What is Ochronosis?
Ochronosis is a medical condition recognized by the reddish-brown color, similar to ‘ochre,’ shown by the affected tissue. This condition was first described by a young doctor called Archibald Garrod in the early 19th century. He linked this disease to something he referred to as an ‘inborn defect of metabolism,’ a concept he invented while studying a rare disease called alkaptonuria, which results in ‘black urine.’ He suggested that this disease was the result of a specific compound – ‘alkaptons,’ building up in the body’s connective tissue because the body lacked the enzyme to break it down. He believed this to be a hereditary condition and described it as ‘chemical individuality.’
Dr. Garrod’s studies have greatly contributed to our understanding of biochemistry, genetics, and medicine today. In fact, Alkaptonuria held historic significance as it was the first condition understood to be an ‘autosomal recessive disease’ – a kind of disease that occurs when an individual inherits the same abnormal gene for the same trait from each parent.
Presently, we comprehend that this disease happens when there is a problem with a particular gene, named HGD, resulting in the decreased creation of an enzyme called ‘homogentisate 1,2 dioxygenase.’ This leads to an increase in levels of ‘homogentisic acid’ (also referred to as Alkaptons), which builds up in tissues over time causing the condition known as ‘endogenous ochronosis.’
This document also discusses another form of ochronosis, called ‘exogenous ochronosis,’ often seen as a side effect of certain medications that hinder the same enzyme. However, in distinction to endogenous ochronosis, the buildup here is typically restricted to the skin.
What Causes Ochronosis?
Alkaptonuria is a condition that a person inherits when they get a certain non-functioning gene from both of their parents. This gene is found on a particular part of chromosome 3 and is meant to produce an enzyme called homogentisate 1,2 dioxygenase (HGD). This enzyme has a crucial role in the process of breaking down certain amino acids, the building blocks of proteins, in the body.
When HGD is missing, a substance called homogentisate builds up in the body. This substance is a type of phenol which is usually colorless but turns black as it breaks down. It can bind irreversibly with collagen, a protein that provides structure to various tissues throughout the body. This binding results in dark discoloration in tissues and turns urine black. More seriously, it causes deterioration and developmental issues in all forms of collagen, which can potentially affect the overall body architecture and functions.
Exogenous ochronosis is a condition that’s very similar to alkaptonuria, except it’s localized to the skin. Just like in alkaptonuria, the enzyme HGD is blocked. However, in exogenous ochronosis, this happens due to certain compounds found in medicines or cosmetics. These compounds include specific anti-malarials, acne medications, picric acid, and hydroquinone, a chemical used in some skin lightening products and medicines.
Risk Factors and Frequency for Ochronosis
Alkaptonuria and endogenous ochronosis are very rare conditions that affect less than 1 in 100,000 people in most ethnic groups. In fact, in the United States, only 22 cases have been confirmed in the last 50 years. However, these conditions can be more common in specific populations such as the Dominican Republic and Slovakia, where they affect 1 in 20,000 people.
On the other hand, exogenous ochronosis, an acquired form of the disease, is significantly more prevalent in sub-Saharan Africa. This larger prevalence can be attributed to the widespread use of certain substances like antimalarials and skin lightening agents, which are used more frequently, in higher concentrations, and for longer periods.
Signs and Symptoms of Ochronosis
One of the first signs of this particular disease in infants is unusually black colored dirty diapers. Over time, the disease may also cause changes in skin and bone coloration. These changes can be quite noticeable, although sometimes the disease can develop slowly and only show symptoms later in life.
People who have this disease may start experiencing back pain and discomfort in large joints in their early adult years or when they are in their early 30s. Characteristic signs, such as skin discoloration of the white part of the eye (sclera) and the small cartilage projection outside the ear (pinna), usually appear later. The intensity of these symptoms can vary greatly from person to person, but this does not necessarily indicate the possible course of the disease.
- Regular rupturing of tendons at various locations, even with minor injuries, is another warning sign.
- During a physical examination, other common signs are thickened Achilles tendon and swollen bursa (a small fluid-filled sac).
Murmurs in the aortic valve, which are usually audible only at an older age, might be heard earlier in individuals with this disease, even without pre-existing heart valve abnormalities such as a bicuspid aortic valve.
Testing for Ochronosis
If your doctor suspects that you might have alkaptonuria, a rare genetic condition, they may recommend some tests. One is a urine test. After your urine is exposed to air, it’s checked for a substance called homogentisate. If it’s present and changes color, this is a good indicator that you have alkaptonuria.
Another approach to confirm this genetic condition is through a genetic test. This test can tell if you have the disease or if you carry the gene mutation that causes it. This data is typically stored in a genetic testing registry.
If the doctor thinks you might have exogenous ochronosis, which is a skin disorder, they might ask about your past medications. Certain drugs known as phenols can cause this condition.
The doctor might use ultraviolet photography to help with the diagnosis. However, because this technique may also identify other skin conditions like melasma, it’s used less frequently now and may also involve a simple examination with a special light, known as a woods lamp.
The best way to confirm whether or not you have exogenous ochronosis is through a skin biopsy. This test involves taking a small sample of your skin and examining it under a microscope.
Finally, another emerging technique called confocal microscopy is being explored. This is a non-invasive way to diagnose the condition, which means it doesn’t require any cuts or poking or removal of tissue.
Treatment Options for Ochronosis
Vitamin C, also known as ascorbate, plays a critical role in various bodily functions, including the breakdown of tyrosine, collagen renewal, and growth. Despite its importance, taking large doses of vitamin C has not proven to be particularly effective.
You might have heard about restricting tyrosine and phenylalanine in the diet as a treatment method for a condition called phenylketonuria. This can be a challenging approach and has similar effectiveness to taking large doses of vitamin C.
A drug called nitisinone, which is primarily used for a related disorder called hereditary tyrosinemia, has been proven to affect the progression of these conditions. It’s significant in treating these disorders, but healthcare professionals need to use it carefully and monitor its effects closely.
It’s important to check the cornea, the front portion of the eye, for abnormal growths that result from medical treatments (known as iatrogenic dendritic keratopathy). Moreover, it’s crucial to assess whether there is normal pressure in the eye chamber and any changes in the coloration that can increase the likelihood of developing glaucoma, an eye disorder that can damage the optic nerve.
Regular monitoring of liver function and measuring tyrosine levels in the blood are also advised. It’s also recommended to get a psychiatric evaluation since related conditions like hereditary tyrosinemia have been associated with significant mental health complications.
Nitisinone works by blocking an enzyme that’s required to form a crucial chemical for these conditions. It’s been promising in maintaining normal levels of this chemical in the blood.
In the past, treating ochronosis, a condition that can be caused by certain medical treatments or exposure to certain substances, was quite difficult. Traditional methods of treatment involved skin grafting or using treatments like a glycolic acid chemical peel to remove damaged skin layers. Primarily, treatment for externally caused ochronosis involved avoiding substances that could spark the condition, along with dietary changes. However, advances in light therapies (photobiomodulation and photodynamic therapy) offer new potential treatment methods.
What else can Ochronosis be?
Alkaptonuria is a condition with a broad spectrum of symptoms that can be mistaken for many other diseases. A primary focus is to check for a group of diseases called seronegative arthropathies, such as spondylosis, because they show similar signs, especially pain in the big joints.
Of particular concern is a condition called “sacroiliac sparing”. But when ruling out inflammatory arthropathies, doctors look out for certain signs like erosion, unnatural widening of joints, and changes in the bone without damage to the articular cartilage (the slippery tissue that covers the end of bones in a joint).
Another tricky point is that the type of arthritis seen here can easily be mistaken for osteoarthritis. In these cases, physicians should keep track of a variety of blood tests related to rheumatic diseases and also whether any relief from symptoms is seen after using NSAIDs (nonsteroidal anti-inflammatory drugs) or DMARDs (disease-modifying antirheumatic drugs).
Melasma, a condition that causes brown patches on the skin, especially the face, should be considered because it can appear like exogenous ochronosis, another condition among the wide range of differential diagnosis. A key point is that first-line treatment with hydroquinone (commonly prescribed for melasma) can actually worsen symptoms of exogenous ochronosis. Furthermore, these conditions often co-exist, and complications can occur if melasma is over-treated, leading to even darker skin than before. However, the best way to manage such patients is still not agreed upon.
Lastly, physicians should bear in mind other diseases that cause changes in skin color. For instance:
- Argyria: This can make the skin look bluish-grey due to the buildup of silver salts
- Chrysiasis: It can change the skin color due to buildup of gold salts.
What to expect with Ochronosis
People with alkaptonuria, a rare genetic disorder, generally have a near-normal lifespan. However, the condition can greatly affect their quality of life and should be closely monitored.
In the early stages of life, most people with alkaptonuria don’t have any symptoms, other than their clothes getting stained. It’s important that their doctors keep track of the buildup of a substance called phenol in their bodies, using regular DEXA scans–tests that measure bone density. They should also check on the growth of the individual, which could slow down, and their nutrition, as foods high in phenylalanine and tyrosine may need to be limited.
People with alkaptonuria often have joint pain and arthritis, possibly needing joint replacement surgery as early as their 30s. This comes from a condition called ochronotic arthritis. In particular, their cartilage – the protective tissue at the ends of bones – gets damaged, leading to the bones rubbing against each other, much like in osteoarthritis. This condition can also affect the thoracic and lumbar spine–areas in the middle and lower back–causing severe back pain.
More concerning is when alkaptonuria affects the heart. The condition, known as ochronosis, can damage the flaps that control blood flow through the heart, particularly the aortic valve. This can lead to aortic insufficiency, where the heart doesn’t pump blood properly, and can be a factor in early heart disease.
Lastly, people with alkaptonuria are more likely to develop kidney and prostate stones–hard, stone-like objects that can form in these organs.
Possible Complications When Diagnosed with Ochronosis
Long-term use of the weed killer, nitisinone, requires careful surveillance, especially for signs of dendritic keratopathy. This is a symptomless and stealthy complication that may occur.
While the kidney continues to function correctly in filtering high amounts of homogentisate, if there is a reduction in creatinine clearance, it’s probably due to other concurrent health issues.
Notices for Long-Term Use:
- Continuous monitoring required
- Watch out for silent complications like dendritic keratopathy
- Kidney function won’t be compromised by filtering homogentisate
- Decrease in creatinine clearance may signal other health problems
Preventing Ochronosis
Gene mapping, or figuring out where genes are located, can be very useful for couples planning to have a child. This process can help figure out if both parents carry the specific genes (referred to as HGA genes) that might lead to certain health disorders in their potential child.
Ochronosis, a condition that darkens the skin, is more commonly seen as a result of external factors such as using certain skin-lightening products. It’s particularly critical in communities where lighter skin is preferred. Many cultures outside of Caucasity, favor lighter skin, pushing some people to use skin-lightening products, including creams containing ingredients like hydroquinone and NCAP (N-acetyl-4-s-cysteaminylphenol), more than they should. However, the effect of these products, especially hydroquinone, is less dramatic and much slower on darker skin tones, causing these individuals to use these products more frequently and in larger amounts. This usage can paradoxically cause ochronosis, darkening rather than lightening the skin.
Supporting the emotional health of patients dealing with this condition, like their self-esteem and general happiness, may be a helpful approach. However, larger societal issues, like discrimination based on skin color, social status, or race, contribute to this situation but are too complex and widespread to be addressed fully here.
