Homogentisic Acid

If your urine turns dark on standing, if you have severe joint pain decades earlier than expected, or if a family member has been diagnosed with alkaptonuria, this urine test answers a single, specific question: is your body unable to break down a particular protein building block, causing a sticky pigment to accumulate in your cartilage, heart valves, and kidneys?

HGA (homogentisic acid) in urine is the defining laboratory finding of alkaptonuria, a rare inherited condition. People with the disorder excrete gram quantities of HGA per day, while healthy people excrete only trace amounts. Knowing your number can resolve years of misdiagnosis and open the door to treatments that meaningfully slow disease progression.

What This Test Actually Measures

HGA is a stepping-stone chemical your liver makes while breaking down two amino acids called tyrosine and phenylalanine, both found in protein-rich foods. In healthy people, an enzyme called HGD (homogentisate 1,2-dioxygenase) immediately converts HGA into the next chemical in the breakdown sequence. When both copies of the HGD gene are faulty, this conversion stops cold. HGA piles up in the blood, the kidneys filter it out, and large amounts end up in urine.

Over time, the HGA that does not leave through urine oxidizes inside the body into a dark pigment that deposits in cartilage, tendons, heart valves, and kidneys. This process is called ochronosis, and it is the reason untreated alkaptonuria causes black cartilage, severe early osteoarthritis, valve disease, and kidney stones.

Why Untreated Alkaptonuria Becomes a Joint and Heart Problem

Alkaptonuria has a long quiet phase followed by rapid progression. Pigment first deposits silently in connective tissue, then a more aggressive phase follows in which joints, spine, and heart valves deteriorate. This pattern argues for finding and treating the condition before clinical damage takes hold.

• Joints and spine: severe early degenerative spine disease and large-joint osteoarthritis are the dominant long-term complications, and many people with the condition end up needing hip or knee replacements decades earlier than is typical.
• Heart valves: pigment deposits cause valve calcification and stenosis, which can require surgery later in life.
• Kidneys: very high urinary HGA contributes to kidney stones, and chronic kidney disease appears to accelerate the disease course.
• Connective tissue: ligament, tendon, and muscle ruptures, fractures, and lower bone density are also reported.

Healthy People vs. People With Alkaptonuria

The contrast between normal and disease ranges is one of the most dramatic in clinical chemistry. Children with alkaptonuria have HGA-to-creatinine ratios many tens to a few hundred times higher than the upper limit seen in healthy children of the same age. Untreated adults excrete gram quantities per day. Healthy children show low, age-dependent values, with higher and more variable ratios in the first six years of life that then settle around adult-like values by about age seven.

Source: Oláh et al., Clinical Chemistry and Laboratory Medicine, 2003; Davison et al., Clinical Chemistry and Laboratory Medicine, 2015.

What this means for you: if your urinary HGA is in the trace range that healthy people show, alkaptonuria is essentially excluded. If it is markedly elevated, the diagnosis becomes straightforward and treatment decisions become possible. There is generally no ambiguous middle ground.

Why a Single Reading Is Usually Enough to Confirm or Exclude the Diagnosis

For the central diagnostic question, urinary HGA behaves unlike most lab biomarkers. The gap between healthy levels and disease levels is so large that a single, well-collected sample analyzed by a reliable method (typically gas chromatography or mass spectrometry) gives a clear answer. In alkaptonuria, values commonly far exceed those seen in healthy people, with case reports showing extraordinarily high HGA-to-creatinine ratios.

Tracking Your Trend If You Have a Confirmed Diagnosis

If you have alkaptonuria, serial trending becomes essential, not for diagnosis but for monitoring treatment. The drug nitisinone reduces daily urinary HGA by roughly 99 percent at standard dosing, and that biochemical change tracks with slower clinical progression over years. Dietary changes that reduce protein intake further lower HGA load.

A reasonable cadence: a baseline test to confirm the diagnosis or establish your starting level, repeat testing 1 to 3 months after starting therapy or changing your diet, then at least annual monitoring while on treatment. If you stop or change therapy, retest within 4 to 8 weeks to see whether your levels are responding as expected.

When Results Can Be Misleading

Several issues can distort a reading and lead to the wrong conclusion.

• HGA breaks down in collected urine: dedicated organic acid analyses typically use a morning spot urine rather than 24-hour collections to avoid both collection errors and HGA decomposition. Samples left at room temperature or exposed to light for too long can lose accuracy.
• Vitamin C (ascorbic acid) can interfere with older color-based assays: specialty labs typically ask you to stop high-dose vitamin C before sample collection. In an experimental study, vitamin C also appeared to roughly double HGA levels in infants with alkaptonuria, which is a real biological effect rather than an assay artifact.
• Age and creatinine adjustment matter: results in young children are higher and more variable when expressed per creatinine, so age-specific reference values must be used.
• HGA itself distorts routine urine tests: if your levels are very high, standard urine creatinine readings can be falsely low and total protein readings (by the common benzethonium method) can be falsely high. This is why specialists rely on urine albumin rather than total protein for kidney assessment in this condition.

What an Unexpected Result Should Make You Do Next

If your urinary HGA comes back markedly elevated, the next steps are well established and worth pursuing without delay. First, confirm with a repeat measurement using a chromatographic or mass spectrometric method if the first was a screening test. Second, ask for HGD gene sequencing to identify the specific mutations you carry, which is useful for family counseling. Third, get a baseline evaluation that includes spine and large-joint imaging, an echocardiogram to look at your heart valves, kidney function tests including urine albumin (not just total protein), and a baseline of your overall metabolic chemistry.

Fourth, consider referral to a metabolic disease specialist or a center experienced with alkaptonuria. Treatment with nitisinone is approved for adults with the condition, and discussion of dietary protein modification often accompanies it. If your result is unexpectedly elevated but lower than the classic alkaptonuria range, repeat testing and review of any vitamin C or methodological factors that could have skewed the reading is the right move before drawing conclusions.

If You Are Testing as a Family Member or Concerned Parent

Alkaptonuria is autosomal recessive, meaning you need two faulty gene copies to have the condition. Carriers (one faulty copy) typically have normal HGA levels and no disease. Testing makes the most sense for: relatives in known alkaptonuria families, especially in regions where the disorder is more common; infants or young children with unexplained pink-brown or dark-stained diapers; adults with unusually severe early-onset spine or joint degeneration with no other explanation; and anyone who finds out that black cartilage was noted during a joint replacement.