of intravenous hydrocortisone (HC) and intravenous fluid with careful correction of hyponatremia. AAD requires lifelong substitutive therapy with two or three daily doses of HC (15–25 mg/day) or one daily dose of dual-release HC, along with fludrocortisone (0.5–2.0 mg/day).

Clinical and biochemical parameters must be used to identify the lowest possible HC dose, thereby minimizing long-term complications, including osteoporosis and alterations in cardiovascular and metabolic function.

Moreover, AAD may be part of the rare group of autoimmune polyendocrine syndromes (APS), characterized by simultaneous or sequential immunomediated functional insufficiency in multiple endocrine glands, particularly as a component of type 1 or, more commonly, type 2, among the four types described. The failure of multiple glands was first described in 1926 by Schmidt (7), who reported the combination of hypothyroidism and adrenal insufficiency with lymphocytic infiltration of both the thyroid and adrenal glands.

In particular, APS-1, also known as APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy), is a rare autosomal recessive inherited disorder with childhood onset, caused by mutations in the autoimmune regulator AIRE gene and characterized by mucocutaneous candidiasis, hypoparathyroidism, and AAD (5). Besides, type 2 is characterized by the association of autoimmune thyroid disorders, AAD, and/or type 1 diabetes mellitus (8,9).

APS type 2 (APS-2) may represent a subtle and sometimes misinterpreted condition, whose variety of clinical manifestations can be confusing and delay diagnosis. Although primarily a specialist condition, it can occasionally present critically as an Addisonian crisis, even in an emergency setting, where recognition is crucial. Therefore, it is essential to be aware of its existence and implications, both for timely treatment and for proper post-crisis management, including treatment of complications with life support, hormonal replacement, and maintenance therapy.

We describe the case of a patient referred to the ED and admitted to the ICU for Addison’s crisis complicated by neurological signs and seizure presentation, in the context of mucocutaneous hyperpigmentation and critical metabolic imbalance, with very severe acute symptomatic hyponatremia, to our knowledge, not previously described in homologous case reports in the literature. Clinical and laboratory investigations led to the diagnosis of AAD in APS. We present this case in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-175/rc).

Case presentation

A 54-year-old female [body mass index (BMI): 17.6 kg/m²] was admitted to the ED of G. Mazzini Hospital in Teramo due to mental confusion and reported global aphasia. Two days before, the patient had experienced vomiting, nausea, and loss of appetite, so she visited a medical clinic for intravenous (IV) rehydration therapy.

Approximately 30 days before this case presentation, she was hospitalized for fever, general weakness, nausea, vomiting, and abdominal pain. She was discharged with no signs of a gastrointestinal infection.

During the collection of medical information, the husband revealed that he had noticed his wife had dark patches on her skin and mucous membranes, along with loss of appetite and about 10 kg weight loss over the past year.

The patient’s past medical history includes hypothyroidism from Hashimoto thyroiditis in levothyroxine replacement therapy, osteopenia, previous gastritis caused by H. pylori, and lactose intolerance.

During the initial evaluation in the ED, the patient appeared confused and globally aphasic.She exhibited extensive and notable hyperpigmentation, characterized by a diffuse, brownish skin “bronzing” aspect, which was prominent in sun-exposed areas, such as the elbows, knees, knuckles, skin creases—especially in the palmar creases—and the mucous membranes of the mouth (gums, buccal mucosa) and genitals. Longitudinal banded pigmentation of the nails was also present.

The patient’s state was reported as tachycardic (125 bpm) and hypotensive [blood pressure (BP): 80/40 mmHg].

A brain CT scan was requested, and no radiological characteristics suggesting parenchymal pathology were found. Before the brain CT scan, the patient experienced an epileptic seizure in the emergency department and was successfully treated with diazepam.

During the post-critical phase, the patient appeared sleepy but awoke to verbal stimuli.

Blood tests revealed severe hyponatremia (98 mEq/L) and hypochloremia (67.4 mEq/L), while potassium levels were normal (5.12 mEq/L), and glycemia values were within the normal range (Table 1).

Careful correction of severe symptomatic hyponatremia (defined as serum Na⁺ <120 mmol/L) with 3% hypertonic saline solution (HSS) has been initiated through continuous infusion at 1 mL/kg/h until the target serum sodium (Na⁺) increase of 6–12 mEq/L within the first 24 hours and symptom improvement as recommended by European clinical guidelines (10).

Due to the severity of the clinical conditions driven by acute severe hyponatremia and suspicion of PAI, the patient was admitted to the ICU for continuous vital sign monitoring and supportive care therapy. For the hypotensive state, constant infusion of noradrenaline was initiated at a dose of 0.35 mcg/kg/min and gradually tapered over the following days until blood pressure parameters returned to normal levels (Table 2). In the highest suspicion of PAI, an immediate administration of an IV bolus of HC (100 mg) was undertaken, followed by a maintenance dose of 50 mg every 6 hours of HC IV until vital signs stabilize.

Given the worsening neurological condition and the onset of fever in the ICU (37.9 ℃), a lumbar puncture was performed due to clinical suspicion of encephalitis. Still, it was negative, as were the blood cultures.

During early ICU recovery, the patient experienced psychomotor agitation, which was successfully treated with IV dexmedetomidine.

An abdominal CT scan showed a “fluid level in the left renal loggia”, while a brain MRI indicated a ‘partially empty sella’. Due to clinical suspicions of adrenal insufficiency, HC was administered promptly.

Blood tests demonstrated cortisol reduced (1.13 mcg/dL) and ACTH increased (1,240.0 pg/mL). Based on the data provided, a specific diagnosis of adrenal crisis was made.To detect AAD, the presence of 21-hydroxylas autoantibodies (21OHAb) was tested and identified (Table 3).

During her subsequent days in the ICU, the patient continued HC and sodium chloride therapy. This led to a gradual normalization of Na⁺ levels and an improvement in her clinical neurological condition. As a result, she was moved to the Internal Medicine Department for ongoing care after 7 days of ICU length of stay.

Consultation with endocrinology and immunology specialists was necessary to confirm the diagnosis of APS-2 and to follow up on its management.

The syndrome is characterized by primary hypothyroidism and Addison’s disease, both of which display autoimmune features. It is possible that a previous infection triggered the onset of Addison’s disease. Specifically, the 21OHAb levels were 395.06 as determined by adrenal cortex antibodies positivity using immunofluorescence. Additionally, screenings for glutamic acid decarboxylase and gastric anti-parietal cell antibodies yielded negative results for type 1 diabetes mellitus and chronic autoimmune gastritis (Table 3).

Conversely, the incidental detection of anti-SSA Ro 60 antibodies at a low titer in the ENA profile did not meet the ACR/EULAR Classification Criteria for Sjӧgren Syndrome (11).

After an 8-day hospitalization in the Medicine Department, the patient was discharged home on hormone replacement therapy and with normalized Na⁺ levels (140 mEq/L). The patient’s care journey timeline from assessment to home discharge is shown in Figure 1. Ongoing monitoring will be performed for type 1 diabetes mellitus and other (minor) autoimmune diseases associated with APS 2.

Figure 1 Timeline illustrating the patient’s care journey, including key visits, and procedures. ACTH, adrenocorticotropic hormone; CT, computed tomography; ED, emergency department; HSS, hypertonic saline solution; ICU, intensive care unit; IV, intravenous; Na⁺, serum sodium.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The first description of APS, defined as a multiple endocrine gland insufficiency associated with an autoimmune disease in a patient, was dated 1980, by Neufeld & Blizzard, who suggested a classification of APS, based on clinical criteria only, described four main types: APS-1, APS-2, APS-3, and APS-4 (12).

Moreover, although more than 150 years have passed since Addison’s disease was first described (13), clinical and pathological features of adrenal failure remain underdiagnosed, resulting in unnecessary morbidity and mortality (14).

APS-2 typically occurs in early adulthood, peaking during the third or fourth decade, and is three times more common in females than males (15).

Subsequently, several reports regarding the APS-2 were published, as isolated events in clinical investigations (16,17) or literature reviews (18,19).

In the case reports reported in the literature, APS-2 was associated with various contributing factors, including pituitary adenoma, sarcoidosis, hyponatremia, and hyperkalemia (20-22).

Regarding our case, the most significant feature is the severe and symptomatic hyponatremia with a serum level of 98 mEq/L. To our knowledge, cases of such severe hyponatremia have not been previously reported.

In our case, the patient had severely low Na⁺ levels in the blood (Na⁺ 98 mmol/L, serum osmolarity of 208 mOsm, calculated serum osmolality 226.9 mOsm/kg). Severely low Na⁺ levels can lead to acute symptomatic seizures, as demonstrated in our patient.

In fact, a severe epileptic seizure complicated the hyponatremia, worsening the patient’s prognosis and requiring admission to intensive care.

Hyponatremia is a common medical issue with various causes. It affects about 30% of hospitalized patients, and in 2.6% of cases, the Na⁺ level falls below 124 mEq/L (23).

One cause of hyponatremia is hypocortisolism. Early detection of this condition is essential because it can be life-threatening, and its symptoms are often nonspecific.

Patients with hypocortisolism can develop hyponatremia due to aldosterone deficiency, which causes renal sodium loss. This is worsened by increased antidiuretic hormone (ADH) release in response to decreased blood pressure and cardiac output resulting from cortisol deficiency (24).

This explains why hyponatremia does not improve with fluid restriction in hypocortisolism. On the other hand, AAD is usually accompanied by hyperkalemia, which was not observed in our case. Interestingly, we observed that during the ED admission, the patient’s potassium levels rose to a maximum of 5.12 mEq/L, which is relatively high compared to the average of 3.6 mEq/L based on previous dosages recorded by the patient.

Identifying whether the root cause of hyponatremia is reversible significantly influences how patients are managed. Some causes are typically quickly reversible, such as hyponatremia from true volume depletion—when correcting hypovolemia suppresses ADH secretion, leading to water diuresis; hyponatremia due to adrenal insufficiency—where administering steroids inhibits ADH secretion and causes water diuresis; and hyponatremia from syndrome of inappropriate antidiuretic hormone secretion (SIADH), like in postsurgical patients or cases triggered by pain or medication. On the other hand, specific causes are considered irreversible, including SIADH linked to conditions like malignancy, severe brain injury, cirrhosis, or heart failure.

In our case, we decided to correct acute severe hyponatremia with a continuous infusion of 0.5–1 mL/kg/h of 3% HSS, monitored by repeated Na⁺ checks, aiming for the Na⁺ to increase by 6–12 mEq/L within the first 24 hours. This approach was used instead of repeated bolus administrations of 100–500 mL or 2–4 mL/kg of 3% HSS over 20–40 minutes. The comparison between the two approaches is equally recommended and remains a topic of debate (10).

Despite being prospective, a multi-center, randomized trial involving 148 patients with symptomatic hyponatremia demonstrated that slow continuous infusion (SCI) and rapid intermittent bolus (RIB) are equally safe treatments, with no difference in the risk of overcorrection (25).

In our case, the choice was dictated by necessity to avoid the possibility of under- or overcorrection, which appears to be greater with the bolus hypertonic saline approach in patients with ≤60 and ≥100 kg body weight (26).

There were no signs of osmotic demyelination syndrome (ODS), a severe condition that can occur after rapid overcorrection of hyponatremia, with symptoms appearing up to 7 days later, in our case. It is diagnosed clinically and varies depending on which brain structure is affected by demyelination. The pons is most commonly affected, but the cerebellum or basal ganglia can also be involved. Symptoms include ataxia, quadriplegia, cranial nerve palsies, and locked-in syndrome.

Anyway, differential diagnoses were excluded by abdominal CT scan, lumbar puncture, and blood cultures, while cortisol and ACTH levels were suggestive of Addison’s disease.

Moreover, a relevant clinical data point that focused our attention was the mucocutaneous hyperpigmentation characteristic of Addison’s disease.

In this disease, hyperpigmentation results from increased production of α-melanocyte-stimulating hormone (α-MSH).

Both α-MSH and ACTH originate from the prohormone peptide pro-opiomelanocortin (POMC). In PAI, POMC production is enormously increased in response to the fall in cortisol levels, with the accompanying release of α-MSH, causing bronze hyperpigmentation.It is crucial to promptly recognize acute adrenal crisis because hypocortisolism can be life-threatening during physical stress. Activation of the hypothalamic-pituitary-adrenal axis is an essential response during illness. This condition often presents with non-specific symptoms, making hyperpigmentation and hyponatremia essential clues in the diagnosis of Addison’s disease (24).

We have already shown that the main cause of Addison’s disease has an autoimmune etiology.

As reported in the literature, our patient showed high titers of 21-hydroxylase autoantibodies, confirming AAD. This, along with autoimmune chronic thyroiditis, led to clinical suspicion of APS-2.

In addition, our patient exhibits at least two of the following three endocrinopathies: type 1 diabetes, autoimmune thyroiditis, and AAD.

According to a cross-sectional, population-based study conducted by Dalin et al. (27), additional manifestations, such as hyperpigmentation of the skin and gums, are more prevalent among APS-2 patients with Addison’s disease.

AAD is a complex condition caused by a combination of genetic factors [such as Human Leukocyte Antigen (HLA) class II], environmental factors, and potentially other autoimmune diseases or infections. These factors can trigger an immune response that, over time, leads to the destruction of the adrenal cortex. The immune response involves CD4⁺ and CD8⁺ T cells, B cells targeting 21OH, antiviral immune response, interferon-gamma (IFN-γ) production, and molecular mimicry mechanisms. This autoimmune-mediated destruction typically starts with a deficiency in the zona glomerulosa and later affects the fasciculata over months (28).

A new onset of adrenal insufficiency can present with nonspecific, minor symptoms, such as fatigue, or it can escalate to a life-threatening adrenal crisis with hemodynamic instability.

In our case, the previously hypothesized infection may have triggered or increased the production of 21OHAb during a preclinical phase.

Besides, the delayed diagnosis of APS-2 may have been caused by misinterpreting gastrointestinal symptoms as nonspecific and varied. At the same time, negative blood and stool cultures, as well as nonspecific mucosal inflammation in the intestinal biopsy, could be confounding factors.

Untreated APS-2 can progress rapidly, leading to a wide range of severity in symptoms, from mild to severe impairment.

These symptoms are often difficult to differentiate from gastrointestinal infectious causes, leading to misdiagnosis, management errors, or conflicting interpretations (29).

So, 21OHAb could serve as an early biomarker to correlate with clinical progression and enable early diagnosis before the onset of hyponatremia. It should be considered in conjunction with basal ACTH, cortisol, renin, aldosterone, and the ACTH test (30).

Betterle et al. demonstrated the predictive role of adrenal antibodies, strictly correlated with 21OHAb, in the development of AAD in 1983. This is significant regarding the potential subclinical and clinical stages of the disease (31).

On the other hand, islet cell antibodies, antibodies to glutamic acid decarboxylase, insulin autoantibodies, and IA-2A can help diagnose either clinical or subclinical type 1 diabetes mellitus in the context of a complete or incomplete APS 2, with or without thyroid autoimmunity and disease.

Furthermore, in addition to the primary conditions, other autoimmune disorders could be linked to APS-2. These may include autoimmune gastritis, pernicious anemia, premature menopause, hypogonadism, vitiligo, alopecia, celiac disease, chronic inflammatory bowel diseases, myasthenia gravis, rheumatic, hematological, or neurological diseases (10).

Extensive literature demonstrates the effectiveness of hormone replacement therapy in these cases.

The primary treatment for adrenal crisis includes HC, intravenous fluids, glucose repletion, and addressing the underlying acute trigger.

These treatments have significantly improved our patient’s quality of life, enabling her to live a better life today. It is essential to diagnose certain medical conditions early. Our patient showed nonspecific and varied symptoms, such as severe hypotension, epileptic seizures, and mental confusion due to severe acute hyponatremia. These symptoms may resemble those of a neurological or infectious condition, making it challenging to reach an accurate diagnosis quickly.

Regarding adrenal gland-related diseases, the presence of anti-adrenal antibodies is an essential indicator for doctors to diagnose the condition before symptoms develop. These antibodies can be detected in a patient’s blood before adrenal gland failure occurs. For instance, if a patient is experiencing hyperpigmentation, measuring the levels of 21-hydroxylases in their blood could help detect the disease early. This early detection can help better monitor the patient’s adrenal function and hormone levels.

Conclusions

Adrenal insufficiency can cause serious patient morbidity and death. However, because of the wide variety of symptoms, different clinical courses, and various causes, diagnosing and managing it can be very challenging, even life-threatening.

The diagnosis is often missed due to the variety of signs and symptoms. In our clinical case, features like severe hyponatremia and skin hyperpigmentation should raise suspicion and prompt an early diagnosis. This syndrome can be severely disabling, so emergency clinicians must be prepared to recognize, evaluate, and manage those with known or suspected adrenal insufficiency or adrenal crisis.

In the context of multiple autoimmune syndromes and/or post-infectious onset and autoimmune features, the predictive role of adrenal autoimmunity should be considered beyond being just a diagnostic tool.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-175/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-175/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-175/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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