The genetic disease most commonly associated with a bronze hue or hyperpigmentation of the skin is Hereditary Hemochromatosis (HH). This inherited disorder causes the body to absorb and store an excessive amount of iron from the diet. This iron overload, known as hemosiderosis, accumulates over time in various organs and tissues. If left untreated, this progressive buildup can lead to severe organ damage.
Hereditary Hemochromatosis: The Genetic Basis
Hereditary Hemochromatosis is an autosomal recessive disorder caused by mutations in the HFE gene on chromosome 6. The most common genetic change is the C282Y missense mutation, where cysteine is replaced by tyrosine at position 282 of the protein. Individuals who inherit two copies of this mutation comprise the majority (85 to 90 percent) of clinically affected patients with type 1 HH.
The HFE gene produces a protein that regulates iron absorption by controlling the production of hepcidin. Hepcidin is a liver hormone that decreases iron absorption from the digestive tract and reduces its release from storage cells when iron levels are high. When the C282Y mutation is present, the faulty HFE protein cannot properly communicate with the liver’s sensing mechanisms.
This failure results in a functional deficiency of hepcidin, even when iron stores are elevated. Intestinal cells absorb iron at an unregulated rate from every meal. The continuous, excessive iron uptake leads to iron overload, progressively depositing iron compounds in vital organs. This genetic defect sets the stage for the clinical manifestations of the disorder.
Systemic Impact and Bronze Skin Pathophysiology
The characteristic bronze or gray-bronze discoloration of the skin, historically called “bronze diabetes,” results directly from iron overload. This hyperpigmentation occurs in approximately 70% of people with advanced Hereditary Hemochromatosis. The color change is caused by the deposition of excess pigment in the skin via two related processes.
One factor contributing to the discoloration is the deposition of hemosiderin, a storage complex of iron, within the skin cells, particularly in the lower dermis and epidermis. However, the more prominent bronzing is caused by iron overload stimulating the production and deposition of melanin. This increased melanin gives the skin its golden-brown or bronze tint, often appearing first in sun-exposed areas.
Beyond the skin, accumulated iron progressively damages other organs, leading to serious systemic complications:
- The liver is particularly susceptible, often resulting in fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma.
- Iron deposition in the pancreas can destroy insulin-producing cells, leading to diabetes mellitus.
- Accumulation in the heart muscle can cause cardiomyopathy, arrhythmias, and heart failure.
- The joints are also affected, with iron buildup causing a specific type of arthritis (arthropathy), most commonly targeting the knuckles and knees.
Diagnosis and Management of Iron Overload
Diagnosis of Hereditary Hemochromatosis begins with blood tests measuring the body’s iron status. The two primary indicators are serum ferritin and transferrin saturation (TSAT). Serum ferritin measures stored iron, which is elevated in iron overload, often rising above 300 ng/mL in men and 200 ng/mL in women.
Transferrin saturation indicates the percentage of the iron-carrying protein transferrin that is actually bound to iron, and a value greater than 45% is highly suggestive of HH. If these iron studies are elevated, genetic testing is then performed to confirm the presence of the HFE gene mutations. Early detection is paramount because treatment initiated before the onset of organ damage, such as cirrhosis, allows for a normal life expectancy.
The standard treatment for iron overload is therapeutic phlebotomy, which is essentially the controlled removal of blood, similar to a blood donation. This procedure removes approximately 200 to 250 mg of iron with each unit of blood taken. The removal of red blood cells forces the body to use its excess iron stores to manufacture new blood cells, thereby gradually depleting the total body iron burden.
The frequency of phlebotomy is initially aggressive, often weekly, until the iron stores are brought down to a safe level, typically targeting a serum ferritin level between 50 and 150 ng/mL. Once the iron overload is resolved, a maintenance phase begins, requiring phlebotomy three to four times per year to prevent iron levels from rising again. This treatment prevents the progression of organ damage, though it cannot reverse damage already sustained, such as joint destruction or established cirrhosis.