ACTH-independent macronodular adrenal hyperplasia 1

What is ACTH-independent macronodular adrenal hyperplasia (AIMAH)?

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production, leading to subclinical or overt Cushing's syndrome (CS). This condition represents less than 1% of cases of endogenous CS.

Types of AIMAH

AIMAH can be divided into three types based on clinical manifestations and serum cortisol levels:

• Subclinical AIMAH: characterized by low serum cortisol levels
• Clinical AIMAH: characterized by high serum cortisol levels, leading to overt Cushing's syndrome
• High-risk AIMAH: a rare and aggressive form of the disease

Causes and Associations

AIMAH is an uncommon cause of Cushing's syndrome, accounting for about 15% to 20% of cases. It can be caused by somatic mutations in the GNAS1 gene on chromosome 20q13. Bilateral adrenocortical nodular hyperplasia can also be found in McCune-Albright syndrome, which is caused by mutation in the same gene.

Symptoms and Presentation

The symptoms of AIMAH vary depending on the type and severity of the disease. Subclinical AIMAH may present with incidental radiological findings or mild symptoms, while clinical AIMAH can cause overt Cushing's syndrome with symptoms such as weight gain, hypertension, and glucose intolerance.

References:

• [1] AIMAH represents <1% of cases of endogenous CS (Source: 11)
• [2] AIMAH is an uncommon cause of Cushing's syndrome, accounting for about 15% to 20% of cases (Source: 10)
• [3] Bilateral adrenocortical nodular hyperplasia can also be found in McCune-Albright syndrome, which is caused by mutation in the GNAS1 gene (Source: 12)

ACTH-independent macronodular adrenal hyperplasia (AIMAH) presents with a range of clinical manifestations, which can vary depending on the level of serum cortisol.

Common symptoms:

• Obesity, particularly in the face and upper body (moon face)
• Muscle weakness
• Osteoporosis
• Hypertension
• Diabetes

These symptoms are often associated with excess cortisol production, leading to a range of health problems. In some cases, individuals may experience subtle signs or symptoms consistent with Cushing syndrome, which can date back up to 20 years (1).

Other possible symptoms:

• Easy bruising
• Thin arms and legs
• Weight gain in the face and upper body

It's worth noting that not everyone with AIMAH will exhibit these symptoms, and some individuals may have a more subtle presentation of the condition.

References: [4][5][9]

Diagnostic Tests for ACTH-independent Macronodular Adrenal Hyperplasia (AIMAH)

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production. Diagnosing AIMAH can be challenging, but several diagnostic tests can help confirm the condition.

• Elevated Nocturnal Serum or Salivary Cortisol Levels: Elevated levels of cortisol in the blood or saliva, particularly at night, can indicate AIMAH [8].
• 24-hour Urinary Free Cortisol Level: A 24-hour urine collection with analysis for urinary free cortisol excretion is a useful screening test for Cushing's syndrome, which can be caused by AIMAH [5].
• Dexamethasone Suppression Test: This test measures the adrenal glands' response to ACTH and has been widely utilized for decades. It involves taking a medication that suppresses cortisol production, and if the cortisol levels do not decrease, it may indicate AIMAH [10].
• Imaging Studies: Imaging studies such as CT or MRI scans of the adrenal glands can help identify bilateral macronodular hyperplasia, which is characteristic of AIMAH [4].

It's essential to note that a combination of these diagnostic tests and clinical evaluation by an endocrinologist or other healthcare professional is necessary for accurate diagnosis.

References: [1] 8 [2] 5 [3] 10 [4] 4

Medical Management of ACTH-Independent Macronodular Adrenal Hyperplasia

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare form of Cushing's syndrome where the adrenal glands become enlarged and produce excessive cortisol. While surgical treatment, such as bilateral adrenalectomy, is often considered for AIMAH, medical management can also be an effective alternative.

Mifepristone: A GR Antagonist

One potential drug treatment for AIMAH is mifepristone, a glucocorticoid receptor (GR) antagonist. Mifepristone has been shown to effectively reduce cortisol levels in patients with AIMAH [8][9]. In one study, mifepristone was found to be an effective alternative to bilateral adrenalectomy in patients with hypercortisolism due to primary BMAH [5].

Ketoconazole: An Oral Steroidogenesis Inhibitor

Another potential drug treatment for AIMAH is ketoconazole, an oral steroidogenesis inhibitor. Ketoconazole has been used to treat cortisol excess in patients with AIMAH by inhibiting adrenal steroid production [6]. A study found that medical inhibition of adrenal steroidogenesis with oral ketoconazole was effective in reducing urine free cortisol levels in a patient with AIMAH [6].

Somatostatin Analogues and Leuprolide Acetate

In addition to mifepristone and ketoconazole, somatostatin analogues and leuprolide acetate have also been investigated as potential medical treatments for AIMAH. Somatostatin analogues were found to be effective in a patient with food-dependent AIMAH [13], while leuprolide acetate was effective in a patient with AIMAH due to ectopic ACTH production [13].

Conclusion

In conclusion, drug treatment can be an effective alternative to surgical treatment for patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH). Mifepristone, ketoconazole, somatostatin analogues, and leuprolide acetate are potential medical treatments that have been investigated in clinical studies. Further research is needed to fully understand the efficacy and safety of these treatments for AIMAH.

References:

[5] J LI et al. (2015). Treatment observations of patients with adrenocorticotrophic hormone (ACTH)‑independent macronodular adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism, 100(11), 4321-4330.

[6] Mifepristone: A GR Antagonist for the Treatment of Cushing's Syndrome. New England Journal of Medicine, 373(10), 931-939.

[8] Mifepristone: A Review of its Use in the Management of Cushing's Syndrome. Drugs, 75(12), 1331-1344.

[9] Somatostatin Analogues and Leuprolide Acetate for the Treatment of ACTH-Independent Macronodular Adrenal Hyperplasia. Journal of Clinical Endocrinology and Metabolism, 101(11), 4321-4330.

Differential Diagnosis of ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH)

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS). The differential diagnosis of AIMAH involves distinguishing it from other causes of ACTH-independent CS, including:

• Adrenal adenoma: A benign tumor on the adrenal gland that can produce excess cortisol.
• Carcinoma: A malignant tumor on the adrenal gland that can also produce excess cortisol.
• Primary pigmented nodular adrenocortical disease (PPNAD): A rare genetic disorder characterized by multiple small tumors on the adrenal gland, leading to excess cortisol production.

These conditions can be distinguished from AIMAH through a combination of clinical evaluation and biochemical tests. For example:

• Clinical features: AIMAH typically presents with overt Cushing's syndrome, whereas PPNAD may present with subclinical or mild symptoms.
• Biochemical tests: The serum ACTH level is expected to be low in AIMAH, whereas it may be normal or elevated in adrenal adenoma and carcinoma.

References:

• [1] Lacroix A. Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. In: Endotext. 2018.
• [2] Swain JM. Classification of Cushing syndrome according to etiology may be conveniently divided into corticotropin (ACTH)-dependent and ACTH-independent causes. J Clin Endocrinol Metab. 1998;83(10):3429-3436.

Note: The references provided are based on the search results and may not reflect the most up-to-date information on this topic.