Rheumatol Int (2005) 25: 8185

DOI 10.1007/s00296-004-0498-1

R EV IE W

Julie M. Keller William Macaulay

Ohannes A. Nercessian Israeli A. Jae

New developments in ochronosis: review of the literature

Received: 2 April 2004 / Accepted: 11 June 2004 / Published online: 21 August 2004
Springer-Verlag 2004

Abstract Ochronosis commonly aects all connective

tissue. Recognition of changes secondary to the deposition of ochronotic pigments has increased with advances
in diagnostic technology, allowing both improved
imaging and early biochemical and genetics-based diagnosis of alkaptonuria, the cause of ochronosis. Successful
symptomatic treatment of ochronotic arthropathy with
joint replacement has been documented, and a new
pharmacotherapeutic agent, nitisinone, is currently
under investigation for both prevention and treatment of
ochronosis. This review of the literature highlights
recently recognized complications, new diagnostic techniques, and treatment options.
Keywords Alkaptonuria Arthrosis Connective tissue
manifestations Diagnosis Ochronosis Review

Introduction
Ochronosis is the connective tissue manifestation of
alkaptonuria, a defect in the metabolism of homogentisic acid (HGA) caused by autosomal recessive muta-

No grants or industrial support were received for this investigation

J. M. Keller W. Macaulay O. A. Nercessian
Department of Orthopedic Surgery,
Columbia University Medical Center,
New York, NY, USA
I. A. Jae
Division of Rheumatology,
Columbia University Medical Center,
New York, NY, USA
W. Macaulay (&)
Center for Hip and Knee Replacement,
622 West 168 Street, PH1146, New York,
NY 10032, USA
E-mail: wm143@columbia.edu
Tel.: +1-212-305-6959
Fax: +1-212-305-4024

tions of the HGO gene on chromosome 3q.

Homogentisic acid is a metabolic product of phenylalanine and tyrosine; it accumulates in patients with
alkaptonuria, polymerizing to form a dark pigment that
is selectively deposited in connective tissues. These tissues become weak and brittle, developing cracks and
chips and leading to chronic inammation, degeneration, and osteoarthritis [1]. The condition is rare,
aecting one in 250,0001 million people, but can lead
to serious disability [2, 3].
The most common presentations include:
Darkening of urine with exposure to air or reducing
agents
Dark pigmentation of the pinna, sclera, and nasal ala
Narrowing of joint spaces and disc calcications,
primarily in the dorsolumbar spine, porotic vertebral
bodies; osteophyte and bone bridge formation. These
lead to lower back pain and stiness, loss of lumbar
lordosis, exaggerated thoracic kyphosis, and loss of
height [4]
Hip and knee pain due to cartilage degeneration, joint
space narrowing, and sclerosis with minimal osteophytic changes
Cardiac valve calcication and stenosis, coronary artery calcications [5, 6]
Renal and prostatic stones
While these manifestations have long been recognized, new techniques allow the diagnosis of other
connective tissue manifestations of alkaptonuria that
often constitute the seminal presentation of ochronosis.
In addition, advances in the understanding of the genetic
basis of the disease, its mechanism of action, and its
implications have led to new methods of diagnosis and
new questions regarding treatment.

Mechanism of disease
Connective tissues including hyaline cartilage, tendons,
ligaments, and muscles are aected by the deposition of

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ochronotic pigment. The tissues become weak, brittle,

and prone to chipping, cracking, and rupture, leading to
rapid degeneration of the joints. There are several theories as to how alkaptonuria results in ochronosis and
the associated connective tissue changes (Fig. 1).
Ochronotic pigment forms as patients grow older and
kidney functions slow, allowing for the accumulation of
HGA, which is polymerized to the pigment by unknown
mechanisms. The HGA may act as a chemical irritant,
causing inammation and more rapid degeneration of
the joints. It is also possible that HGA physically binds
to connective tissue and alters the structure and interactions of the macromolecules [7].
Other evidence suggests that it is not HGA itself but a
byproduct of its oxidation that causes degeneration. As
HGA accumulates both inter- and intracellularly, it is
oxidized to benzoquinoneacetate (BQA). This oxidation
occurs spontaneously in urine, where the environment is
alkaline and aerobic. In the neutral, relatively anaerobic
environment of the body, HGA polyphenol oxidase, an
enzyme found in skin and connective tissue cells, is required to catalyze the reaction. It is thought that BQA,
polymerized BQA, or a melanin-like pigment formed
from BQA forms chemical bonds to connective tissue
macromolecules, altering the cross-linking structure of
the tissue (Fig. 1) [7, 8].
Oxidation also leads to free radical formation; free
radicals are associated with tissue damage and are
thought to cause degeneration by inciting inammation,

Fig. 1 Alkaptonuria and ochronosis. Absence of the enzyme

homogentisic acid oxidase, found mainly in the liver and kidneys,
leads to the accumulation of homogentisic acid (HGA). HGA can
be excreted by the kidneys, but as kidney function decreases with
age, it accumulates. HGA can bind to connective tissue (CT)
macromolecules, changing the structural integrity of the CT. Its
oxidative product benzoquinoneacetic acid (BQA) is also formed,
leading to free radical formation and inhibition of lysyl hydroxylase and tissue damage

leading to degeneration such as that seen with rheumatoid arthritis [8]. Finally, the structural integrity of the
tissue may decrease due to inhibition of lysyl hydroxylase, a cartilage enzyme required for the formation of
hydroxylysine residues that are essential for cross-linking. It is not clear how this inhibition occurs, but decreased activity has been found in patients with
ochronosis. The nal result of the ochronotic process is
weak connective tissue that chips and fractures, leading
to further inammation and exacerbating the existing
problem [7].

Connective tissue changes

The consequences of these connective tissue changes
were recognized long before any idea of the disease
mechanism was understood. Relentlessly progressive
arthropathy is characteristic of ochronosis. Ochronotic
arthritis diers from other forms of arthritis in that,
while joint space narrowing and sclerosis are characteristic, osteophytic changes are not as evident. Also
unique is that articular cartilage of the synovial joints,
particularly the knees and hips, is often found to be
completely black and very brittle; the surrounding bone
usually appears unaected [9]. Spinal changes pathognomonic for ochronosis include severe disc calcication, disc space narrowing, osteophytosis, and sclerosis.
Changes occur primarily in the dorsolumbar spine rather than the lumbosacral spine, as is characteristic of
degenerative disease [5].
Other connective tissue changes have been increasingly recognized, partially due to the increased use of
MRI. In one large study, the majority of patients involved were found to have tendon-related ndings on
MRI. Thickened Achilles tendons, tears of anterior
cruciate and ankle ligaments [10], and rupture of the
patellar and Achilles tendons during normal activity or

83

with minimal trauma [3] have all been identied.

Quadriceps and hamstring muscle tears due to minimal
trauma, asymptomatic supraspinatus tears [11], and
knee, ankle, and metacarpophalangeal synovitis have
also been observed [10]. In the case of ruptures and
tears, deposition of ochronotic pigment discretely
localized to the area of rupture has been observed.
Sometimes the nearby articular cartilage was also noted
to have ochronotic changes.
Lumbar disc herniation has also been observed in
case studies as the presenting symptom of ochronosis.
Such cases are unusual in that disc herniation occurred
without prior disc calcication, which is usually an early
manifestation of disease. The intervertebral discs were
all found to contain black material on discectomy, and it
is likely that herniation occurred due to weakening of
the cartilage by pigment deposition, much as weakening
of tendons and ligaments occurs. Pigment deposition
was highly localized and discectomy results were excellent in all cases [4].
In the past, upper extremity involvement in ochronosis has been identied as a rare, late complication of
the disease. Patients usually presented in their 40s to 50s,
with histories of spinal changes and multiple lower
extremity joint involvement progressing to include
shoulder pain, decreased range of motion, degenerative
changes, and sometimes calcications of nearby tendons. Elbow, wrist, and hand joint involvement were
uncommonly recognized [11]. Recent studies have found
that late shoulder involvement is common and identied
several novel presentations involving the upper extremity. Case studies have included patients presenting with
symptoms including joint space narrowing, sclerosis and
small osteophyte formation of the shoulder, carpalmetacarpal and distal interphalangeal (DIP) joints [2],
and narrowing and sclerosis in the shoulders and DIP
joints [5]. Another case series identied patients in various stages of ochronosis with degenerative arthritis
involving multiple upper extremity joints including all or
some of the elbow, shoulder, proximal interphalangeal,
and DIP joints [12]. One study of 64 patients aged 4 to
80 years with recognized ochronosis found several cases
of synovitis of the metacarpophalangeal joints. Earlier
case studies have reported pigmentation of the exor
digitorum profundus [13], stenosing synovitis of the
exor tendons [14], and pigment deposition of hand
tendon sheaths and knuckle pads [12]. These studies
together suggest that upper extremity involvement is not
uncommon but perhaps commonly unrecognized or
incorrectly attributed to other disease processes.

Diagnosis
While it is true that the diversity of presentation in
ochronosis has seemingly increased, it should also be
noted that advances in technology have promoted the
detection of many manifestations that would have remained unseen in early studies. Magnetic resonance

imaging shows thickened tendons and asymptomatic

tears. Echocardiogram and CT have allowed detection
of coronary artery calcications and cardiac valve defects. Ultrasound and X-ray detect renal and prostatic
stones. It is unclear whether the nature of the disease has
changed or whether our tools to detect these changes
have just improved.
New molecular diagnostic techniques are also being
increasingly employed, allowing for denitive diagnosis
of alkaptonuria before it presents symptomatically as
ochronosis. Alkaptonuria is caused by a mutation to the
HGO gene, located on chromosome 3q. Forty mutations
have been found involving 106 of the 114 alleles of this
gene, including missense, nonsense, and frameshift
mutations and splice site abnormalities [10]. Homozygous and compound heterozygous loss of function
mutations have been described and vary in prevalence,
depending on the population; it is thought that mutations vary by the origin of the population and have been
distributed according to human migration patterns [15].
New techniques have been developed for rapid detection
of ve of these mutations which could allow easy recognition of the condition before symptoms occur [16].
Recent studies have also discovered an increase in
bone resorption in patients with alkaptonuria. In addition to the possible clinical implications of increased
bone loss, the abnormalities in metabolism lead to
higher urinary excretion of type I collagen N-telopeptide. Measurements of this value could aid in early,
convenient diagnosis of the condition. Preventative
treatment of bone loss could be instigated prior to the
development of severe osteopenia or osteoporosis [17],
and with the diagnosis of alkaptonuria, it is much more
likely that a patients connective tissue symptoms could
be accurately attributed to ochronosis, improving
prognostic predictions and allowing for proper education and denitive treatment of the joint pain.

Treatment options
Currently, symptomatic treatment of the complications
of alkaptonuria is the only option. Ochronosis leading to
degenerative joint disease has been treated with exercise
and analgesics but inevitably progresses, often to signicant debilitation [18]. Alleviation of pain and significant increases in activity have been achieved with total
joint replacement of both the hips and knees [19]. Outcomes have been successful with both cemented and
cementless implants, though many patients require
multiple joint replacement or remain debilitated secondary to back or other joint pains, making this an
imperfect solution [9]. Tendon ruptures due to ochronosis have been xed successfully with primary repair
[3]. It is thought that the successes of joint replacement
and tendon repair are due to the structural integrity of
the surrounding tissue, allowing for normal healing and
bone growth once the ochronotic depositions are
removed [3, 9]. The implications for joint replacement

84

and connective tissue repair of recent studies suggesting

that ochronosis increases bone resorption have not yet
been investigated. Treatment and prevention of ochronotic osteopenia are also in need of further study.
There is currently no preventative treatment for the
complications of alkaptonuria that has proven ecacious. The ideal would involve replacement of the
missing enzyme, whether by gene therapy or exogenous
hormone. This would prevent the accumulation of HGA
and the occurrence of ochronosis, cardiac calcications,
and renal and prostatic stones. This therapy is not currently possible. Other attempts at preventing complications have included diets low in tyrosine and
phenylalanine, so that the toxic by-product HGA is not
made, and increasing vitamin C intake to prevent oxidation to BQA and free radical formation [20]. Some
studies have shown that these changes lower urine HGA
excretion but do not prevent its accumulation and
complications [19]. Others have not shown such a
reduction [10]. The clinical eect of any of these treatments has been minimal.
Nitisinone has been shown to signicantly lower the
urinary excretion of HGA in both murine models and
humans. Nitisinone is a triketone herbicide that inhibits
4-hydrophenylpyruvate dioxygenase by rapid, reversible
binding; this action would cause direct pharmacological
reduction of HGA production by inhibiting the tyrosine
degradation pathway and, theoretically, would prevent
HGA accumulation. Nitisinone is FDA-approved for
the treatment of tyrosinemia type I, but further investigations into the ecacy of this treatment are required, as
there are several unknowns regarding long-term results.
It has the known side eect of elevating plasma tyrosine,
leading to corneal irritation. This can be prevented by
severe restriction of tyrosine and phenylalanine in the
diet [21], but the ocular eects of long-term treatment
are unknown and complying with the dietary restriction
necessary to prevent elevated tyrosine would be extremely dicult.
Nitisinone could also theoretically lead to the development of tyrosinemia type III, which is associated with
neurological complications including tremor, ataxia,
seizure, intellectual impairment, and delayed development [7]. In addition, there is not yet evidence that
treatment with nitisinone prevents ochronosis, can
eectively treat existing ochronosis, or has any eect on
bone metabolism. Though questions remain, nitisinone
is the rst possibility for potent pharmacotherapy of
ochronosis [20].

Conclusions
Review of the literature suggests that ochronosis commonly aects all connective tissue and includes early
changes in the upper extremity and small joints as well
as decreased integrity of tendons, ligaments, and muscles. Recognition of the changes secondary to deposition
of ochronotic pigments has increased with advances in

diagnostic technology allowing both improved imaging

and early biochemical and genetics-based diagnosis of
alkaptonuria. Symptomatic treatment of ochronotic
arthropathy includes successful use of total joint
replacement and primary repair of connective tissue
damage, but no preventative treatment has proven
eective. Nitisinone is the rst pharmacotherapeutic
agent that seems to prevent ochronosis, though further
studies are required to assess its ecacy and possible
side eects.

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