Ochronosis is a rare condition characterized by the accumulation of pigments in the body’s connective tissues, leading to a bluish-black or grayish-blue discoloration. This pigmentation can affect various parts of the body, including the skin, cartilage, and eyes. The term “ochronosis” originates from the yellowish (ochre-like) discoloration observed microscopically in affected tissues, even though they appear bluish-gray macroscopically due to light scattering.
Forms of Ochronosis
Ochronosis has two main forms: endogenous and exogenous. Endogenous ochronosis is an inherited metabolic disorder, also known as alkaptonuria or “black urine disease.” It is present from birth, though symptoms may appear later in life. Exogenous ochronosis is an acquired condition resulting from external factors. This form is caused by the long-term application of topical agents, such as skin-lightening creams containing hydroquinone. While both forms result in similar discoloration, their origins—internal metabolic dysfunction versus external chemical exposure—are different.
Underlying Causes
Endogenous ochronosis is caused by alkaptonuria, an autosomal recessive genetic disorder. Individuals must inherit an abnormal gene from both parents to develop the condition. This involves a mutation in the HGD gene, which produces the enzyme homogentisate 1,2-dioxygenase (HGD). This enzyme breaks down homogentisic acid (HGA), a byproduct of amino acid metabolism.
Without a functional HGD enzyme, HGA accumulates in the body’s tissues. Excess HGA oxidizes and polymerizes into a dark, melanin-like pigment. This pigment binds to collagen and elastin fibers in connective tissues, causing the characteristic bluish-black discoloration. In infants with alkaptonuria, an early sign can be dark staining in diapers, as HGA is excreted in urine and darkens upon exposure to air.
Exogenous ochronosis results from the prolonged and excessive use of topical agents, most notably hydroquinone. Hydroquinone is a chemical in skin-lightening creams used to treat hyperpigmentation. When applied over extended periods, hydroquinone interferes with enzymes that break down homogentisic acid in the skin, leading to its localized accumulation and pigmentation. Other substances like phenol, resorcinol, and some antimalarials can also induce exogenous ochronosis.
Manifestations and Development
Ochronosis causes physical manifestations. The primary sign across both forms is the bluish-black or grayish-blue discoloration of connective tissues. This pigmentation is often visible in areas with thick connective tissue or those close to the skin’s surface, such as the ear cartilage, the whites of the eyes (sclera), and the nose. Discoloration of the ear cartilage can make it appear thickened and rigid. In exogenous ochronosis, hyperpigmentation is localized to areas where the causative topical agent was applied, often appearing as speckled macules or “caviar-like” papules.
In endogenous ochronosis, pigment accumulation can also affect major joints, leading to ochronotic arthropathy. Individuals may experience chronic joint pain, stiffness, and reduced range of motion, particularly in the spine, hips, and knees. Intervertebral discs can calcify, and cartilage becomes brittle, potentially leading to spinal injuries. Cardiac complications, such as hardening and dysfunction of heart valves, especially the aortic valve, can also occur due to pigment deposition.
Identification and Care
Identifying ochronosis often begins with a physical examination, where clinicians look for the characteristic bluish-black pigmentation of the skin, ears, and eyes. For endogenous ochronosis (alkaptonuria), a urine test can detect homogentisic acid, which turns dark when exposed to air. Imaging studies, such as X-rays, may reveal calcification in joints and the spine, indicating ochronotic arthropathy. A skin biopsy can confirm the diagnosis of both forms by identifying pigment deposits in the dermis.
Management of ochronosis focuses on alleviating symptoms and providing supportive care, as there is no known cure. For endogenous ochronosis, treatments may include physical therapy, pain management for joint issues, and in some cases, joint replacement surgery. Dietary modifications to reduce intake of phenylalanine and tyrosine may help lower homogentisic acid levels, though effectiveness varies. A medication called nitisinone can reduce homogentisic acid production and is being researched for its potential benefits.
For exogenous ochronosis, discontinuing the causative topical agent, such as hydroquinone, is the primary step. Laser therapy, including Q-switched alexandrite lasers, has shown success in lightening discolored skin areas.