Homogentisic Acid

If your urine sometimes darkens after sitting out, if a family member has been diagnosed with alkaptonuria, or if you have unusually early and severe joint pain that does not fit a typical arthritis diagnosis, this is the test that can tell you what is going on. It looks for a single molecule that builds up only when a specific step in amino acid digestion is blocked.

Standard urine panels measure creatinine, protein, and dipstick markers, but they do not detect HGA (homogentisic acid). People with alkaptonuria can excrete grams of HGA per day while their routine labs look unremarkable or are even falsely abnormal. Knowing your level gives you a specific answer that no standard panel provides.

What This Test Measures

HGA is a short-lived chemical your liver normally produces and then immediately breaks down as it digests the amino acids tyrosine and phenylalanine, both common in protein-rich foods. The next step in this digestion is carried out by an enzyme called HGD (homogentisate 1,2-dioxygenase). When both copies of the HGD gene are faulty, that step stalls, HGA accumulates in the blood, and the kidneys flush large amounts of it into the urine.

Over years, the leftover HGA that does not exit in urine slowly oxidizes inside cartilage, tendons, heart valves, and other connective tissues, where it forms a dark pigment. This pigment-driven damage is called ochronosis, and it is what eventually produces the joint, spine, heart, and kidney problems linked to alkaptonuria.

Why Alkaptonuria Matters

Alkaptonuria is rare, but its consequences are not subtle. The condition follows a recognizable arc: gram quantities of HGA appear in urine from birth, pigment quietly accumulates for decades, and then a rapidly progressive phase begins in adulthood with severe spine and large-joint arthritis, ruptured tendons and ligaments, kidney stones, and calcified heart valves. People are often misdiagnosed with ankylosing spondylitis for years before the true cause is identified.

Catching alkaptonuria early matters because treatment exists. The drug nitisinone blocks an upstream step in the same pathway and lowers urinary HGA dramatically. In a four-year randomized trial of 138 adults with alkaptonuria, 10 mg of nitisinone per day cut daily urinary HGA by 99.7 percent at 12 months and slowed clinical progression. A smaller dose-finding trial in 40 patients found that 4 weeks of treatment dropped daily urinary HGA from about 31.5 mmol without treatment to 0.15 mmol at the 8 mg dose, about a 98.8 percent reduction. The FDA-approved alkaptonuria-specific formulation (Harliku) is dosed at 2 mg once daily, lower than the 10 mg used in the SONIA 2 trial, reflecting a balance between HGA suppression and the rise in blood tyrosine that nitisinone causes.

Joint, Spine, and Bone Damage

The most consistent clinical signature of alkaptonuria is early, multi-joint degenerative disease. Spine involvement often resembles ankylosing spondylitis on imaging but follows a different mechanism. Hip and knee cartilage become discolored and brittle, leading to early joint replacement. Tendon, ligament, and muscle ruptures, fractures, and reduced bone density are also reported. These are the changes nitisinone-driven HGA lowering is intended to slow.

Heart Valve and Kidney Disease

HGA pigment also accumulates in heart valves, where it contributes to calcification and stenosis later in life. In the kidneys, very high urinary HGA can promote kidney stones and contribute to chronic kidney disease in advanced cases. The high urine excretion is partly protective by clearing HGA from circulation, but it does not prevent long-term tissue deposition.

Why Routine Labs Can Mislead You

One of the most practical reasons to know your HGA level is that very high HGA distorts other urine tests. In a case report of a young child with alkaptonuria, HGA caused urine creatinine to read falsely low, and the benzethonium chloride method for urine total protein read falsely high, mimicking nephrotic-range proteinuria and hyperoxaluria. Urine albumin, measured by a different method, was unaffected. The mismatch between high total protein and normal albumin is itself a clue. Specialists recommend avoiding peroxidase-coupled creatinine assays and benzethonium-based total protein assays when monitoring alkaptonuria, and relying on urine albumin to assess kidney involvement.

How Levels Compare Across Groups

Source: Oláh et al. 2003 (children); SONIA 1 (Ranganath et al. 2014); SONIA 2 (Ranganath et al. 2020).

What this means for you: a single urine HGA measurement can separate alkaptonuria from normal physiology by orders of magnitude, not by a few percent. There is no ambiguous middle ground for most readings. If your level is in the gram-per-day range, the answer is essentially settled.

Tracking Your Trend

A single urine HGA reading is enough to identify alkaptonuria, because the difference between affected and unaffected people is so large. But tracking matters once you are on therapy. Nitisinone is dosed and monitored using 24-hour urinary HGA, and dietary changes that limit tyrosine and phenylalanine can further reduce HGA load. In one small study of 9 patients, low-dose nitisinone reduced daily urinary HGA from about 4.0 g/day to about 0.2 g/day, with additional reduction when patients also followed a low-protein diet.

A reasonable schedule is a baseline measurement to establish your starting point, a follow-up at 3 to 6 months after starting or changing treatment, and at least annual measurements thereafter. People without alkaptonuria who are testing once for reassurance generally do not need to repeat the test unless symptoms or family history change.

When Results Can Be Misleading

• Sample handling: HGA can break down in urine that sits at room temperature for too long, which can lower the measured value. Morning spot collections analyzed promptly are preferred over poorly preserved 24-hour collections.
• Age in children: Healthy children under 6 years have higher and more variable HGA-to-creatinine ratios than adults. Pediatric results need to be interpreted against age-specific ranges.
• Vitamin C supplements: In adults, vitamin C lowers a related oxidation product called benzoquinone acetic acid, but in a small early report it appeared to roughly double urinary HGA in 2 of 3 infants studied. Many specialists stop vitamin C before testing to avoid interference with colorimetric assays.
• Assay choice for kidney markers: Very high HGA itself does not mean the test is wrong, but it can crash the accuracy of routine creatinine and total protein assays performed on the same urine, leading to spurious diagnoses of kidney disease.

What to Do With an Unexpected Result

If your urinary HGA is markedly elevated, the next steps are to confirm the diagnosis with HGD gene sequencing, evaluate organ involvement with focused imaging (spine, hips, knees, echocardiogram), and connect with a metabolic specialist familiar with alkaptonuria. Family members, especially siblings and children, may benefit from testing as well, because the condition is inherited. If your level is normal but you carry symptoms that initially raised suspicion, it is worth investigating other causes of early arthritis or pigmentation before closing the file.

If you are already on nitisinone, the goal of serial testing is to confirm that your HGA has dropped by roughly two orders of magnitude and stays suppressed. Persistent high levels should prompt a review of adherence, dose, and dietary protein intake, since protein load appears to matter more than the specific HGD variant in determining how much HGA the body produces.