What Is Primary Macronodular Adrenal Hyperplasia (PMAH)?
Primary macronodular adrenal hyperplasia (PMAH) is a condition marked by multiple small lumps (nodules) in the adrenal glands situated atop each kidney. These nodules, typically found in both adrenal glands, vary in size and lead to an enlargement of the adrenal glands, causing them to produce excessive amounts of cortisol, a crucial hormone with anti-inflammatory properties that helps the body cope with physical stress, such as infections or injuries, by elevating blood glucose levels.
PMAH commonly manifests in individuals during their 40s or 50s. It falls under Cushing syndrome, characterized by elevated cortisol levels stemming from various potential causes. The surplus cortisol contributes to symptoms like facial and upper body weight gain, delicate skin, bone loss, fatigue, and other health issues. Nevertheless, some individuals with PMAH may not exhibit these signs and symptoms, being classified as having subclinical Cushing syndrome.
How Often Does Primary Macronodular Adrenal Hyperplasia Occur?
PMAH is a rare condition, making up less than one percent of instances of endogenous Cushing syndrome. Endogenous Cushing syndrome refers to situations where factors within the body, rather than external influences like prolonged use of specific medications called corticosteroids, cause the syndrome. The overall prevalence of endogenous Cushing syndrome is approximately one in 26,000 people.
What Is the Cause of Primary Macronodular Adrenal Hyperplasia?
In about half of individuals with PMAH, the condition is caused by changes in the ARMC5 gene. This gene provides instructions for generating a protein that acts as a tumor suppressor, meaning it helps prevent cells from growing too quickly or in an uncontrolled manner. Mutations in the ARMC5 gene are thought to hinder the protein's tumor-suppressing abilities, allowing certain cells to overgrow. The reason for this overgrowth, specifically in the form of adrenal gland nodules in people with PMAH, is not clear.
PMAH can also result from mutations in the GNAS gene, which instructs the production of a component called the stimulatory alpha subunit in a protein complex popular as a guanine nucleotide-binding protein (G protein). This G protein, produced by the GNAS gene, helps stimulate the activity of an enzyme called adenylate cyclase, which is involved in controlling the production of hormones regulating the activity of various endocrine glands, including the adrenal glands. Mutations in the GNAS gene causing PMAH are thought to create an overactive G protein. Studies suggest that this overactivity may increase adenylate cyclase levels, leading to excess production of a compound called cyclic AMP (cAMP). Too much cAMP may trigger abnormal cell growth, resulting in the adrenal nodules characteristic of PMAH. Other gene mutations, some of which are unknown, can also be responsible for causing PMAH.
Is Primary Macronodular Adrenal Hyperplasia Inherited?
If someone has PMAH due to ARMC5 gene mutations, they inherit one altered copy of the gene from each parent. This inheritance is called autosomal dominant because having just one mutated gene is enough to make an individual prone to PMAH. However, the condition only develops when these individuals also acquire another mutation in the other copy of the ARMC5 gene, and this second mutation is called somatic. Unlike genetic mutations passed from parents to children, somatic mutations happen during a person's lifetime and are present only in certain cells. Since somatic mutations are necessary for PMAH, some individuals with the altered ARMC5 gene may not develop the condition, a situation known as reduced penetrance.
On the other hand, when PMAH is caused by GNAS gene mutations, it is not inherited. These GNAS gene mutations leading to PMAH are somatic, occurring early in embryonic development. Cells with the mutated GNAS gene are present in both adrenal glands.
What Are the Other Names of Primary Macronodular Adrenal Hyperplasia?
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ACTH-independent macronodular adrenal hyperplasia.
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ACTH-independent macronodular adrenocortical hyperplasia.
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Adrenal Cushing syndrome due to AIMAH.
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Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia.
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AIMAH.
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Corticotropin-independent macronodular adrenal hyperplasia.
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PMAH.
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Primary bilateral macronodular adrenal hyperplasia.
How to Diagnose Primary Bilateral Macronodular Adrenal Hyperplasia?
Diagnosing primary macronodular adrenal hyperplasia requires a multidimensional approach, encompassing clinical, biochemical, and radiological assessments. The cornerstone of diagnosis is the demonstration of cortisol overproduction through laboratory tests. Elevated cortisol levels, lack of suppression during Dexamethasone suppression tests, and abnormal circadian rhythm of cortisol secretion are indicative of PMAH.
Imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), play a pivotal role in identifying the characteristic nodular growth of the adrenal glands. However, differentiating PMAH from other adrenal conditions, such as adrenal adenomas or carcinomas, can be challenging. Advanced imaging techniques, like positron emission tomography (PET) scans, may provide additional insights into the functional aspects of these nodules.
Genetic testing also plays a role, especially in cases with a suspected familial component. Identifying mutations in genes like ARMC5 not only aids in confirming the diagnosis but also opens avenues for genetic counseling and family screening.
What Are the Treatment Options for Primary Macronodular Adrenal Hyperplasia?
Once diagnosed, the management of primary macronodular adrenal hyperplasia necessitates a tailored approach, considering the individual patient's symptoms, comorbidities, and overall health. The primary goal is to normalize cortisol levels while minimizing the adverse effects of excessive hormone production.
Surgical intervention, such as adrenalectomy (removal of the affected adrenal gland), may be considered in certain cases. However, the decision to pursue surgery is complex and depends on various factors, including the extent of adrenal involvement, the severity of symptoms, and the patient's overall health. Postoperative care and long-term monitoring are crucial to assess the effectiveness of the procedure and address any potential complications.
In cases where surgery is not a viable option or is deemed too risky, medical management becomes the cornerstone of treatment. Medications, such as Ketoconazole or Metyrapone, may be recommended to inhibit cortisol synthesis and alleviate symptoms. However, these medications are not without side effects and require careful monitoring to ensure efficacy and safety.
Ongoing research is exploring novel therapeutic approaches for PMAH, including the development of targeted drugs that can modulate the underlying molecular mechanisms driving adrenal hyperplasia. Clinical trials are important to evaluate the safety and effectiveness of these emerging treatments, offering hope for improved results and quality of life for individuals with PMAH.
Conclusion
Primary macronodular adrenal hyperplasia (PMAH) is a rare condition characterized by the presence of nodules in the adrenal glands, causing excessive cortisol production. Commonly associated with gene mutations, PMAH poses challenges in diagnosis, requiring a comprehensive approach involving clinical, biochemical, and radiological assessments. While surgical intervention like adrenalectomy may be considered in certain cases, medical management with medications such as Ketoconazole or Metyrapone is an alternative for those not suitable for surgery. Ongoing research, including clinical trials, aims to explore innovative therapeutic options for PMAH, offering hope for improved treatment outcomes and improved quality of life for affected individuals.
