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Case Report *Corresponding author

Pedro T. Mota, Av. Dr. Francisco Sá Carneiro, 5400-249

Alkaptonuria, a Rare Cause of Chaves, Portugal, Tel: 351- 276-300-900 / Ext. 5909;

Osteoarthritis – Case Report

Submitted: 09 January 2015
Accepted: 26 October 2015
Published: 29 October 2015
Pedro T. Mota1,2*, Rui Cândido1 and Carlos Pintado1 Copyright
1
Department of Orthopedics, Hospital of Tras-os -Montes and Alto Douro, Portugal © 2015 Mota et al.
2
School of Health Sciences, University of Minho, Portugal
OPEN ACCESS

Abstract Keywords
• Alkaptonuria
Alkaptonuria is a rare metabolic autosomal recessive disease, caused by the
• Ochronosis
lack of the homogentisic acid (HGA) oxidase, resulting in the accumulation of HGA in
• Ochronotic arthropathy
connective tissues, conferring them a dark-bluish discoloration known as ochronosis. It
• Knee arthroplasty
is a progressive condition, causing degenerative alterations of weight-bearing joints.
We report the case of a 67 year old woman, with pain in the left knee and clinical
and radiological evidence of knee osteoarthritis, who underwent cemented total knee
arthroplasty. During surgery, black discoloration of cartilage was observed. Histologic
evaluation suggested alkaptonuria, confirmed upon detection of high levels of HGA
in urine.
Alkaptonuria is usually asymptomatic until the development of ochronotic
arthropathy and its discovery is often a finding during a joint replacement. There
is no specific therapy for alkaptonuria and its treatment is symptomatic and based
on osteoarthritis management. When conservative treatment can no longer mitigate
symptomatology and joint replacement should be done.

ABBREVIATIONS Ochronotic arthropathy usually affects weight-bearing joints, like

HGA: Homogentisic Acid; NSAID: Non-Steroidal Anti-
inflammatory Drugs
INTRODUCTION
Bone and joint surfaces hyper pigmentation is rare and can
occur due to several causes: metabolic bone diseases, metal
deposits, sequestrum, metastatic disease, minocycline use and
ochronotic arthropathy [1].
Alkaptonuria is a rare metabolic disease, with a prevalence
of 1 case per 250,000 to 1 million live births, in the United States
[2]. This was the first human disorder found to conform to the
principles of mendelian autosomal recessive inheritance [3]. The
disease is caused by an inborn error of tyrosine metabolism – the
lack of the homogentisic acid (HGA) oxidase enzyme, which is
normally highly expressed in hepatocytes [4] - resulting in the
accumulation of HGA in connective tissues, mainly in cartilage
but also in tendons, ligaments, sclera, heart valves, the intima of
blood vessels and skin [5]. The accumulation of HGA confers a
dark-bluish discoloration to tissues and is known as ochonosis.
Alkaptonuria is a progressive condition and the patients
are distinguished by a classic triad: dark urine since birth,
ochronosis becoming evident around the fourth decade of life
and osteoarthritis secondary to ochronotic arthropathy around
the sixth. Most of the patients are only diagnosed when they
develop arthropathy, i.e., late on the natural history of the disease.
hips, knees and lumbar spine. The spine involvement resembles
ankylosing spondylitis but differs in sparing the sacroiliac joints
[3] and the most characteristic findings are narrowing and
calcification of the intervertebral disks. The peripheral arthritis
closely resembles that of primary osteoarthritis, however,
hands and feet are usually spared [6]. Another characteristic of
ochronotic arthropathy is the sparse ostheophytic reaction seen,
when compared with primary osteoarthritis.
Other disease manifestations include renal and prostate
stones, aortic valve calcification and stenosis, and coronary
artery calcification [7].
CASE PRESENTATION
We report the case of a 67 year old woman who was referred
to orthopedic consultation for evaluation of a longstanding left
knee pain. The pain was characterized as mechanical, which
increased with motion and was more intense at the end of the day.
Other complaints involved knee edema after moderate distance
walks. Pain during bedtime impairing ability to sleep was denied.
Withal, the patient reported pain on the contra lateral knee, both
hips and lower back. Non-steroidal anti-inflammatory drugs
were prescribed by her primary care physician, which no longer
provided relief of symptomatology.
On physical examination, the patient walked with stable gait,
felt tenderness on palpation over the joint line of the left knee and
had a diminished range of motion associated with crepitation.

Cite this article: Mota PT, Cândido R, Pintado C (2015) Alkaptonuria, a Rare Cause of Osteoarthritis – Case Report. JSM Clin Case Rep 3(3): 1083.
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Instability of the knee was not detected. The contra lateral

knee and both hips also showed signs of osteoarthritis, although
to a lesser degree.
The patient was submitted to bilateral knee and hip and
lumbar spine radiographies. Both knees showed characteristic
findings of osteoarthritis, more evident on the left side, such
as narrowing joint space and subchondral sclerosis (Figure 1).
Surprisingly, no osteophytosis was seen in either side. Same
changes were found in hip radiographies, although not so evident
(Figure 2). Lumbar spine radiographies showed narrowing of
intervertebral spaces with severe calcification of intervertebral
discs (Figure 3).
The patient underwent cemented total left knee arthroplasty
and, during surgery, black discoloration of cartilage and of
Figure 3 Radiography of lumbar spine showing calcified intervertebral
surrounding ligamentous and tendinous structures was observed discs.
(Figures 4,5). No other intra- or post-surgery complications were
reported.
Histologic evaluation of bone and soft tissues showed
thickened and fibrotic areas of cartilage with dark pigmentation.
After these findings, the patient was re-examined and we
found black spots on both sclerae, ear cartilage and nail beds of
both thumbs (Figures 6,7). Alkaptonuria was diagnosed upon
detection of high levels of HGA in urine. We referred the patient
to Genetic consultation.
At 15 month follow-up, the patient is fully independent,
ambulates without support, has an adequate range of motion
and is pain-free. Plain radiographies of the knee do not show any Figure 4 Intraoperative photography of the knee joint showing
abnormality on the components of the prosthesis (Figure 8). ochronosis.

Figure 1 Radiography of the knees showing narrowing joint space Figure 5 Intraoperative photography of the knee joint showing
and subchondral sclerosis. ochronosis.

Figure 2 Radiography of the hips showing irregularities at the

articular surface. Figure 6 Black discoloration in nail beds.

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Figure 7 Black spots in sclera.
Figure 8 Radiography of the knee 15 months after surgery, without
signs of loosening of components.
DISCUSSION
In most of the case reports found in literature, alkaptonuria is
asymptomatic until the development of ochronotic arthropathy
[8]. Usually, patients only seek for medical evaluation when the
effects of the disease on weight-bearing joints is noticed, namely
pain. This was true for our patient as well. The diagnosis was
considered upon intra operative findings, when the patient was
submitted to an arthroplasty.
Alterations on bone and cartilage characteristics found
intraoperatively are worrisome and raises doubts about the
potential integration of prosthetic components. For this, it is
essential that the Orthopedist is able to recognize the typical
clinical signs of alkaptonuria when he first evaluates a patient
with presumed osteoarthritis of the knee.
Alkaptonuria may be confused with exogenous ochronosis,
the ochre like pigment deposition in the skin and sometimes
in the cartilage or other organs as a result of exposure to a
variety of exogenous compounds [9]. These compounds include
topical phenol, topical hydroquinone bleaching creams, quinine
injections, oral antimalarial drugs, amiodarone, cytotoxic
drugs, minocycline and levodopa and methyldopa [9]. They are
distinguished from alkaptonuria by the absent HGA excretion in
urine. The distinction is necessary because the prognosis of the
two conditions is quite different and so the management.
JSM Clin Case Rep 3(2): 1083 (2015)
Mota et al. (2015)
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Treatment is symptomatic and is based on osteoarthritis
management. It can decrease symptons in early stages of the
disease but it cannot decrease the rate of joint degeneration.
One prospective study showed that regular swimming, spine
mobilization and development of good truncal strength likely
provide benefit to these patients, when initiated early in the
disease [10]. The same study demonstrated that the average age
of arthroplasty in alkaptonuric patients is lower than the national
mean (53 vs. 67) [10].
Here upon, when conservative treatment (NSAID’s,
physical therapy) no longer can mitigate symptomatology, joint
replacement should be done.
There is no specific pharmacologic therapy for alkaptonuria
treatment. Ascorbic acid, once considered a potential therapy for
alkaptonuria, showed inconsistent results and overall it has not
been dramatically effective [10]. Nitisone, approved by de FDA
for hereditary tyrosinemia treatment, has been investigated for
use in alkaptonuria [3]. Although a randomized study involving
40 patients treated for 3 years with nitisone showed a great
reduction in plasma and urine HGA levels, hip motion range and
musculoskeletal functions were not different when compared
with no-treated patients [11].
Since alkaptonuria can cause cardiovascular alterations, these
patients should be monitored for aortic dilatation and valvular
calcification. They should also be treated for prostate and renal
stones as needed [12].
Joint replacement is the treatment of choice for primary or
secondary knee osteoarthritis, when conservative treatment is
no longer effective. So far, the information available indicates
that total knee arthroplasty has similar results in alkaptonuric
patients, when compared with general population. Nevertheless,
there are few case reports of this pathology and the time of
follow-up of the patients is not long yet. More investigation in
this condition is needed so we can conclude if the durability of
prosthetic components is compromised.
REFERENCES
1. Reed DN, Gregg FO, Corpe RS. Minocycline-induced black bone disease
encountered during total knee arthroplasty. Orthopedics. 2012; 35:
737-739.
2. Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in
ochronosis: review of the literature. Rheumatol Int. 2005; 25: 81-85.
3. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD,
Fitzpatrick DL, et al. Natural history of alkaptonuria. N Engl J Med.
2002; 347: 2111-2121.
4. Kobak AC, Oder G, Kobak S, Argin M, and Inal V: Ochronotic arthropathy:
disappearance of alkaptonuria after liver transplantation for hepatitis
B-related cirrhosis. J Clin Rheumatol 2005; 11: 323-325.
5. Konttinen YT, Hoikka V, Landtman M, Saari H, Santavirta S, Metsärinne
K, et al. Ochronosis: a report of a case and a review of literature. Clin
Exp Rheumatol. 1989; 7: 435-444.
6. Forslind K, Wollheim FA, Akesson B, Rydholm U. Alkaptonuria and
ochronosis in three siblings. Ascorbic acid treatment monitored by
urinary HGA excretion. Clin Exp Rheumatol. 1988; 6: 289-292.
7. Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in
ochronosis: review of the literature. Rheumatol Int. 2005; 25: 81-85.
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8. Ozmanevra R, Güran O, Karatosun V, Günal I. Total knee arthroplasty 2006; 33: 2280-2285.
in ochronosis: a case report and critical review of the literature. Eklem
11. Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat
Hastalik Cerrahisi. 2013; 24: 169-172.
P, et al. A 3-year randomized therapeutic trial of nitisinone in
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12. Authors Introne WJ, Gahl WA. Alkaptonuria. Alkaptonuria. ;.
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Musculoskeletal findings and disability in alkaptonuria. J Rheumatol.

Cite this article

Mota PT, Cândido R, Pintado C (2015) Alkaptonuria, a Rare Cause of Osteoarthritis – Case Report. JSM Clin Case Rep 3(3): 1083.

JSM Clin Case Rep 3(2): 1083 (2015)

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