Homogentisic Acid Oxidase (HGD) Deficiency

Homogentisic acid oxidase deficiency is a rare, inherited metabolic disorder. It happens when the body cannot make enough of an enzyme called homogentisate 1,2-dioxygenase (HGD). This enzyme sits in the middle of the tyrosine and phenylalanine breakdown pathway. When the enzyme is low or absent, a chemical called homogentisic acid (HGA) builds up in the blood and is passed into the urine.
Outside the body (or in alkaline conditions), HGA slowly oxidizes and turns the urine dark brown or almost black. Over many years, extra HGA also sticks to collagen-rich tissues (cartilage, tendons, discs, skin). It polymerizes into a melanin-like pigment. This process is called ochronosis. Ochronosis makes tissues stiff, brittle, and dark blue-black. Because of this, adults may develop early, severe “wear-and-tear” arthritis, spine stiffness, tendon problems, and sometimes kidney or prostate stones and calcification of heart valves.

Homogentisic acid oxidase deficiency—also called alkaptonuria (AKU)—is a rare, inherited metabolic disease. Your body normally breaks down two amino acids, phenylalanine and tyrosine. In AKU, a liver enzyme called homogentisate 1,2-dioxygenase (HGD) does not work properly. Because this enzyme is weak or missing, a chemical called homogentisic acid (HGA) builds up in the blood and tissues. Extra HGA slowly turns into a dark pigment that deposits in cartilage, tendons, skin, eyes, heart valves, and spine. This process is called ochronosis. Over many years, ochronosis stiffens and damages joints and tissues, causing back pain, early arthritis of the hips and knees, tendon problems, dark ear cartilage, blue-black sclera (eye whites), and sometimes valve disease in the heart or kidney stones. Many people notice that urine becomes dark (brown/black) after standing. AKU is lifelong, but careful care can reduce pain, protect joints, and slow damage. A medicine called nitisinone can strongly lower HGA levels, but it raises blood tyrosine, so diet and eye monitoring are important while using it. NCBI+1

Key points

• The enzyme HGD is missing or weak.

• HGA piles up, darkens urine, and slowly stains and damages connective tissues.

• Children often only show dark urine; most joint and heart problems appear in adulthood.

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Other names

• Alkaptonuria (AKU) – the classic name of the disease.

• Homogentisate 1,2-dioxygenase (HGD) deficiency – the exact enzyme name.

• Ochronosis due to alkaptonuria or endogenous ochronosis – describes the pigment deposition caused by AKU (different from exogenous ochronosis due to topical chemicals).

• Inborn error of tyrosine metabolism – places the disease in the metabolic map.

• Black urine disease – old descriptive term referring to the darkening of urine on standing.

Proteins → phenylalanine → tyrosine → HGA → (needs HGD enzyme) → maleylacetoacetic acid → … → energy products.
When HGD is deficient, the pathway stalls at HGA. Excess HGA:

1. Leaves via kidneys → urine turns dark after air/alkali exposure.

2. Deposits in collagen → ochronosis → joint, spine, tendon, ear cartilage, sclera become pigmented and fragile.

3. Contributes to stone formation and valve calcification in some people.

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Types

There is one root cause (HGD gene changes), but doctors see different clinical patterns:

1. Infant/childhood presentation: Mainly dark urine; otherwise healthy.

2. Classic adult ochronosis: Blue-black ear cartilage/sclera, skin patches, progressive large-joint and spine degeneration.

3. Spine-dominant form: Early lumbar stiffness, disc calcification, and back pain before large-joint disease.

4. Large-joint-dominant form: Hips, knees, shoulders wear out early; may need joint surgery earlier than usual.

5. Cardio-renal predominant pattern: Kidney/prostate stones, aortic/mitral valve calcification/stenosis in mid-to-late adulthood.

6. Genotype-informed patterns:

   • Null/near-null variants: little to no enzyme, often earlier, more severe disease.

   • Residual-activity variants: some enzyme activity, often milder or later disease.

7. Severity bands over time: mild (urine changes only) → moderate (ochronosis signs) → severe (advanced joint and valve disease).

These “types” are descriptive, not separate diseases.

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Causes

The true cause is genetic. Many items below are modifiers—they do not create the disease by themselves but can change how early or how strongly it appears.

1. Biallelic HGD gene variants (autosomal recessive): You inherit one faulty copy from each parent. This is the core cause.

2. Consanguinity: Parents who are related share genes more often, raising the chance a child inherits two HGD variants.

3. Founder effect communities: Some regions and families carry specific HGD variants more frequently, increasing local risk.

4. Compound heterozygosity: Two different harmful HGD variants (one from each parent) can combine and still cause disease.

5. Nonsense/frameshift variants: “Stop” or shifted codes in HGD often remove enzyme production completely, leading to severe deficiency.

6. Missense variants: A single amino acid change in HGD can reduce enzyme function to varying degrees.

7. Splice-site variants: Changes at intron–exon boundaries can mis-assemble HGD mRNA, lowering enzyme levels.

8. Copy-number variants (deletions/duplications): Larger missing/extra pieces in the HGD gene can disrupt the enzyme.

9. Parental mosaicism (rare): A parent may carry the variant in some cells, affecting recurrence risk in families.

10. High lifetime intake of tyrosine/phenylalanine (dietary load): Does not cause AKU, but can raise HGA burden and symptoms.

11. Kidney function decline: Less renal clearance may allow more HGA to remain in the body, increasing deposition.

12. Chronic joint mechanical stress: Heavy physical load can speed cartilage wear once pigment has weakened tissue.

13. Aging: Pigment builds slowly; more years = more tissue load = more symptoms.

14. Male sex (observational): Men often show earlier/more severe joint disease, possibly due to biomechanics/hormones.

15. Estrogen changes (e.g., post-menopause): May alter connective tissue and pain perception, shifting symptom timing.

16. Chronic dehydration: Concentrated urine can favor stone formation in people with AKU.

17. Metabolic milieu (oxidative stress): Higher oxidative stress may speed HGA oxidation and pigment formation.

18. Vitamin C (ascorbate) deficiency: Vitamin C is an antioxidant; low levels might favor HGA oxidation (evidence mixed).

19. Coexisting osteoarthritis tendencies: If you also have risk for osteoarthritis, joint damage may advance faster.

20. Delayed diagnosis/no lifestyle adaptation: Without awareness (hydration, joint care), complications can accumulate earlier.

Remember: Only the HGD gene problem actually causes AKU. The other factors mainly change severity or timing.

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Symptoms and signs

1. Dark urine after standing: Fresh urine may look normal but turns brown-black after minutes to hours, faster in alkaline conditions.

2. Blue-black ear cartilage (ochronosis): The rim of the ear becomes darker and stiffer over years.

3. Brown-gray scleral spots: At the junction of cornea and sclera (often at 3 and 9 o’clock), small slate-gray patches appear.

4. Skin discoloration: Sun-exposed or sweat-prone areas (cheeks, axillae, groin) can look blue-brown.

5. Early, severe large-joint pain: Hips, knees, and shoulders develop painful “wear-and-tear” arthritis earlier than usual.

6. Low back pain and stiffness: Intervertebral discs calcify; bending forward becomes difficult.

7. Reduced range of motion: Joints feel tight and creak; daily tasks (squatting, reaching, climbing stairs) get harder.

8. Tendon problems: Achilles and patellar tendons may thicken or become painful; there is a risk of rupture with minor trauma.

9. Spine curvature or rigidity: Calcified discs can cause a stiff, stooped posture or decreased flexibility.

10. Crepitus: Grating or crackling sensation during joint motion due to damaged cartilage surfaces.

11. Kidney stones: HGA handling and chronic changes make stones more likely; may cause flank pain or blood in urine.

12. Prostate stones or enlargement (men): Can cause urinary symptoms.

13. Heart valve disease: Aortic or mitral valves may calcify, leading to breathlessness, chest discomfort, or fainting in later life.

14. Pigmented sweat stains: Clothing may show brownish discoloration where sweat dries.

15. Fatigue from chronic pain: Long-term joint and back pain can reduce sleep quality and activity levels.

Symptoms usually start with dark urine in infancy, then joint/spine issues in the 3rd–5th decade, and valve or stone problems later.

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Diagnostic tests

A) Physical examination

1. General inspection for ochronosis: The doctor looks for blue-black ear rims, brown-gray scleral patches, and skin darkening in typical areas. These are classic clues to long-standing HGA deposition.

2. Large-joint examination: The clinician checks pain points, swelling, warmth (usually minimal), range of motion, and crepitus in hips, knees, and shoulders. Findings point toward degenerative changes earlier than expected for age.

3. Spine examination: Posture, forward flexion, extension, and lateral bending are assessed. Limited lumbar flexion and tenderness suggest disc calcification and degeneration.

4. Cardiac auscultation: Listening for murmurs that may indicate aortic or mitral valve calcification/stenosis in older adults with AKU.

B) Manual/bedside tests

5. Urine darkening observation test: Fresh urine is collected and left exposed to air or gently alkalinized. Progressive brown-black color supports HGA oxidation. This is a screening clue, not a definitive test.

6. Schober test (lumbar flexibility): A simple tape-measure test quantifies how much the lower back flexes when bending forward. Reduced excursion fits spine involvement.

7. FABER (Patrick) test for hip: Flexion–abduction–external rotation maneuver can reproduce hip pain and stiffness consistent with early hip degeneration.

C) Laboratory & pathological tests

8. Quantitative urinary HGA (GC-MS or LC-MS/MS): The gold-standard biochemical test. HGA levels are markedly elevated in AKU.

9. Plasma HGA concentration: Confirms systemic excess and can help follow disease activity or response to interventions in specialized centers.

10. HGD gene testing (sequencing + deletion/duplication analysis): Confirms the molecular diagnosis, clarifies inheritance for the family, and may help with prognosis.

11. 24-hour urinary HGA excretion: Measures the total daily HGA load; useful for baseline and follow-up in experienced clinics.

12. Urinalysis with pH manipulation ± ferric chloride/NaOH spot tests (historic): May produce a rapid color change. These are supportive only and less specific than modern mass spectrometry.

13. Histology of affected tissue (if obtained during surgery): Cartilage or skin shows ochronotic pigment (brown/black granules) that may bleach with certain reagents; confirms pigment deposition.

14. Amino acid and organic acid profiles (to exclude other disorders): Rules out different tyrosine/phenylalanine pathway problems in unclear cases.

D) Electrodiagnostic tests

15. Electrocardiogram (ECG): Looks for rhythm or strain patterns that might accompany significant valve disease in older AKU patients.

16. Pure-tone audiometry: If a patient reports reduced hearing, testing can document conductive or sensorineural loss possibly related to long-standing tissue changes around the ear structures.

E) Imaging tests

17. Spine X-rays: Often show calcified intervertebral discs, loss of disc height, vacuum phenomena, and osteophytes. Useful for staging back involvement.

18. Large-joint X-rays (hips, knees, shoulders): Reveal joint-space narrowing, osteophytes, subchondral sclerosis/cysts—early for age compared with typical osteoarthritis.

19. Echocardiography: Ultrasound of the heart evaluates aortic/mitral valve calcification and stenosis and measures pressure gradients if disease is suspected clinically.

20. Renal/prostate imaging (ultrasound or non-contrast CT): Detects kidney and prostate stones and helps plan management if symptoms suggest stones or obstruction.

Non-pharmacological treatments (therapies and other measures)

1. Education & self-management
   Purpose: Understand the disease, triggers, and safe activity.
   Mechanism: Knowledge leads to safer choices (joint protection, diet with nitisinone, follow-up). Programs at AKU specialty centers can guide day-to-day decisions. PMC

2. Regular physiotherapy
   Purpose: Keep joints mobile and muscles strong; reduce pain.
   Mechanism: Range-of-motion, core and hip strengthening, posture training reduce stress on ochronotic cartilage and spine. PMC

3. Low-impact exercise
   Purpose: Maintain fitness without pounding joints.
   Mechanism: Swimming, cycling, elliptical and walking improve function with less compressive load on degenerating cartilage and discs. PMC

4. Weight management
   Purpose: Reduce load on weight-bearing joints.
   Mechanism: Even modest weight loss decreases knee/hip forces and pain; supports longevity of future joint replacements if needed. PMC

5. Activity modification & joint protection
   Purpose: Avoid micro-trauma.
   Mechanism: Limit heavy lifting, repetitive jumping, and hard-surface running; use pacing and ergonomic tools. PMC

6. Heat & cold therapy
   Purpose: Ease stiffness and flares.
   Mechanism: Heat relaxes muscles; ice reduces acute inflammation after activity.

7. Assistive devices
   Purpose: Reduce pain and improve stability.
   Mechanism: Braces, shoe inserts, canes or trekking poles off-load painful joints and improve gait safety. PMC

8. Occupational therapy
   Purpose: Protect joints during daily tasks.
   Mechanism: Adaptive techniques and tools (raised seats, reachers, jar openers) reduce strain.

9. Spine care
   Purpose: Manage early spondylosis and stiffness.
   Mechanism: Core stabilization, gentle extension/flexion, and posture re-education to reduce facet/disc stress in ochronotic spine. PMC

10. Fall-prevention training
    Purpose: Lower fracture risk in brittle ochronotic bone.
    Mechanism: Balance work (e.g., Tai Chi), home hazard reduction, vision checks. ajp.amjpathol.org

11. Bone health plan (non-drug)
    Purpose: Support bone strength.
    Mechanism: Weight-bearing exercise within comfort, adequate calcium and vitamin D from food, sunlight exposure as appropriate. (Drug options listed later.) Wiley Online Library

12. Pain coping skills & CBT
    Purpose: Improve quality of life.
    Mechanism: Cognitive-behavioral tools reduce pain amplification and stress.

13. Hydration strategy
    Purpose: Lower risk of kidney/prostate stones linked to pigment and metabolic changes.
    Mechanism: Higher urine volume reduces crystal concentration.

14. Skin and eye care
    Purpose: Monitor pigmentation and corneal health.
    Mechanism: Regular ophthalmology—especially if on nitisinone—to detect tyrosine-related keratopathy early. PMC

15. Cardiovascular monitoring
    Purpose: Detect aortic/mitral valve involvement.
    Mechanism: Periodic echocardiography if symptomatic or advised by specialist. PMC

16. Dietary counseling if using nitisinone
    Purpose: Control tyrosinaemia and protect the cornea.
    Mechanism: Restrict dietary phenylalanine/tyrosine to safe levels (often ~0.5–1.0 g protein/kg/day with a minimum ~0.75 g/kg/day target under specialist guidance) and use medical foods if needed. Wiley Online Library+2PMC+2

17. Smoking cessation
    Purpose: Improve bone, tendon, and heart health.
    Mechanism: Better tissue oxygenation and healing.

18. Workplace/ergonomic adjustments
    Purpose: Reduce repetitive strain.
    Mechanism: Sit-stand desks, lumbar support, job task rotation.

19. Pre-habilitation before surgery
    Purpose: Better surgical outcomes.
    Mechanism: Strengthening and nutrition support before joint/valve surgery improve recovery. PMC

20. Genetic counseling
    Purpose: Family planning and screening.
    Mechanism: Explain autosomal recessive inheritance and options. NCBI

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Drug treatments

Important: Medication plans must be individualized by a specialist. Many drugs below are used symptomatically (for pain, bone health, or complications). Nitisinone is the only HGA-lowering therapy with strong evidence; it is off-label for AKU in many countries and requires dietary/eye monitoring.

1. Nitisinone (NTBC)
   Class: 4-hydroxyphenylpyruvate dioxygenase inhibitor.
   Purpose: Strongly reduces HGA production and pigment formation.
   Mechanism: Blocks the step upstream of HGA, lowering HGA excretion by >95% in trials.
   Dose/time: In AKU trials (SONIA-2), 10 mg once daily significantly reduced HGA; lower doses (e.g., 2 mg) may also reduce HGA but with variable tyrosine rise; dosing is center-specific. Requires long-term use with monitoring.
   Key risks: Hypertyrosinaemia causing corneal keratopathy; needs phenylalanine/tyrosine-restricted diet, regular tyrosine levels, and ophthalmology checks. Other AEs: photosensitivity, liver enzyme changes (rare). Nature+3The Lancet+3PubMed+3

2. Paracetamol (acetaminophen)
   Class: Analgesic/antipyretic.
   Purpose: First-line for chronic joint pain.
   Mechanism: Central COX inhibition (weak peripheral).
   Dose: Typical 0.5–1 g every 6–8 h (max 3–4 g/day; adjust for liver disease).
   Side effects: Hepatotoxicity if overdose or with alcohol.

3. Topical NSAIDs (diclofenac gel/patch)
   Class: NSAID topical.
   Purpose: Local joint/tendon pain with fewer systemic risks.
   Mechanism: Local COX-2/COX-1 inhibition.
   Side effects: Local irritation; minimal systemic effects.

4. Oral NSAIDs (e.g., ibuprofen, naproxen)
   Purpose: Pain and stiffness relief.
   Mechanism: COX inhibition reduces inflammation in ochronotic arthropathy.
   Dose: Use the lowest effective dose, shortest duration.
   Side effects: GI bleed/ulcer, renal effects, ↑BP; consider PPI protection if risk.

5. COX-2 selective NSAID (celecoxib)
   Purpose: Pain control in patients at higher GI risk.
   Mechanism: Preferential COX-2 inhibition.
   Side effects: CV risk, renal effects; avoid with sulfonamide allergy.

6. Intra-articular corticosteroids
   Purpose: Flares of knee/hip/shoulder pain.
   Mechanism: Potent local anti-inflammatory effect.
   Timing: Episodic; not too frequent to protect cartilage.
   Side effects: Transient hyperglycemia, rare infection.

7. Short oral corticosteroid taper (selected cases)
   Purpose: Severe inflammatory flares not controlled otherwise.
   Mechanism: Systemic anti-inflammatory.
   Side effects: Hyperglycemia, mood change, osteoporosis with repeated use; keep brief and sparing.

8. Duloxetine
   Class: SNRI.
   Purpose: Chronic musculoskeletal pain component.
   Mechanism: Central pain modulation.
   Side effects: Nausea, somnolence, BP changes.

9. Tramadol (short term)
   Class: Weak opioid/SNRI.
   Purpose: Rescue for acute severe pain.
   Mechanism: μ-receptor and monoamine reuptake effects.
   Risks: Dependence, dizziness, serotonin syndrome with SSRIs; use sparingly.

10. Bisphosphonates (e.g., alendronate)
    Purpose: Treat osteoporosis if present.
    Mechanism: Inhibit osteoclasts to reduce fractures.
    Side effects: GI irritation, rare ONJ/atypical femur fractures; upright posture after dose. Wiley Online Library

11. Teriparatide
    Class: Recombinant PTH (anabolic).
    Purpose: Severe osteoporosis or fractures not responding to bisphosphonates.
    Mechanism: Stimulates bone formation; case evidence supports benefit in AKU fractures.
    Side effects: Hypercalcemia, cramps; daily injections; treatment duration limited. PMC

12. Proton-pump inhibitor (omeprazole) with NSAIDs if needed
    Purpose: GI protection.
    Mechanism: Lowers gastric acid to prevent ulcers.
    Risks: Hypomagnesemia, C. difficile risk with long use; reassess regularly.

13. Topical capsaicin
    Purpose: Focal joint pain.
    Mechanism: Substance P depletion.
    Side effects: Burning sensation initially.

14. Hyaluronic acid intra-articular injections (selected knees)
    Purpose: Symptomatic relief in some; evidence mixed.
    Mechanism: Viscosupplementation to improve lubrication.
    Side effects: Local flare; variable benefit. ajp.amjpathol.org

15. Calcitonin (limited role)
    Purpose: Adjunct pain control in vertebral compression fractures.
    Mechanism: Anti-resorptive and analgesic effects.
    Side effects: Nausea, flushing; modest efficacy.

16. Vitamin D (as a drug when deficient)
    Purpose: Correct deficiency to support bone health.
    Mechanism: Improves calcium absorption and muscle function.
    Dose: As per labs and guidelines. Wiley Online Library

17. Calcium (as a drug when intake inadequate)
    Purpose: Bone support if dietary intake is low.
    Mechanism: Mineral supply; avoid excess (stone risk).
    Note: Prefer food sources; tailor to stone risk and labs.

18. Topical lidocaine
    Purpose: Focal neuropathic/mixed pain patches.
    Mechanism: Sodium channel blockade.
    Side effects: Local rash; minimal systemic effects.

19. Muscle relaxant (short course, e.g., cyclobenzaprine)
    Purpose: Painful muscle spasm around arthritic joints/spine.
    Mechanism: Central muscle relaxation.
    Risks: Sedation; short-term only.

20. Antihypertensives/lipid therapy (comorbidity care)
    Purpose: Reduce cardiovascular risk that may complicate surgery/rehab and valve disease.
    Mechanism: Standard CV risk reduction supports overall outcomes in AKU with cardiac involvement. PMC

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Dietary molecular supplements

Always discuss supplements with your specialist—some can interact with medicines or increase stone risk.

1. Vitamin C (ascorbic acid)
   Dose: Often 500–1000 mg/day used historically.
   Function/mechanism: Antioxidant; proposed to slow HGA oxidation to pigment.
   Evidence note: Trials show no reduction in urinary HGA; may delay urine darkening only. Use with realistic expectations. Nature+1

2. Vitamin D
   Dose: Per deficiency status (commonly 800–2000 IU/day or individualized).
   Function: Bone and muscle health.
   Mechanism: Calcium absorption; fall/fracture risk reduction when deficient. Wiley Online Library

3. Calcium (diet-first; supplement if needed)
   Dose: Adjust to reach ~1000–1200 mg/day total intake.
   Function: Bone mineralization.
   Mechanism: Supplies calcium; avoid excess if stone-prone.

4. Omega-3 fatty acids (fish oil)
   Dose: Commonly 1–2 g/day EPA+DHA.
   Function: Modest anti-inflammatory effect; joint comfort.
   Mechanism: Eicosanoid shift.

5. Collagen peptides/gelatin
   Dose: 5–15 g/day.
   Function: Possible support for cartilage matrix turnover.
   Mechanism: Provides amino acids (glycine, proline); clinical effect variable.

6. Turmeric/curcumin
   Dose: Standardized extract per product (often 500–1000 mg curcuminoids/day).
   Function: Anti-inflammatory adjunct.
   Mechanism: NF-κB modulation; check interactions (anticoagulants).

7. Magnesium
   Dose: 200–400 mg/day (form/tolerance dependent).
   Function: Muscle relaxation; bone co-factor.
   Mechanism: Neuromuscular modulation; avoid excess in renal disease.

8. Protein medical foods (if on nitisinone diet)
   Dose: As prescribed to meet protein needs while limiting phe/tyr.
   Function: Adequate protein without excess phe/tyr.
   Mechanism: Specialty amino-acid formulas support growth/repair. Wiley Online Library

9. Riboflavin & B12
   Dose: Per RDAs or deficiency.
   Function: Prevent deficiency when protein is restricted with nitisinone.
   Mechanism: Cofactors for energy and hematologic health. BioMed Central

10. Potassium citrate (only if prescribed)
    Dose: Individualized.
    Function: Stone prevention in selected patients.
    Mechanism: Urine alkalinization and citrate provision; medical supervision required (electrolytes/renal function).

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Immunity booster / regenerative / stem-cell” drugs

Honest status: AKU is not an immune-deficiency, and there are no approved “immunity booster” or stem-cell drugs for AKU. Items below are research or conceptual directions—not standard care.

1. AAV-based HGD gene replacement (pre-clinical concept)
   Mechanism: Deliver a working HGD gene to liver to restore enzyme activity and reduce HGA. Status: Experimental; not available clinically.

2. CRISPR/base-editing of HGD (research stage)
   Mechanism: Correct HGD mutations in hepatocytes. Status: Pre-clinical risk/benefit unknown.

3. mRNA therapy for HGD (theoretical)
   Mechanism: Provide transient HGD mRNA to make enzyme in the liver. Status: Concept only.

4. Pharmacologic chaperones for HGD (discovery)
   Mechanism: Small molecules to stabilize mutant HGD protein and improve residual activity. Status: Early research.

5. Autologous iPSC-derived cartilage grafts (experimental orthopedics)
   Mechanism: Replace focal cartilage damage; unknown benefit in ochronotic cartilage. Status: Experimental.

6. Mesenchymal stromal cell injections (experimental)
   Mechanism: Paracrine anti-inflammatory effect in joints; no proven disease-modification in AKU. Status: Investigational; discuss risks/costs.

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Surgeries

1. Total knee arthroplasty (knee replacement)
   Why: End-stage ochronotic knee arthritis with pain/disability.
   Notes: Outcomes can be good; pigment does not prevent success. PMC

2. Total hip arthroplasty (hip replacement)
   Why: Severe hip joint destruction and pain.
   Notes: Standard technique; pre-hab improves recovery.

3. Spine surgery (decompression ± fusion)
   Why: Nerve compression, severe spinal stenosis or instability from ochronotic spondylosis.
   Notes: Reserved for neurologic deficit or intractable pain after conservative care. PMC

4. Aortic valve replacement/repair
   Why: Ochronotic aortic stenosis or regurgitation causing symptoms or LV dysfunction.
   Notes: Managed as per standard cardiology practice. PMC

5. Urolithiasis procedures (e.g., ureteroscopy)
   Why: Symptomatic kidney/prostate stones.
   Notes: Plus hydration and metabolic evaluation going forward. PMC

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Preventions

1. Early diagnosis and specialist follow-up to plan joint, eye, heart, and bone monitoring. PMC

2. If on nitisinone: follow the phe/tyr-restricted diet and scheduled tyrosine blood tests. Wiley Online Library+1

3. Regular ophthalmology to catch tyrosine-related keratopathy early. PMC

4. Low-impact activity and physiotherapy to protect joints. PMC

5. Maintain healthy weight to reduce joint load. PMC

6. Bone health plan (vitamin D repletion, weight-bearing as tolerated). Wiley Online Library

7. Hydration to reduce stone risk. PMC

8. Cardiac surveillance if symptoms (murmur, breathlessness) appear. PMC

9. Avoid smoking to support bone/tendon/heart health.

10. Genetic counseling for family planning. NCBI

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When to see a doctor (red flags)

• New or worsening joint swelling, locking, or severe pain limiting daily life.

• Back/leg pain with weakness, numbness, or bladder/bowel changes (possible nerve compression). PMC

• Eye pain, light sensitivity, or blurred vision—especially if taking nitisinone (possible tyrosine keratopathy). PMC

• Chest pain, breathlessness, fainting, or new heart murmur (possible valve disease). PMC

• Kidney stone symptoms: severe flank pain, bloody urine, fever. PMC

• Unexplained fractures or height loss (possible osteoporosis/vertebral fracture). Wiley Online Library

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What to eat and what to avoid

• If you are NOT on nitisinone: there is no strong proof that strict protein restriction alone changes long-term outcomes, but moderate protein intake and balanced diet are reasonable. Stay hydrated. Medscape

• If you ARE on nitisinone: follow a diet low in phenylalanine and tyrosine with specialist support. Aim for adequate but not excessive protein (often ≥0.75 g/kg/day total protein using medical foods if needed). This helps prevent high tyrosine and protects the cornea. Wiley Online Library+2PMC+2

Good choices: fruits, vegetables, whole grains, healthy fats, and measured portions of protein per your plan; water for hydration.
Be careful with: large portions of high-tyrosine/phenylalanine protein (meat, fish, dairy, soy, nuts) if on nitisinone—portion size and medical foods are adjusted by your metabolic team. Avoid crash diets or unsupervised restriction. Wiley Online Library

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FAQs

1. Is AKU the same as HGD deficiency?
   Yes. AKU is caused by defects in the HGD enzyme, leading to HGA buildup. NCBI

2. Why does my urine turn dark?
   HGA oxidizes and polymerizes on standing, making urine appear brown-black. NCBI

3. What is ochronosis?
   It’s bluish-black pigment deposited in connective tissues from long-term HGA accumulation. NCBI

4. What problems happen over time?
   Spine stiffness, early hip/knee arthritis, tendon issues, valve disease, and sometimes stones. PMC

5. Does nitisinone cure AKU?
   No, but it dramatically lowers HGA and is the best studied disease-modifying option today; monitoring and diet are essential. The Lancet+1

6. What dose of nitisinone is used?
   Trials used 10 mg once daily; some centers individualize (e.g., lower doses). Your team will tailor and monitor tyrosine levels and eyes. The Lancet+1

7. Why do I need a special diet on nitisinone?
   Nitisinone raises blood tyrosine, which can injure the cornea; restricting phe/tyr helps keep tyrosine safe. Wiley Online Library+1

8. Is vitamin C helpful?
   It does not lower HGA; it may slightly delay urine darkening. Consider only as an adjunct with realistic expectations. Nature

9. Will exercise make my joints worse?
   Low-impact exercise helps. Avoid high-impact pounding; a physiotherapist can guide you. PMC

10. Can AKU affect my heart?
    Yes, ochronosis may involve aortic/mitral valves; echo is done if symptoms or as advised. PMC

11. What eye checks do I need on nitisinone?
    Regular ophthalmology exams to detect tyrosine keratopathy; report irritation or photophobia early. PMC

12. Are there stem-cell treatments that work now?
    No approved stem-cell or gene therapies for AKU at present; these remain experimental. (Your doctor can update you on trials.)

13. Will I need joint replacement?
    Some people do when arthritis is advanced; knee/hip replacements can work well in AKU. PMC

14. Can I take NSAIDs safely?
    They can help pain, but GI/renal/cardiac risks exist; use lowest effective dose, consider PPI if at risk, and review with your clinician.

15. Where can I find expert care?
    Metabolic/genetic clinics and AKU centers provide coordinated care including nitisinone, dietetics, eye, bone, heart, and surgery planning. PMC

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: September 12, 2025.

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