Kristin Etzkorn, DO
Georgia Regents University
Augusta, GA

• HPI: 55 y/o white female
– Low back and cervical pain and stiffness
• Improved with activity and heat
• Morning pain lasting 2-3 hours
• Moderate relief w Percocet, Aleve, Nabumetone
– Knee pain bilaterally presented first
• X-ray consistent with OA
– Seen by neurosurgery with CT, MRI and myelogram which showed stenosis of the cervical spine and a “bamboo spine”

– 20 lb. unintentional weight loss x 1 year,
+ fatigue, decreased appetite
– No changes vision, no history uveitis
– Dyspnea on exertion
– No chest pain, edema
– Color changes noted on hands and ears
– Bruising tendency
– Joint pain, no swelling
– No changes in urination
– Anxiety, depression

• PMH:
– Hemochromatosisdiagnosed by blood work, not phlebotomized
– HTN
– Emphysema
– Sensory neuropathy
• FH:
– Mother: same arthritis and involvement of her joints,
RA, possible AS, bone cancer, emphysema
– Father: psoriasis, HTN, esophageal cancer
• PSH: Appendectomy
• Social: +tobacco abuse
• Meds:
– Naproxen 220mg
– Caltrate 600 mg w/ D
– Clonazepam 0.5mg
– Melatonin
– Neurontin 100mg
– Percocet 5/325
– Albuterol INH
– HCTZ/Lisinopril 12.5/20mg
– Nabumetone 750 mg

• 96.7 121/68 93 20 BMI 22
• Thin, AAOx3, NAD
• PERRLA, EOMI, normal conjunctiva
• OP clear
• Supple, NT
• CTAB, respirations non-labored
• RRR, no m/r

• MSK:
– Limited abduction of the right shoulder
– Crepitus of the knees bilaterally, pain with full extension
– Full ROM of all other joints, no swelling or deformity
– C-spine- natural position slightly flexed, cannot extend beyond neutral,
– L-spine- cannot extend beyond neutral
– Schober- 1 cm increase on forward flexion opposed to neutral back
– Levoscoliosis

140
4.5
105 23
32 0.48
121
5.9
13.2
244
38.7
• Calcium: 9.5
• TP: 6.9
• Albumin: 4.1
• AST: 24
• ALT: 12
• Alk ф: 79
• T. bili: 0.4
• ESR: 13
• Ferritin: 50
(normal 11-307)
• Transferrin: 220
(normal 200-360)

A. HLA-B27
B. Quantiferon gold and Hepatitis profile
C. Intact PTH
D. TSH
E. IGF-1
F. Ceruloplasmin
G. SPEP/UPEP

• Urine screen for organic acids
– Significantly elevated excretion of homogentisic acid
– 2563 mmol/mol cr, reference value <11

• 1902- Sir Archibald Garrod
• Rare inborn error of metabolism, autosomal recessive inheritance
– Annually 1 case per 250,000 to 1 million live births

Ranganath, LR, et al. J Clin Pathol 2013; 66: 367-373

• Large quantities of HGA excreted daily in urine
– 5-8 gm/dy
• Specimen dark iron oxide-like discoloration when exposed to sunlight or alkalized
Baeva et al. RadioGraphics 2011; 31:1163-1167

• Accumulation in tissues of homogentisic acid (HGA) and its metabolites
• Deposits in connective tissues and binds irreversibly to them and stimulates degeneration
– High affinity for fibrillary collagens
• Blue-black discoloration of connective tissues including sclera, cornea, auricular cartilage, heart valves, articular cartilage, tendons, ligaments
• Pigmentation due to oxidation and polymerization of
HGA

• Dark pigmentation pinna, sclera, nasal ala
• Darkening urine with exposure to air
• Low back pain, stiffness, height loss
• Hip and knee pain
• Cardiac valve calcification and stenosis, coronary artery calcification
• Renal and prostatic stones
Ryan, A. et al. NEJM 2012; 367:e26

• Manifestation of long-standing alkaptonuria
• Accumulation of pigment deposition in the joints of the axial and peripheral skeleton
• Symptoms manifest in 3 rd -4 th decade
• Most common presentation is low back pain
– Long-standing pain and limited ROM in the spine and large joints
– Severe degenerative arthritis and spondylosis
• More rapid progression in men than women

• H&E stain- extensive degenerative changes and brown pigmented deposits
• Mechanism not fully understood of HGA accumulation leading to ochronosis and arthropathy
Baeva et al. RadioGraphics 2011; 31:1163-1167

• Imaging with characteristic findings
• Measure excretion homogentisic acid in urine
• Characteristic findings on physical exam

• Lumbar spine affected initially
• Widespread calcification of intervertebral disks
• Narrowing intervertebral spaces
• Osteopenia
• Vacuum disk phenomenon
Baeva et al. RadioGraphics 2011; 31:1163-1167

• Long standing disease:
– Obliteration intervertebral spaces
– Marginal intervertebral osteophytes
Baeva et al. RadioGraphics 2011; 31:1163-1167

• Knee most commonly involved
– Joint involvement more pronounced lateral compartment
• Typically lack prominent osteophyte formation
• Often see intra-articular osteochondral fragments in knees, hip, shoulder
• Degenerative changes of the SI joints and pubic symphysis
Baeva et al. RadioGraphics 2011; 31:1163-1167

• Ankylosing spondylitis
– Loss of lordosis, disk calcification, end-plate changes
– Lack of erosions
• OA
– Unexpectedly advanced changes for the patient’s age
– Less predominance of osteophyte formation than of joint space loss
– Prominence of intra-articular osteochondral fragments
• Disk calcification- most characteristic finding of ochronosis
– Also seen in: Degenerative changes, trauma, CPPD, AS, hemochromatosis, hyperparathyroidism, acromegaly, amyloidosis

• No medical treatment to prevent or slow progression
• Education, PT
• Analgesics
• Dietary restriction
• Antioxidants: Vitamin C , n-acetyl cysteine
• Nitisinone
• Joint replacement

• Dietary Restriction
– Restrict tyrosine and phenylalanine
– Significant reduction in HGA levels achieved in <12 y/o
– Not demonstrated in older patients
– Difficult to maintain

• Antioxidants
– Vitamin C
• Prevent oxidation HGA to benzoquinones that form deposits in cartilage and bone
• Prevent rather than treat
• Efficient if supplemented to infants before the onset ochronosis
• Dose 1gram/day recommended for older children and adults
– n-acetyl cysteine
• In vitro shown to reduce HGA polymerization and accumulation
• Combination with vitamin C may be effective in preventing or delaying ochronotic arthropathy
Ranganath, LR, et al. J Clin Pathol 2013; 66: 367-373

• Nitisinone (Orfadinᴿ)
– Inhibitor 4hydroxyphenylpyruvate oxidase
– Drug approval in
2002 for hereditary tyrosinemia
Ranganath, LR, et al. J Clin Pathol 2013; 66: 367-373

• Nitisinone
– 95% reduction in urinary and serum HGA
– Long-term randomized trial in 40 patients completed in
2009
• Primary outcome- total hip ROM
– Treatment group with gain 2◦ per year over the 3 years vs placebo group average decline of 0.37◦/year
– Not statistically significant
• Secondary outcome- Schobers measurement of spinal flexion, 6minute walk times, timed get up and go
– No significant differences between the 2 groups
• No patients in treatment group progressed to aortic stenosis or sclerosis
• Well tolerated
– No evidence prevents or reverses ochronosis
– Longer clinical trial indicated to demonstrate clinical efficacy

• Baeva et al. RadioGraphics 2011; 31: 1163-1167
• Capkin E., et al. Rheumatol Int 2007; 28: 61-64
• Introne, et al. Mol Gen Metab 2011; 103(4): 307-314
• Ranganath, LR, et al. J Clin Pathol 2013; 66: 367-373
• Ryan, A., et al. NEJM 2012; 367: e26
• Tinti, et al. J. Cell. Physiolo. 225:84-91, 2010
• Zhao et al. Knee Surg Sports Traumatol Arthrosc
2009; 17: 778-781