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Anesthesia recommendations for patients suffering from
Hereditary ochronosis, Homogentisate dioxygenase deficiency
Alkaptonuria (AKU) is a rare autosomal recessive disorder with an incidence of 1:250 000 to 1:1000 000 live births. AKU is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGO). This enzyme converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. Accumulated HGA is rapidly cleared in the kidney and excreted in the urine. HGA blood levels are kept very low through rapid kidney clearance, but over time HGA is deposited in cartilage throughout the body and converted to a pigment-like polymer. This occurs through an enzyme-mediated reaction in collagenous tissues like ligaments, tendons, cartilage, and sclera.
Find more information on the disease, its centres of reference and patient
organisations on Orph
As a result, AKU has three major features:
- Darkening of the urine upon contact with air. HGA is oxidized to form a pigment-like
polymeric material responsible for the black color of standing urine, or after exposure to an
- Ochronosis (bluish-black pigmentation of connective tissue). Accumulation of HGA and its
oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis
– brown pigmentation of the sclera which does not affect vision, blue or gray discoloration
and calcification of ear cartilage, possible discoloration on the skin of the hands,
corresponding to underlying tendons and gray and black discoloration of cartilages in the
- Arthritis. It often begins in the spine. Degenerative changes, mainly in intervertebral disks,
may be seen throughout the entirety of the vertebral column, where the lumbar spine is the
most commonly affected region. With progression of the disease it may cause changes
resembling those of ankylosing spondylitis. Patients may complain of stiffness in their lower
back with no other symptoms or signs of lumbar spine disease. The culprit of spinal
abnormalities could possibly be disk space narrowing, widespread disk calcifications and
mild osteophytosis with minimal calcification of the intervertebral ligaments. Radiographs of
the large joints may show joint space narrowing, subchondral cysts, and infrequent
osteophyte formation. Knees, hips, and shoulders are frequently affected. Fifty percent of
individuals require at least one joint replacement by age 55 years.
Pigment deposition can be also seen in heart endocardium, valves, and kidneys. Therefore,
patients may have valvular disease, nephrolithiasis, and other renal complications in the
Impaired renal function can accelerate the development of arthritis and ochronosis due to
inability to excrete HGA and worsen the progression of the disease. By around age 60, 50%
of individuals with alkaptonuria have a history of renal stones.
Hip or knee replacement, shoulder joint replacement, lumbar laminectomy, valve replacement. Any synovial joint may require arhtroplasty. Renal stone disease may require urological procedures including nephrostomy. Repair of ruptured ligaments and tendons may require a surgical approach. Any surgery required in non-Alkaptonuric patients may also be needed in AKU patients.
Type of anaesthesia
There are controversial recommendations for either general or regional anesthesia.
General anesthesia may be not appropriate in case of severe valvular regurgitations. Limitation in the range of motion of the cervical spine most likely would cause certain problems with tracheal intubation. Deep sedation can provoke respiratory insufficiency in compromised patients. For unclear reasons, hypotension during and after surgery, complicates surgery including arthroplasty.
Degenerative changes of the lumbar spine would make the regional technique unsuccessful. Calcification of interspinous ligaments makes epidural approaches to anaesthesia difficult if not impossible. Caution should be kept while performing spinal anesthesia because of the fact that the dura and arachnoid membrane can be damaged by HGA what predisposes to post-punction headaches.
Necessary additional diagnostic procedures (preoperative)
- Assessment of the mobility of the lumbar spine (ROM: Schober test) as well as cervical spine, X-ray of the lumbar spine.
- Pulmonary function tests should be done in patients with respiratory complaints which may be impaired due to ochronotic fibrosis of the costal cartilages and correspond to restrictive pulmonary diseases.
- Evaluation of the cardiovascular system is required and assessment of heart valves is crucial. Cardiovascular abnormalities such as generalized atherosclerosis, and conduction blocks may also be associated with ochronosis. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis. Therefore, electrocardiogram and echocardiogram should be done in all individuals older than age 40 years.
- Impairment of renal function can manifest with frequent urinary tract infections and nephrolithiasis. Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi is recommended if renal involvement is suspected.
Particular preparation for airway management
Limitation in the range of motion of the cervical spine most likely would cause certain problems with tracheal intubation. Because of strong evidence possibility of difficult airway should be taken into account.
Particular preparation for transfusion or administration of blood products
There is no special consideration for transfusion or administration of blood products in patients with alkaptonuria. However, these patients may be on long-term aspirin or NSAID therapy which may result in platelet dysfunctions, prolonged bleeding time, and
gastrointestinal bleeding. Parenteral fluid administration may be needed for hypotensive complications.
Particular preparation for anticoagulation
There is no evidence to support the need of particular anticoagulation.
Particular precautions for positioning, transport or mobilisation
Patients with alkaptonuria may have some joint and spine deformity due to cartilage destruction and thus difficulty may be faced during positioning and pressure points should be adequately padded to prevent any undue pressure on the diseased joints.
Probable interaction between anaesthetic agents and patient’s long term medication
Dosages of intravenous anesthetics and muscle relaxants should be modified according to the existing renal dysfunction.
Neuraxial sonography can be considered with or without a real-time ultrasound-guided approach in spinal anesthesia.
Particular or additional monitoring
Caution should be exercised in pulse oximeter monitoring of patients with excessive pigment deposition.
The deposition of HGA products in the tissues renders them resistant to the near-infrared photons, making near-infrared spectroscopy cerebral oximetry technically unfeasible. The pigmentation of the forehead, the systemic connective tissues degeneration, the pigmentation of the periosteum, or even the possibility of dura mater involvement in AKU may explain the inability of NIR spectroscopy photons to penetrate the frontal cortex.
In case of high risk surgery especially in patients with cardiac abnormalities arterial cannulation for invasive blood pressure measurement and central line placement is recommended.
There is a report of a 24-year-old alkaptonuric man with severe decreased kidney function who developed fatal metabolic acidosis and intravascular hemolysis. Hemolysis may have been caused by rapid and extensive accumulation of HGA and subsequent accumulation of plasma soluble melanins. Toxic effects of plasma soluble melanins, their intermediates, and reactive oxygen side products are increased when antioxidant mechanisms are overwhelmed. A decrease in serum antioxidative activity has been reported in patients with chronic decreased kidney function. However, despite administration of large doses of an antioxidant agent and ascorbic acid and intensive kidney support, hemolysis and acidosis could not be brought under control and hemolysis led to the death of the patient.
Increased predisposition to post-puncture headaches should be taken into account because the dura and arachnoid membrane are made vulnerable by HGA and could be damaged.
Hypotensive complications during and after surgery requiring general anaesthesia is frequently seen requiring agrressive fluid therapy.
Failure to wean from mechanical ventilation after general anesthesia or dispnea can develop due to stiffness of cartillage in the chest wall.
Information about emergency-like situations / Differential diagnostics
caused by the illness to give a tool to distinguish between a side effect of the anaesthetic procedure and a manifestation of the diseases, e.g.:
Disk herniation at the lumbar level is rare but it can cause symptoms resembling those in spinal anesthetic toxicity or other post-punctural complications.
In general disease triggered emergency-like situations are not common in alkaptonuria.
Ambulatory anesthesia can be performed according to common guidelines in patients without severe cardiac, respiratory and renal abnormalities.
Obstetrical anaesthesia can be performed according to common guidelines in patients without severe cardiac, respiratory and renal abnormalities.
Literature and internet-links
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with alkaptonuria in the UAE. Ann Hum Genet. 2009 Jan;73(1):125-30. doi: 10.1111/j.1469-1809.2008.00485.x. Epub 2008 Oct 20.
2. Ahmed S, Shah Z, Ali N. Chronic low backache and stiffness may not be due ankylosing
spondylitis. J Pak Med Assoc. 2010 Aug;60(8):681-3.
3. Al-Mahfoudh R, Clark S, Buxton N. Alkaptonuria presenting with ochronotic
spondyloarthropathy. Br J Neurosurg. 2008 Dec;22(6):805-7. doi: 10.1080/02688690802226368.
4. Argiriadou H, Anastasiadis K, Antonitsis P, et al. The inability of regional oxygen saturation
monitoring in a patient with alkaptonuria undergoing aortic valve replacement. J Cardiothoracic Vasc Anesth 2009; 23:586–588.
5. Brueck M, Bandorski D, Kramer W, et al. Aortic valve stenosis due to alkaptonuria. J Heart
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chronic backache: a review of the literature. Rheumatol Int. 2007 Nov;28(1):61-4. Epub 2007 Jun 13.
7. Carrier DA, Harris CM. Bilateral hip and bilateral knee arthroplasties in a patient with
ochronotic arthropathy. Orthop Rev. 1990 Nov;19(11):1005-9.
8. Collins E, Hand R. Alkaptonuric ochronosis: a case report. AANA J. 2005 Feb;73(1):41-6. 9. Cox TF, Ranganath L. A quantitative assessment of alkaptonuria: testing the reliability of two
disease severity scoring systems. J Inherit Metab Dis. 2011 Dec;34(6):1153-62. doi: 10.1007/s10545-011-9367-8. Epub 2011 Jul 9.
10. Drakoulakis E, Varvitsiotis D, Psarea G et al. Ochronotic arthropathy: diagnosis and
management: a critical review. Am J Orthop (Belle Mead NJ). 2012 Feb;41(2):80-3.
11. Effelsberg NM, Hügle T, Walker UA. A metabolic cause of spinal deformity. Metabolism. 2010
Jan;59(1):140-3. doi: 10.1016/j.metabol.2009.06.034. Epub 2009 Sep 17.
12. Gercek A, Koc D, Erol B, et al Co-existence of Pott's disease and alkaptonuria in a 21-month-
old child. Paediatr Anaesth, 2008 Jun;18(6):569-71. doi: 10.1111/j.1460-9592.2008.02495.x. Epub 2008 Feb 2.
13. Gonzales ME. Alkaptonuric aortic stenosis: a case report. AANA J. 1999 Apr;67(2):145-51. 14. Grasko JM, Hooper AJ, Brown JW, et al. A novel missense HGD gene mutation, K57N, in a
patient with alkaptonuria. Clin Chim Acta. 2009 May;403(1-2):254-6. doi: 10.1016/j.cca.2009.03.032. Epub 2009 Mar 21.
15. Gupta A, Jayanti A, Prasanna K. Premature arthritis in an elderly woman. Int J Clin Pract.
16. Hamdulay SS, Finegold J, Boyer L, et al. Clinical images: Magnetic resonance imaging
appearance of alkaptonuria. Arthritis Rheum. 2012 Jan;64(1):129. doi: 10.1002/art.33357.
17. Hegedus ZL. The probable involvement of soluble and deposited melanins, their intermediates
and the reactive oxygen side-products in human diseases and aging. Toxicology. 2000 Apr 14;145(2-3):85-101.
18. Heng AE, Courbebaisse M, Kemeny JL, et al. Hemolysis in a patient with alkaptonuria and
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19. Kalevski SK, Haritonov DG, Peev NA. Alcaptonuria with lumbar disc prolapse: case study and
review of the literature. Spine J. 2007 Jul-Aug;7(4):495-8. Epub 2006 Dec 29.
20. Kastsiuchenka S, Mikulka A. Anaesthesia and orphan disease: a patient with alkaptonuria. Eur
J Anaesthesiol 2013 Dec; Vol 30(12):779-80 doi: 10.1097/01.EJA.0000434959.14590.46
21. Kopeć K, Kusz D, Wojciechowski P, et al. Orthopaedic problems in patients affected by
alkaptonuria. A case report. Ortop Traumatol Rehabil. 2007 Mar-Apr;9(2):206-14.
22. Laxon S, Ranganath L, Timmis O. Living with alkaptonuria. BMJ. 2011 Sep 29;343:d5155. doi:
23. Liu W, Prayson RA. Dura mater involvement in ochronosis (alkaptonuria). Arch Pathol Lab
24. Mannoni A, Selvi E, Lorenzini S, et al. Alkaptonuria, ochronosis, and ochronotic arthropathy.
Semin Arthritis Rheum. 2004 Feb;33(4):239-48.
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abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem. 2003 Jan;40(Pt 1):108-11.
26. Parambil JG, Daniels CE, Zehr KJ, et al. Alkaptonuria diagnosed by flexible bronchoscopy.
27. Paul R, Ylinen SL. The "whisker sign" as an indicator of ochronosis in skeletal scintigraphy.
28. Raaijmaakers M, Steenbrugge F, Dierickx C. Ochronosis, arthroscopy of a black knee: a case
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29. Rallis E, Kintzoglou S. Ashy ears. ScientificWorldJournal. 2010 Aug 3;10:1530-1. doi:
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systems. J Inherit Metab Dis. 2011 Dec;34(6):1141-51. doi: 10.1007/s10545-011-9374-9. Epub 2011 Jul 12.
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review of literature. Spinal Cord. 1998 Jul;36(7):523-4.
32. Sag AA, Silbergleit R, Olson RE et al. T1 hyperintense disc in alkaptonuria. Spine (Phila Pa
33. Shimizu I, Hamada T, Khalpey Z, et al. Ochronotic arthropathy: pathological evidence of acute
destruction of the hip joint. Clin Rheumatol. 2007 Jul;26(7):1189-91. Epub 2006 Jun 20.
34. Steinmann B, Gnehm HE, Rao VH, et al. Neonatal severe primary hyperparathyroidism and
alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia. Helv Paediatr Acta. 1984 May;39(2):171-86.
35. Suwannarat P, O'Brien K, Perry MB et al. Use of nitisinone in patients with alkaptonuria.
36. Suwannarat P, Phornphutkul C, Bernardini I, et al. Minocycline-induced hyperpigmentation
masquerading as alkaptonuria in individuals with joint pain. Arthritis Rheum. 2004 Nov;50(11):3698-701.
37. Tsunashima T, Arima T, Tsuboi S, et al. A case of alcaptonuria with fatal cardiovascular
disturbance. Acta Med Okayama. 1976 Apr;30(2):87-94.
38. Yancovitz M, Anolik R, Pomeranz MK. Alkaptonuria. Dermatol Online J. 2010 Nov
39. Zaraa I, Labbène I, Trojjet S et al. Endogenous ochronosis with a fatal outcome. J Cutan Med
Last date of modification: November 2013
These guidelines have been prepared by:
Siarhei Kastsiuchenka, anaesthesiologist, University-hospital Minsk Regional Clinical
Hospital, Minsk, Belarus
Peer revision 1
Arzu Gercek Irban, Department of Anesthesiology, Medipol University School of Medicine,
Peer revision 2
Lakshminarayan Ranganath, Department of Clinical Biochemistry and Metabolic Medicine,
Royal Liverpool University Hospital, Liverpool, UK
John Davidson, Orthopaedic Surgical colleague, Royal Liverpool University Hospital,
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