Another Case of Low Back Pain

1. Another Case of Low Back Pain Kristin Etzkorn, DO Georgia Regents University Augusta, GA

2. CC: Low back pain • 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”

3. Review of Systems • 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

4. History • PMH: • Hemochromatosis- diagnosed 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

5. Physical Exam • 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

6. Physical Exam • 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

7. Laboratory Results 13.2 140 105 23 • 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) 121 244 5.9 4.5 0.48 32 38.7

8. X-rays: C-spine

9. X-ray: C-spine

10. X-ray: C-spine

11. X-ray: Pelvis

12. X-ray: Pelvis

13. X-ray: L-spine

14. X-ray: L-spine, flexion/extension

15. X-ray: L-spine

16. What would you do next ? • HLA-B27 • Quantiferon gold and Hepatitis profile • Intact PTH • TSH • IGF-1 • Ceruloplasmin • SPEP/UPEP

17. Physical Exam

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

19. X-ray: L-spine

20. Name This Gentleman

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

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

23. Alkaptonuria • 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

24. Ochronosis • 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

25. Ochronosis: Presentation • 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

26. Ochronotic arthropathy • Manifestation of long-standing alkaptonuria • Accumulation of pigment deposition in the joints of the axial and peripheral skeleton • Symptoms manifest in 3rd-4th 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

27. Ochronosis: Pathology • 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

28. Ochronosis: Diagnosis • Imaging with characteristic findings • Measure excretion homogentisic acid in urine • Characteristic findings on physical exam

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

30. Ochronosis: Imaging of the Spine • Long standing disease: • Obliteration intervertebral spaces • Marginal intervertebral osteophytes Baeva et al. RadioGraphics 2011; 31:1163-1167

31. Ochronosis: Imaging of the Peripheral Joints • 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

32. Differential Diagnosis • 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

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

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

35. Ochronosis: Treatment • 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

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

37. Ochronosis: Treatment • 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- Schobersmeasurement of spinal flexion, 6-minute 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

38. References • 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