Hyperpigmentation and tanning: signs, symptoms and causes
Hyperpigmentation is a valuable symptom, seen in 92% of patients with primary adrenal insufficiency and it is one of the earliest manifestations of this disease. It is also of value in distinguishing between primary and secondary adrenal insufficiency.
Two different concepts, with similar manifestations, are related to different medical conditions.
Manifestations of iron overload
Hyperpigmentation is often described as bronze/green or tile black. Generally, it occurs all over the body, but it can be seen more clearly on the face, neck, and stretched skin.
Manifestations of Addison's disease
Darkened areas of the body - especially sun-exposed areas, areas prone to pressure sores, skin folds, scars, and stretch marks.
Figure. Hyperpigmentation is seen in Addison's disease
Addison's disease (ACTH-dependent causes) – common.
Cushing's disease (ACTH-dependent causes) – uncommon.
Iron stasis disease.
ACTH activates the receptors of melanocytes-stimulating hormone (MSH) on melanocytes, secreting melanin, making the skin dark.
Pro-opiomelanocortin (POMC) is a precursor for the synthesis of two molecules MSH and ACTH. One form of MSH, α-MSH, causes tanning, which is similar in structure to ACTH in the first 13 amino acids. With this similarity, ACTH is thought to be able to stimulate melanocytes to secrete melanin, which is then absorbed by skin cells to impart its tanning properties.
In Cushing's disease, when ACTH is secreted by a pituitary tumor, darkening of the skin can occur from melanocyte stimulation in a process similar to Addison's disease.
Iron overload disease
Two separate mechanisms characterize hyperpigmentation in iron overload. These include the accumulation of haemosiderin in the skin and increased production of melanin.
Iron overload is a disease caused by excessive iron absorption. Excess iron can be deposited in various organs, including the skin. When accumulated in the skin, haemosiderin will change skin pigmentation, making the skin blue.
Pigmentation changes are also caused by iron retention which irritates skin tissue and causes inflammation. This inflammatory process stimulates the production of melanin.
Figure. Mechanism of hyperpigmentation in Addison's disease
Hyperpigmentation is a valuable symptom, seen in 92% of patients with primary adrenal insufficiency and it is one of the earliest manifestations of this disease. It is also of value in distinguishing between primary and secondary adrenal insufficiency. In secondary adrenal insufficiency (due to destruction of the pituitary gland), ACTH is not secreted, so no hyperpigmentation occurs.
In Cushing's disease, hyperpigmentation is less common in 4–16% of patients, so the negative predictive value is low. If this symptom is present, the cause will be localized in the hypothalamic axis. Because in Addison's disease, hyperpigmentation is dependent on ACTH, so when hyperpigmentation occurs, the cause of Cushing's syndrome is narrowed down to ACTH-producing diseases.
Hyperpigmentation helps to localize the problems of Endocrine disorders
Given the explanations above, hyperpigmentation is a valuable symptom that you can use to localize the cause of both Addison's disease and Cushing's syndrome. Hyperpigmentation helps to determine if ACTH is excessively elevated. Summary:
Suspected Addison's disease + hyperpigmentation?
Think of: adrenal gland damage (primary adrenal insufficiency)
Autoimmune – most common in developed countries.
Infection – Tuberculosis (most common in developing countries), CMV, HIV.
Congenital adrenal hyperplasia.
Medicines (eg, ketoconazole).
Suspected Cushing's syndrome + hyperpigmentation
Think about: ACTH .-dependent excessive cortisol secretion
Abnormal ACTH-secreting tumor (not located in the pituitary gland).
CRH-secreting abnormal tumor (rare).