Rheumatology 2013;52:599–608

RHEUMATOLOGY doi:10.1093/rheumatology/kes395
Advance Access publication 12 January 2013

Review
Occurrence of tendon pathologies in metabolic
disorders
Michele Abate1, Cosima Schiavone1, Vincenzo Salini1 and Isabel Andia2

Downloaded from http://rheumatology.oxfordjournals.org/ at University of Victoria, McPherson Library Serials on October 26, 2014
Abstract
This article reviews the pathogenetic role of metabolic disorders, which are of paramount relevance to the
progression of tendon damage. In diabetes, the prevalence of rheumatological diseases is high, mainly
because of the deleterious effects of advanced glycation end products that deteriorate the biological and
mechanical functions of tendons and ligaments. In heterozygous familial hypercholesterolaemia, most
patients develop Achilles xanthomatosis, a marker of high risk for cardiovascular disease caused by
cholesterol deposition in the tendons. Tendon degeneration has also been observed in non-familial hyper-

R EV I E W
cholesterolaemia. Monosodium urate crystal deposition in soft tissues is a hallmark of chronic gouty
arthritis. In this group of diseases, the mobilization of cholesterol and uric acid crystals is presumably
followed by low-grade inflammation, which is responsible for tendon degeneration. Adiposity may con-
tribute to tendon disorders via two different mechanisms: increased weight on the load-bearing tendons
and systemic dysmetabolic factors that trigger subclinical persistent inflammation. Finally, tendon abnorm-
alities have been observed in some rare congenital metabolism disorders such as alkaptonuria.
Key words: tendinopathy, diabetes mellitus, hypercholesterolaemia, hyperuricaemia, obesity.

Introduction magnitude, frequency, duration and/or direction, overuse

Progress in research has increased our understanding of
tendon physiology and the pathogenetic pathways of
chronic tendinopathies. Trans-membrane proteins called
integrins connect the extracellular collagen fibrils to the
cytoskeleton of tenocytes. Under normal exercise condi-
tions, fibril stretching activates subcellular biology,
releasing growth factors and triggering the subsequent
synthesis of extracellular matrix components, pre-
dominantly proteoglycans and collagen neofibrils [1].
Homeostasis is maintained by the simultaneous produc-
tion of appropriate metalloproteinases (MMPs), which
counteracts the anabolic effects of growth factors [2].
When fibril stretching is increased but remains within the
physiological window, synthesis prevails over degradation
and tendon hypertrophy occurs. However, when repeated
loading deviates from normal limits by differences in
1
Department of Medicine and Science of Aging, University G.
d’Annunzio, Chieti-Pescara, Italy and 2BioCruces Health Research
Institute, Cruces University Hospital, Barakaldo, Spain
Submitted 20 June 2012; revised version accepted
23 November 2012.
Correspondence to: Michele Abate, Department of Medicine and
Science of Aging, University G. d’Annunzio, Chieti-Pescara, Via dei
Vestini 31, 66013 Chieti Scalo [CH], Italy.
E-mail: m.abate@unich.it
injury may develop. An aberration in proteoglycan me-
tabolism is likely to drive the pathogenesis of tendon dam-
age, as excess proteoglycan production leads to water
retention and pressure from swelling. The biochemical
adaptation to these changes involves the production of
pro-inflammatory agents such as IL-1 b, TNF-a and pros-
taglandins (PG). Some of the detrimental effects of these
pro-inflammatory cytokines include enhanced production
of MMPs that cause matrix destruction.
The following pathogenetic cascade is very complex
and involves tenocyte apoptosis, hypoxia, neovessel
proliferation, smoldering disorganized fibrillogenesis, col-
lagen fibre disruption and hyaline and mucoid degener-
ation, usually with an absence of inflammation in the
advanced stages [1–4].
Of note, the progression of the disease is characterized
by substantial individual differences. Indeed, tendon in-
tegrity is disrupted at comparably high loads only in
some individuals, and in a small subset of individuals,
exposed to such environmental chemicals as fluoroquino-
lone antibiotics and statins, tendon integrity disruption
can occur even within a normal mechanical load range
[5]. Intrinsic and extrinsic factors, including genetics,
age, drugs, hormones and blood supply, influence the
biological milieu and tendon adaptation to mechanical
loading.

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Michele Abate et al.
In this context, the role of metabolic factors is of para-
mount importance. Clinical and experimental research
shows that diabetes [6], obesity [7] and, to a lesser
extent, hypercholesterolaemia [8], hyperuricaemia [9]
and some rare congenital metabolism disorders (alkapto-
nuria, glucose-6-phosphatase deficiency and hypergalac-
tosaemia) [10] are frequently associated with tendon
degeneration, thus influencing the mechanical properties
of tendons and even impairing the healing process after
surgery. The aim of this review is to summarize the pre-
sent knowledge on this topic and to analyse the mechan-
isms for the negative effects of these metabolic disorders.
A search of English language articles was performed in
PubMed, Web of Knowledge (WOK) and EMBASE using
the key search terms tendinopathy or tendon, combined
with obesity, diabetes, hypercholesterolaemia, hyperuri-
caemia, alkaptonuria, glucose-6-phosphatase or hyper-
galactosaemia, independently. Bibliographies were hand
searched to include any applicable studies that were not
captured by our search. Articles were eligible if they pro-
vided specific information related to the correlation be-
tween tendon disease and metabolic disorders.
Diabetes
Clinical observations
Several rheumatological conditions complicate the clinical
course of diabetes mellitus. For example, Dupuytren’s
disease, characterized by thickening, shortening and
fibrosis of the palmar fascia, and trigger finger (also
called flexor tenosynovitis) have been found in 10–15%
of subjects with diabetes versus 1% in non-diabetic con-
trols (matched for age and sex). Similarly, carpal tunnel
syndrome and shoulder adhesive capsulitis (frozen shoul-
der) have been reported in 11–25% and 10–20% of pa-
tients with diabetes, respectively. The prevalence of these
conditions increases with the duration of both Type I and
Type II diabetes and with poor glycaemic control [11–13].
Symptomatic rotator cuff tears (Fig. 1) are more com-
monly observed both in subjects with overt Type I or
Type II diabetes [14, 15] and in those with high, yet
normal, plasma glucose levels [16]. In asymptomatic dia-
betic subjects, an increased thickness of supraspinatus
and biceps tendons and a significantly higher prevalence
of tears have been found [17]. These observations are of
clinical relevance because, as follow-up studies show
[18], pain and functional limitation are likely to occur in a
large percentage of people with asymptomatic tears at
baseline. In addition, after surgical repair, subjects with
diabetes show a restricted range of shoulder motion [19]
and a higher incidence of retears [20]. These adverse out-
comes can be related to the intrinsically poor quality of the
tissue that is being repaired.
In the lower limbs, increased thickness and structural
abnormalities of the plantar fascia and Achilles tendon
have been observed in both Type I and Type II diabetes
mellitus using sonography or magnetic resonance imaging
[21–24]. These changes are more severe in patients with
neuropathic complications and previous foot ulcers but
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FIG. 1 Complete supraspinatus tear in a 61-year-old
diabetic patient.
A small, full defect (insertional portion) in the tendon from
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the bursal to the articular margin, with retracted tendon
end (calipers), is observed (A, transverse scan). In the
same patient, an effusion (anechoic area, arrows) in the
bicipital tendon sheath can also be detected (B, trans-
verse scan). B: bicipital tendon; SST: supraspinatus
tendon; D: deltoid muscle; H: humeral bone.
can also be found in subjects without diabetic complica-
tions [25, 26].
Accordingly, reduced ankle joint range of motion, which
may restrain the forward progression of the tibia on the
fixed foot during the stance phase of walking, has been
documented in patients with diabetes [27, 28]. This in turn
results in prolonged and excessive weight-bearing stress
under the metatarsal heads during the foot–floor inter-
action, which is thought to contribute to the development
of foot ulcers in individuals with diabetes mellitus [28–30].
Imaging techniques, such as magnetic resonance imaging
and the more widely used sonography, show that
disorganized echotexture, focal hypoechoic areas and
increased thickness of the tendons and ligaments are
common in diabetic patients [21–24].
Histopathology
According to clinical observations, histopathology shows
that joint capsules, ligaments and tendons lose their
normal glistening white appearance. In the more affected
portions, these structures become grey and amorphous,
with poorly marked areas where diffuse, fusiform or nodu-
lar thickening may be observed. Electron microscopic in-
vestigation shows that collagen fibrils appear twisted,
curved, overlapping and otherwise highly disorganised.
There is an increased packing density of collagen fibrils,
with a decreased number of fibroblasts and tenocytes per
unit of surface area. The reduction of elastic fibres is con-
sistent. Finally, the number of capillaries per unit of sur-
face area, and therefore the arterial blood flow, is
reduced, particularly in elderly subjects [31].
Pathogenesis
According to an accepted hypothesis, tendon damage in
diabetes is caused by an excess of advanced glycation
end products (AGEs; Fig. 2). AGEs form at a constant but
slow rate and accumulate with time in the normal body.
However, their formation is markedly accelerated in dia-
betes because of the increased availability of glucose.
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FIG. 2 Common pathogenetic pathways of tendon damage in metabolic disoders.
Diabetes and obesity are the best-known factors of tendon degeneration. Hypecholesterolaemia and hyperuricaemia are
frequently associated. The ensuing collagen cross-linking, tenocyte apoptosis and release of inflammatory cytokines lead
progressively to tendon damage.
A key characteristic of reactive AGEs is their ability to form
a covalent cross-link within collagen fibres, altering their
structure and functionality [13].
Essentially, collagen cross-links can generate via
two different pathways: (i) the enzymatically driven,
hydroxylysine-derived aldehyde pathway and (ii) the
non-enzymatic glycation or oxidation-induced AGE
cross-link [32–34]. As opposed to the beneficial effects
on collagen strength bestowed by enzymatic cross-links,
AGE cross-linking is generally thought to cause deteriora-
tion of the biological and mechanical function of tendons
and ligaments [35]. In fact, once formed, AGEs can be
degraded only when the protein they are linked to is
itself degraded. Therefore the most extensive accumula-
tion of AGEs will occur in tissues with low turnover, such
as cartilage, bone and tendon.
Other major features of AGEs relate to their interactions
with a variety of cell-surface AGE-binding receptors (i.e.
AGE-R1, AGE-R2, AGE-R3 and RAGE) [36]. Ligand en-
gagement of AGE-binding receptors activates several crit-
ical molecular pathways and triggers a number of effects,
including pro-oxidant events, via generation of reactive
oxygen species, and further pro-inflammatory events via
NF-ib signalling [37]. This in turn accelerates AGE
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Tendinopathy and metabolic disorders
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cross-linking in collagen fibres and leads to sustained
upregulation of pro-inflammatory mediators and to a dys-
functional cell phenotype [38, 39].
Further AGE negative effects include (i) the modification
of short-lived proteins, such as the basic fibroblast growth
factors, which is followed by markedly decreased mito-
genic activity; (ii) intracellular AGE formation, which leads
to the quenching of nitric oxide and impaired growth
factor signalling and (iii) enhanced apoptosis via oxidative
stress, increased caspase activities and/or extrinsic sig-
nalling through pro-apoptotic cytokines [40, 41].
Tendon damage ensues from these complex pathways.
In addition to degeneration, tendon and ligament thick-
ness increases as expression of the abnormal storage
and the architectural distortion of collagen layers [42,
43]. From the biomechanical point of view, several studies
have demonstrated that collagen toughness and stiffness
and the elastic modulus are strongly influenced by AGE
cross-link formation [44, 45].
In addition to the AGE-mediated pathogenetic mechan-
ism, hyperglycaemia in itself may lead to alterations in the
redox environment, specifically in the polyol pathway, re-
sulting in increased intracellular water and cellular
oedema. Microvascular disease may lead to tissue
601
Michele Abate et al.
hypoxia with overproduction of oxygen free radicals,
creating a permissive apoptotic environment [46].
It is not surprising that these metabolic abnormalities
may be present in the early clinical stages of Type II dia-
betes [24]. Indeed, while Type I diabetes is diagnosed at
an early stage because of a relatively acute clinical onset
characterized by extreme elevations in glucose concen-
trations, Type II diabetes is usually diagnosed later, when
many patients already exhibit chronic complications.
Certainly these subjects could have glucose intolerance
or mild Type II diabetes mellitus for a significant length of
time before diabetes is clinically diagnosed.
The ultrasonographic finding of reduced neovas-
cularization inside the degenerated tendons [47] is con-
sistent with several observations that show decreased
vascular endothelial growth factor levels and reduced
angiogenesis in different experimental and clinical dia-
betic conditions [48–50]. This finding adds to our know-
ledge about the pathogenesis of diabetic tendinopathy.
The downregulation of this factor can limit vessel and
nerve ingrowth and can also affect neurogenesis, redu-
cing neural progenitor cell recruitment, axonal outgrowth,
neuronal survival and the proliferation of Schwann cells
[51]. The association between reduced nerve proliferation
inside tendons and sensitive neuropathy reduces pain
perception. Consequently, diabetic patients, who lack dis-
tress signals, may excessively exercise their tendons,
making them prone to overuse damage.
Hypercholesterolaemia
Clinical observations and histopathology
Heterozygous familial hypercholesterolaemia (HeFH) is
caused by a defect in the catabolism of low-density lipo-
protein (LDL), usually resulting from the inheritance of a
mutant LDL receptor gene. Untreated HeFH is associated
with a high mortality and morbidity from coronary heart
disease, but when intensive treatment occurs early, life
expectancy can be substantially improved.
Most patients with HeFH develop tendon xanthoma,
mainly in the Achilles tendon (Fig. 3), which becomes in-
creasingly common from the third decade onwards. The
early detection of xanthoma is thus exceptionally import-
ant. Unfortunately, in several cases the clinical diagnosis
is difficult because the nodules are too small to be de-
tected or because the pain is ascribed to an unspecific
tenosynovitis. In this regard, Beeharry et al. [52] have
shown that episodes of Achilles tendon pain lasting
more than 3 days are very common in patients with
HeFH, even in the absence of apparent xanthomatosis.
Therefore these authors suggest that serum cholesterol
measurement in young patients presenting with a painful
Achilles tendon is mandatory because it could allow the
early diagnosis of HeFH.
Sonography is very useful for detecting tendon abnorm-
alities (Grade 1: minor sonographic changes; Grade 2:
diffuse heterogeneous echo pattern; Grade 3: focal
hypoechoic lesions). Sonography can visualize xanthoma
located deep within the tendon that cannot be detected
602
FIG. 3 Bilateral Achilles tendon abnormalities in a
53-year-old hypercholesterolaemic patient.
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Both midportion Achilles tendons appear hypoechoic,
dishomogeneous and thickened (calipers), with loss of the
normal fibrillar pattern (longitudinal scan). Neovessels
inside the tendon can be detected by means of power
Doppler examination (panel 1). Panel 1: left Achilles
tendon; Panel 2: right Achilles tendon.
by palpation. Tsouli et al. [53], in a large case–control
study, found a Grade 2 Achilles tendon echostructure in
30 of 80 patients and a Grade 3 in 8 of 80 patients. The
thickness of the tendon was increased in patients with
HeFH compared with controls in proportion to the echo-
structural abnormalities. Only patients with minor sono-
graphic changes showed significant reductions in
Achilles tendon thickness after statin treatment (from
4.9 ± 0.55 mm to 4.5 ± 0.43 mm, P < 0.01), whereas pa-
tients with Grade 2 and Grade 3 abnormal echostructures
remained unchanged, and no significant reduction was
observed [53]. Exacerbations of Achilles tendinopathy
can occur when statin treatment is started and is attribut-
able to the rapid lowering of cholesterol [53]. The condi-
tion would seem to be akin to the exacerbations of gout
that occur when allopurinol treatment begins and the
serum uric acid level decreases rapidly. The mobilization
of cholesterol, like that of uric acid crystals, presumably
provokes an inflammatory cell reaction [52, 54].
Histologically, cholesterol deposition is observed both
extracellularly and inside histiocytes and other foam cells,
which show numerous intracytoplasmic lipid vacuoles,
lysosomes and myelin figures. An inflammatory cell infil-
trate and a fibrous reaction may be associated.
The deleterious effects of non-familial hypercholesterol-
aemia on tendons have been debated. Some studies have
shown that in patients with Achilles tendon rupture, the
concentration of serum lipids is higher than in controls [8]
and that the esterified fraction of cholesterol is elevated
in biopsies from degenerated Achilles tendons [55].
However, in a study comparing the sonographic charac-
teristics of Achilles tendon in subjects with familial hyper-
cholesterolaemia with those of patients with non-familial
hypercholesterolaemia, abnormal patterns were noted
only in subjects with familial hypercholesterolaemia [56].
Similarly, conflicting results have been reported for rotator
cuff tendons. According to Abboud et al. [57], total chol-
esterol, triglycerides and LDL cholesterol concentrations
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are higher in patients with rotator cuff tendon tears, and
their high-density lipoprotein cholesterol is lower than that
of the control group. However, these results are chal-
lenged by the findings of Longo et al. [58] who found no
differences in the lipid profiles of subjects who underwent
surgery for rotator cuff tears or meniscectomy.
Pathogenesis
The pathogenetic mechanisms leading to the formation of
xanthoma have been elucidated. LDL derived from the
circulation accumulate into tendons and become oxi-
dized. Oxidized LDL (oxLDL) contains various oxidatively
modified phospholipids and cholesterols, isoprostanes,
oxidized arachidonoyl residues, lysolipids and lysopho-
sphatidic acid [59]. As might be expected from this, the
effect of oxLDL on inflammatory cells is complex, depend-
ent on the concentration of the particles and the extent
and mode of oxidation [60]. It is worth mentioning that
specific oxidative-truncated phospholipids rapidly enter
nucleated cells, travel to the mitochondria and initiate
the mitochondrial dependent pathway to apoptotic cell
death [59].
Artieda et al. [61] have shown that macrophages from
HeFH patients with tendon xanthoma have a higher pre-
disposition to form foam cells after oxLDL overload than
those from HeFH patients without xanthoma. Moreover,
macrophages from HeFH patients exhibit a differential
gene expression profile characterized by increased
plasma tryptase, TNF-a, IL-8 and IL-6 expression [61].
In a familial form of massive tendon xanthomatosis,
Matsuura et al. [62] showed decreased high-density
lipoprotein-mediated cholesterol efflux associated with
genetic variation in the reverse cholesterol transport and
LDL oxidation pathways [63]. Interestingly, xanthomatosis
and atherosclerosis share these genetic abnormalities and
therefore may result from the same pathophysiological
mechanisms. This explains why tendon xanthoma is a
marker of high risk for cardiovascular disease.
The mechanism by which non-familial hypercholester-
olaemia subjects develop damaged tendon tissues is
unknown. It has been hypothesized that microscopic
cholesterol deposition inside the tendons, undetectable
with the usual imaging techniques, could initiate and
maintain a low-grade, persistent inflammation; this, in
turn, may be responsible for chronic tendon degeneration
and biomechanical changes, as shown by experimental
studies of the patellar and rotator cuff tendons of hyperch-
olesterolaemic knockout mice [64].
Hyperuricaemia
Clinical observations and histopathology
Monosodium urate monohydrate (MSU) crystal depos-
itions (called tophi from the Latin word tofus, porous
stone) in joints (cartilage, synovial membranes and ten-
dons) and in other soft tissues are hallmarks of chronic
gouty arthritis. In inter-critical periods, they appear as in-
dolent nodules, which are difficult to differentiate from
rheumatoid nodules and other types of subcutaneous
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Tendinopathy and metabolic disorders
nodules. Gout is diagnosed with certainty upon the finding
of MSU crystals. Evaluated via polarized light microscopy,
these crystals are typically needle-shaped and negatively
birefringent, whereas calcium pyrophosphate dehydrate
crystals (pseudogout) are weakly positively birefringent
and more rectangular than MSU crystals. Specific diag-
nostic sonographic features include a hyperechoic, irregu-
lar band over the superficial margin of the articular
cartilage described as a double contour sign; hypoechoic
to hyperechoic, inhomogeneous material surrounded by a
small anechoic rim represents tophaceous material [65].
An increase of blood flow surrounding MSU deposits
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using power Doppler has been described as an indicator
of inflammatory activity [66]. The histopathological equiva-
lent of the anechoic rim is the tophus wall, formed by
macrophages, lymphocytes and large foreign body giant
cells.
Gouty arthritis is predominantly a disease of the lower
extremities. The toe is the most common site of initial in-
volvement, followed in order of frequency by the ankles,
heel, knee, wrists, fingers and elbows. Gouty bursitis also
occurs, and the pre-patellar and olecranon bursae are the
most commonly involved sites.
Interestingly, urate deposits in tendons and the syno-
vium and the prevalence of patellar and Achilles entheso-
pathy (15% vs 1.9%; P = 0.0007) occur more frequently in
subjects with asymptomatic hyperuricaemia than in
asymptomatic, normouricaemic individuals [9, 67].
Pathogenesis
The mechanisms of MSU deposition have been eluci-
dated. In vitro studies show that when serum uric acid
levels reach approximately 7 mg/dl, MSU crystals begin
to precipitate. However, the in vivo threshold of precipita-
tion depends on several biological factors. Traumas,
mechanical stress and lower temperature favour MSU
precipitation and explain the frequent localization of
tophi in the first metatarsal–phalangeal joint and the
helix of the ear. Poor blood supply also plays a role, as
shown by the preferential deposition in tissue with little or
absent vascularization (tendon, ligaments and cartilage).
Other factors that can contribute to the decreased solu-
bility of sodium urate and crystallization are alterations in
the extracellular matrix, which lead to an increase in non-
aggregated proteoglycans, chondroitin sulfate, insoluble
collagen fibrils and other molecules in the affected
joint [54].
Chronic cumulative urate crystal deposition leads to
tophi formation. Tophi are usually walled off, but
microtrauma-related changes in the size and packing of
the crystal may loosen tophi from the organic matrix. This
activity leads to crystal shedding and facilitates crystal
interaction with residential inflammatory cells, leading to
an acute gouty flare. A variety of inflammatory mediators,
such as IL-1b, chemokines and PGs, are released. A
number of factors have been identified to explain the
self-resolution of the acute attack: crystal dissolution
or coating with proteins, neutrophil apoptosis, the
inactivation of inflammatory mediators and the release of
603
Michele Abate et al.
anti-inflammatory mediators. As for cholesterol, it
is highly probable that microscopic deposition of MSU
crystals can occur in tendons, followed by low-grade
persistent inflammation that causes chronic tendon de-
generation [67].
Obesity
Clinical observations
Adiposity is a well-known risk factor for tendinopathies [7].
Load-bearing tendons, such as the Achilles and patellar
tendons, are more frequently affected, and plantar fasciitis
is commonly observed [28, 68–70]. Recently adiposity
has also been recognized as a risk factor for tendinopathy
in non-load-bearing tendons. A positive correlation has
been found between increasing adiposity and rotator
cuff tendinopathy [71], and obesity has also been shown
to have a negative impact on the functional outcomes
after arthroscopic rotator cuff repair surgery [72].
Further studies have shown that the probability of
tendon abnormalities is higher in males with an increased
waist circumference (74% in subjects with a waist
circumference >83 cm vs 15% in males with a waist
circumference <83 cm). In a population-based study,
asymptomatic Achilles tendon pathology was associated
with central fat distribution in men and peripheral fat dis-
tribution in women. It has been hypothesized that in men
Achilles tendon pathology is linked to metabolic syn-
drome, whereas in women oestrogens may prevent the
central accumulation of adipose tissue [73]. In another
study, Gaida et al. [74] observed that subjects with symp-
tomatic Achilles tendinopathy had higher triglyceride
levels (P = 0.039), lower HDL cholesterol (HDL-C)
(P = 0.016), higher triglyceride/HDL-C ratio (P = 0.036)
and further elevated apolipoprotein B concentration
(P = 0.017) compared with controls matched for gender,
age and body mass index. Typically this pattern of dysli-
pidaemia is displayed by individuals with insulin resist-
ance and is common in those with metabolic syndrome.
Pathogenesis
Prevailing hypotheses of tendon damage in obese sub-
jects are associated with two different mechanisms: the
increased yield on the load-bearing tendons and the
biochemical alterations attributed to systemic dysmeta-
bolic factors.
Indeed, weight-bearing tendons are exposed to higher
loads with increasing adiposity, and the higher loads lead
to overuse tendinopathy. Alternatively, the systemic hy-
pothesis is based on studies showing that the association
with adiposity is equally strong for the non-load-bearing
and load-bearing tendons [74].
Adipose tissue is now recognized as a major endocrine
and signalling organ. In obese subjects, adipose tissue
releases bioactive peptides and hormones; the adipoki-
nome includes a full range of proteins such as chemerin,
lipocalin 2, serum amyloid A3, leptin and adiponectin [75].
These proteins influence several activities in various mes-
enchymal cell phenotypes (tenocytes, chondrocytes and
604
osteocytes), which may directly modify tendon structure.
In particular, adipokines are able to modulate cytokines,
prostanoids and MMP production [76, 77].
The persistently raised serum levels of PGE2, TNF-a
and LTB4 observed in obesity and in subjects with
impaired insulin sensitivity provide supplementary evi-
dence that a systemic state of chronic, subclinic,
low-grade inflammation is present in these conditions
and may act as a prolonged disruptor of tendon homeo-
stasis [78–81].
Moreover, the migration of immune cells, such as
macrophages and mast cells, into adipose tissue is asso-
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ciated with a decrease in the circulating levels of these
cells. As a consequence, the release of pro-fibrotic fac-
tors, such as TGF-b, is reduced, and this may have a
detrimental effect on tendon healing, especially if the pro-
duction of Type I and III collagen is also reduced [81, 82].
In subjects with visceral fat, the cluster of metabolic
abnormalities is considered the consequence of insulin
resistance [73]. Elevated insulin concentrations fail to
stimulate increased glucose uptake into muscle, which
leads to fasting hyperglycaemia, impaired glucose toler-
ance and eventually Type II diabetes mellitus. Therefore
AGE formation is increased in obesity.
So, it is evident that obesity and diabetes share
common pathogenetic pathways characterized by
increased cross-linking between collagen fibrils mediated
by AGEs and low-grade inflammation, both of which amp-
lify the deleterious effect of tendon overuse (Fig. 2) [73].
Interestingly, ultrastructural studies demonstrate that
genetically obese Zucker rats have a relative prevalence
of larger collagen fibrils as a consequence of excessive
covalent cross-links. Consequently, the fibril diameter
shows unimodal distribution, in contrast with the bimodal
pattern observed in regularly exercised lean animals.
Because thin fibrils confer greater elasticity to tendons,
the relative lack of these fibrils in obese animals could
be responsible for increased stiffness and microruptures
as a consequence of excessive exercise [83].
Congenital metabolism disorders
Tendon abnormalities have also been described in some
inherited metabolism disorders.
Alkaptonuria is a rare inborn metabolic disease caused
by a deficiency of the enzyme homogentisic acid oxidase,
which is involved in the metabolism of homogentisic acid,
a metabolic product of the aromatic amino acids phenyl-
alanine and tyrosine. The homogentisic acid accumulates
in the fibrillary collagens and binds to them irreversibly,
becoming polymerized to form a dark pigment, which
confers a characteristic ochre or yellow appearance to
connective tissues (ohcronosis). The accumulation of
homogentisic acid inhibits collagen cross-linking, leading
to a reduction in the structural integrity of collagen, thus
increasing the likelihood of spontaneous rupture [84].
By the fourth or fifth decade, the disease usually pro-
gresses from simple alkaptonuria (characterized by dark
urine caused by homogentisic acid and without symp-
toms) to alkaptonuric arthropathy in approximately 30%
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of subjects [10]. Achilles and patellar tendons are more
frequently affected; they appear yellow or brown, defibril-
lated and degenerated, mainly at the site of the tendon’s
insertion into bone (enthesis). Ruptures, frequently spon-
taneous, occur in about 20–30% of cases [85, 86].
Hyperuricaemia is a well-known consequence of
glucose-6-phosphatase deficiency, the enzymatic abnor-
mality that characterizes glycogen storage disease. Gouty
tenosynovitis is a very rarely occurring manifestation of
this congenital disease [87].
Finally, for the sake of thoroughness, it must be noted
that increased tendon collagen cross-linking by non-
enzymatic galactosylation has been observed in cases
of congenital hypergalactosaemia. However, to our know-
ledge, no clinical tendinopathies have been described in
this disease [88].
Conclusions
Ample evidence shows that metabolic disorders have
deleterious effects on tendons and favour tendon degen-
eration. This observation has relevant clinical implications.
Subjects with diabetes or who are overweight, particularly
young people practicing sport activities, should maintain
adequate dietary regimens and pharmacological treat-
ments to achieve a proper body weight and metabolic
control. Because physical exercise is an important thera-
peutic measure, the program of physical activity should
be individually prescribed; indeed, an excess of exercise
could favour tendon degeneration.
Subjects who participate in sports that selectively over-
load some tendons (e.g. running) should be monitored
more frequently. Orthopaedic surgeons must be aware
that when a dysmetabolic condition is present, the healing
of fractures is delayed, the osseointegration of autologous
bone grafts is sometimes unsatisfactory and post-surgery
complications are more frequent. Therefore the treatment
of diabetes, obesity, hypercholesterolaemia and hyperur-
icaemia before and after orthopaedic surgery is manda-
tory to minimize negative outcomes and to reduce the
length of hospital stay.
In subjects referred to orthopaedic observation for
tendinopathies or tendon tears, the possibility of undiag-
nosed hypercholesterolaemia, diabetes or glucose intoler-
ance should be considered. Finally, the treatment of
dysmetabolic risk factors could be an additional strat-
egy to slow the progression of asymptomatic
tendinopathies.
Rheumatology key messages
. Tendon degeneration is often caused by metabolic
disorders (e.g. diabetes, hypercholesterolaemia,
hyperuricaemia and obesity).
. Proper control of diabetes, obesity, hypercholes-
terolaemia and hyperuricaemia could minimize
negative effects on tendons.
. Hypercholesterolaemia, diabetes or glucose intoler-
ance should be considered when treating subjects
affected by tendinopathies.
www.rheumatology.oxfordjournals.org
Tendinopathy and metabolic disorders
Acknowledgements
All authors participated in the work and agreed to the
submission of the paper to the journal.
Disclosure statement: The authors have declared no
conflicts of interest.
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Clinical vignette
T-cell lymphoma manifesting as a uvular mass
A 54-year-old woman had a 5-year history of RA on regu-
lar medication presented with a 3-month history of swel-
ling in her throat and muffled voice. Physical examination
revealed a uvular mass (Fig. 1A). CT showed an ill-defined
mass in the oropharynx (Fig. 1B) and small enhancing
cervical lymph nodes. Oropharyngeal biopsy identified
the mass as a malignant T-cell lymphoma. Whole-
body PET showed increased fluorodeoxyglucose uptake
in the oropharynx and cervical lymph nodes. She
achieved partial remission after three courses of cyclo-
phosphamide + hydroxydoxorubicin + oncovin + predni-
sone (CHOP) chemotherapy but died of sepsis before the
fourth course.
Several autoimmune diseases, including SS, SLE, cryo-
globulinaemia and RA, are associated with an elevated
risk of lymphoma development [1]. Peripheral T-cell
lymphoma is aggressive with a high relapse rate despite
the currently available chemotherapies. More than half
of extranodal head and neck lymphomas occur in
Waldeyer’s ring, and those expressing T-cell markers
arise predominantly in the paranasal sinuses and nasal
cavity. Oropharyngeal involvement from peripheral T-cell
lymphoma is extremely rare.
Disclosure statement: The authors have declared no
conflicts of interest.
Wen-Sen Lai1,2, Chih-Hung Wang1 and
Cheng-Ping Shih1
1
Department of Otolaryngology–Head and Neck Surgery,
Tri-Service General Hospital, National Defense Medical
Center, Taipei and 2Department of Otolaryngology–Head and
608
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1991;40:1049–56.
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Rheumatology 2013;52:608
doi:10.1093/rheumatology/kes372
Advance Access publication 22 December 2012
FIG. 1 The appearance of uvula and CT of the neck in a
patient with T-cell lymphoma.
(A) A uvular mass (arrow) was noted by visual inspection.
(B) Contrast agent-enhanced CT of the neck showed a
heterogeneous mass measuring 3.1 cm in diameter
(arrow).
Neck Surgery, Taichung Armed Forces General Hospital,
Taichung, Taiwan.
Correspondence to: Cheng-Ping Shih, Department of
Otolaryngology–Head and Neck Surgery, Tri-Service General
Hospital, 325 Cheng-Kung Road, Sec. 2, Neihu District, Taipei
114, Taiwan.
E-mail: zhengping@mail.ndmctsgh.edu.tw
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