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Introduction
Inflammatory bowel disease (IBD) mainly affects the
gastrointestinal system but is associated with various
chronic diseases of other organs that are jointly
called extraintestinal manifestations (EIM). In some
of these disorders, onset and clinical manifestations
are associated with the course of the intestinal dis-
ease while in others they are independent of the
intestinal disease. The former include peripheral
arthritis, erythema nodosum or aphthous ulcers and
episcleritis; the latter are pyoderma gangrenosum,
uveitis, spondylarthropathy and primary sclerosing
cholangitis (PSC). Other extradigestive-associated
diseases are represented by gallstones and
nephrolithiasis. Non-disease-specific complications
such as amyloidosis, osteoporosis and thromboem-
bolic complications are also common [1] (Table 1).
EIM are more common when the colon is inflamed,
i.e. in patients with Crohn’s disease (CD) of the colon
rather than small bowel involvement. EIM can
involve many organs, such as the skin, joints, eyes,
liver/biliary system and kidney. They significantly
influence morbidity and mortality of bowel disease,
so their treatment is of major importance in the
course of the intestinal disease [2].
Pathogenesis
Just as the pathogenesis of IBD is the result of a
genetic predisposition due to an altered mucosal bar-
rier and disrupted immune system in response to
environmental antigens, the development of EIM is
Extraintestinal Manifestations of Inflammatory Bowel
Disease
Giacomo C. Sturniolo, Michela Barollo, Renata D’Incà
Table 1. Extraintestinal manifestations of inflammatory bowel disease (IBD)
Musculoskeletal
Arthritis: ankylosing spondylitis, isolated joint involvement
Hypertrophic osteoarthropathy: colitic type, clubbing, periosteitis, metastatic Crohn’s disease
Miscellaneous: osteoporosis, aseptic necrosis, polymyositis
Skin and mouth
Reactive lesions: erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruptions, necrotizing
vasculitis
Specific lesions: fissures and fistulas, oral Crohn’s disease, drug rashes
Nutritional deficiency: acrodermatitis enteropathica (Zn), purpura (vitamins C and K), glossitis (vitamin B), hair loss and
brittle nails (protein)
Associated diseases: vitiligo, psoriasis, amyloidosis, epidermolysis bullosa acquisita
Hepatobiliary
Specific complications: primary sclerosing cholangitis and bile duct carcinoma
Associated inflammation: autoimmune chronic active hepatitis, pericholangitis, portal fibrosis and cirrhosis, granuloma
in Crohn’s disease
Metabolic: fatty liver, gallstones associated with ileal Crohn’s disease
Ocular
Uveitis (iritis), episcleritis, scleromalacia, corneal ulcers, retinal vessel disease
Metabolic
Growth retardation in children and adolescents, delayed sexual maturation
62 G.C. Sturniolo, M. Barollo, R. D’Incà
also multifactorial (Fig. 1). Though pathogenesis of
these manifestations has yet to be clearly understood,
it seems to be immunologically mediated and proba-
bly involves an autoimmune process. Studies on fam-
ilies support a role for genes in the expression of
EIM. The high prevalence of autoantibodies such as
perinuclear antineutrophil cytoplasmic antibodies
(p-ANCA) in PSC is suggestive of humoral immuni-
ty. Many studies have demonstrated that ulcerative
colitis (UC) patients have other associated autoim-
mune diseases more often than normal individuals
or CD patients, thus supporting the role of immunity
[3]. In a large population study conducted in Sweden,
21% of patients with UC had EIM that were found
correlated with the extent of colonic involvement.
Genetic susceptibility was also supported by the
higher prevalence of extracolonic manifestations in
familial UC [4]. Moreover, the positive effect of
immunosuppressants on many EIM substantiates the
hypothesis that immunity has a major part to play.
Many humoral and cellular abnormalities have
been found in patients with IBD [5]. The process
leading to EIM is little known, but the inflamed
colonic mucosa is probably the source of the immune
responses in the other organs [6, 7]. Studies on rat
models have pointed to the importance of mucosal
barrier dysregulation and the crucial role of enteric
bacteria in the onset of chronic inflammation of the
colonic mucosa. In the transgenic model of rat
expressing human leukocyte antigen (HLA)-B27,
arthritis and psoriasis develop together with colitis,
but in a germ-free environment, the animals develop
no such colitis or other manifestations, suggesting a
role for cross-reaction between colonic antigens and
joints and the essential role of bacterial flora and
genetic factors in disease induction [8, 9]. As for
humoral immunity, autoantibodies cross-reactive to
both colonic and biliary epithelium have been
demonstrated in patients with PSC and UC. The fac-
tors capable of causing an autoimmune response
include tissue damage, release of sequestered anti-
gens, increased major histocompatibility complex
(MCH) expression, ectopic expression of molecules
and dysregulation of cytokines. Autoantibody pro-
duction may also be triggered by molecular mimicry
[10–12].
The importance of genetic factors in the onset of
IBD with EIM has been demonstrated by familial
studies showing high concordance for EIM in sib-
lings with IBD [13]. In UC, HLA-DRB1*0103 has been
associated with joint and eye complications. P-ANCA
were reported in 59–84% of UC patients and 10–40%
of CD patients; they were also frequent (80%) in cases
of PSC and in 25% of family members of PSC
patients, thus suggesting genetic susceptibility
[14–16]. HLA-B27 is associated with the presence of
spondylitis in UC. Colonic epithelium does not
express class II MCH, but an aberrant expression has
been reported in the inflamed colon of IBD patients,
thus allowing presentation of autoantigens to T lym-
phocytes [17, 18].
Fig. 1. A Proposed model
for the pathogenesis of UC
and extraintestinal mani-
festations based on the dis-
tribution of “shared
autoantigens” (Modified
from [1])
Extraintestinal Manifestations of Inflammatory Bowel Disease 63
Joint Manifestations: Arthralgia,Arthritis and
Ankylosing Spondylitis
Peripheral arthralgia and arthritis are the most com-
mon EIM in IBD patients and are mainly reactive.
When the colon is inflamed, the prevalence of joint
manifestations in both CD and UC varies between
26% and 39% whereas in Crohn’s ileitis it is 8%. It has
recently been demonstrated that lymphocytes from
CD patients react with human synovia, thus confirm-
ing the importance of common antigens in the patho-
genesis of these manifestations [19].
Arthritis in IBD is usually pauciarticular and
asymmetrical, and it affects knees, ankles, wrists and
elbows while joints such as the hands and shoulders
are less involved. It has a migratory pattern and is
transient and generally nondeforming although it
may become chronic and erosive in 10% of patients
[20]. The onset of arthralgia usually parallels intes-
tinal disease activity whereas arthritis often develops
independently, and joint manifestations may precede
bowel disease by years [21].
Orchard distinguished between two types of
arthritis: type 1 involves fewer than five joints, is self-
limiting and associated with active bowel disease;
type 2 involves more than five joints and symptoms
persist for several months and independently from
the activity of the underlying bowel disease [22].
There is no increased incidence of HLA-B27 in these
two types. The presence of peripheral arthritis is fre-
quently associated with other EIM, such as erythema
nodosum and uveitis. Common blood markers of
arthritis are difficult to interpret when such joint
involvement is associated with IBD because there are
two different inflammatory events involved. In our
study, we evaluated human serum cartilage glycopro-
tein 39 (HC-gp39) in IBD patients with and without
arthritis. HC-gp39 was higher in IBD patients with
arthritis and correlated with the number of joints
involved. HC-gp39 might be a marker of arthropathy
in IBD and could also be proposed as a disease activ-
ity marker in arthritis associated with IBD [23].
Axial involvement includes sacroiliitis and
spondylitis and affects a smaller proportion of IBD
patients. Its onset is frequently insidious and its
course independent of the bowel disease, making it
indistinguishable from idiopathic ankylosing
spondylitis. The prevalence of axial involvement is
hard to estimate because a large number of patients
with radiographically diagnosed sacroiliitis are
asymptomatic, and it is hard to say how many will
progress to symptomatic disease [24]. In a recent
study, the prevalence of ankylosing spondylitis was
0.9% in UC and 1.2% in CD, but another study
reported rates of 1.6–7% in UC and up to 8% in CD.
Greenstein reported a prevalence of 3.8% in UC and
4% in CD, suggesting lack of predilection for either
disease [19]. In our experience, we analysed 100
sacroiliac joints of 50 IBD patients with inflammato-
ry back pain and found that 14% had no sacroiliac
joint alterations, 38% had minimal alterations, 16%
had monolateral sacroiliitis and 28% had ankylosing
spondylitis. These data confirm the relevance of axial
and peripheral joint symptoms in patients with IBD,
who need to be carefully evaluated [25].
Symptomatic disease has a clinical pattern identi-
cal to that of idiopathic disease. Patients develop low
back pain, especially during the night, followed by
morning stiffness and buttock, chest or neck pain.
The characteristic clinical signs are spine motility
impairment and chest expansion. The main feature
of axial involvement is that its onset and course are
independent of the bowel disease. HLA-B27 has a
high prevalence in ankylosing spondylitis (
90%)
while in patients with IBD and spondylitis, its preva-
lence varies from 50–75%. The simultaneous pres-
ence of HLA-B60 and HLA-B44 seems to increase the
patient’s susceptibility to axial involvement [26].
The approach to arthralgia and arthritis type 1 is
to treat the bowel disease flare. Controlling disease
activity with steroids leads to remission of joint man-
ifestations. When arthralgia is independent of bowel
disease activity, however, it should be treated with
paracetamol because nonsteroidal anti-inflammato-
ry drugs may activate and exacerbate the bowel dis-
ease [27]. Type 2 arthritis and ankylosing spondylitis
(the course of which is independent of the bowel dis-
ease) should be treated preferably with sul-
phasalazine. Many studies have demonstrated the
efficacy of this medication in patients with peripher-
al arthritis and, to a lesser degree, in spondylitis –
especially in the long term. The use of methotrexate
and 6-MP seems promising for controlling peripher-
al arthritis and spondylitis. In very severe and resist-
ant cases, infliximab has been used successfully, but
new randomised controlled trials are necessary [28].
Osteoporosis
Osteoporosis is a common skeletal health problem
characterised by low bone mass and bone
microstructural deterioration leading to bone fragili-
ty and susceptibility to fracture. Peak bone mass
depends on many factors, such as nutritional, hor-
monal, genetic and environmental factors. Vitamin D
and calcium absorption, and the consequent
parathormone levels, determine the degree of bone
loss. Low bone mass can derive from a diminished
bone formation/resorption ratio and/or increased
remodeling process. Bone mass is evaluated and
64 G.C. Sturniolo, M. Barollo, R. D’Incà
diagnosed by measuring bone mass density [29].
Bone mass density is measured in many different
ways, but the preferred method is dual energy X-ray
absorptiometry (DEXA), which measures X-ray
attenuation during its passage through bone. This
method is highly sensitive and can evaluate bone
mass in both cortical (radius) and trabecular (lumbar
spine) bone.
Criteria for assessing bone loss are expressed by
two densitometric parameters, called T and Z scores,
which are standard deviation scores expressed in
relation to reference values for young healthy sub-
jects (T score) and for gender- and age-matched
healthy controls (Z score). A review of studies using
DEXA demonstrated that osteopenia occurs in
40–50% and osteoporosis in 30% of patients with
IBD. Osteoporosis and osteopenia are also reported-
ly more frequent in CD than in UC [30]. A recent lit-
erature review showed that, in uncontrolled studies,
patients with IBD had a prevalence of severe dem-
ineralisation ranging from 18% to 42%. On the other
hand, larger studies including a healthy control
group showed a prevalence of severe bone mass den-
sity reduction in only 2–16% of IBD cases [31, 32].
Bone disease is of relevance in IBD, but most data in
studies on this issue are pooled from IBD clinics, so
the problem may be overestimated. Longitudinal
changes in bone mass in IBD patients were found
much the same as in the general population.
Osteoporosis in IBD is probably caused by many
factors, such as corticosteroid therapy, inflammatory
cytokines and malnutrition/malabsorption. Dinca et
al. evaluated the frequency and evolution of osteope-
nia in IBD patients and found that a low bone densi-
ty is frequent in both CD and UC but apparently
remains stable in CD. The evolution of bone mass
density suggests that a low bone density is associated
with the pathogenesis of CD whereas in UC, it seems
to be correlated with the effects of corticosteroids
[33].
Corticosteroids are an important cause of bone
demineralisation in IBD patients. They suppress
bone formation through a direct inhibitory effect on
osteoblasts, inhibiting growth factors, increasing
osteoblast apoptosis and accelerating bone resorp-
tion by reducing androgens and oestrogens and
increasing secretion of parathyroid hormone. They
also reduce intestinal calcium absorption and
increase its renal excretion. Corticosteroids cause
osteoporosis in 50% of treated patients, irrespective
of the disease involved. The role of corticosteroids is
hard to distinguish from the role of active inflamma-
tion. Bone loss occurs mostly during the first weeks
of treatment and persists throughout the treatment.
A study has demonstrated a 27% loss of bone mass
density after 1 year of treatment with prednisone [34,
35]. Many studies have demonstrated a direct corre-
lation between corticosteroid treatment and loss of
bone mass density. A recent large population-based
study showed that CD patients with fractures were
significantly more likely to have used corticosteroids
in the previous 2 years than those without fractures.
Patients with CD and osteoporosis were also more
likely to be on steroid treatment and at a higher
cumulative dose than patients without osteoporosis.
New bone formation is also reduced in IBD patients
treated with steroids [36].
Other steroids, e.g. budesonide, are rapidly
metabolised and poorly absorbed by comparison
with standard steroids such as prednisone, but a
recent study by Greenberg et al. demonstrated that
budesonide offered no advantage over low-dose
prednisone in terms of preserving bone mass densi-
ty, possibly due to its more limited effect on inflam-
mation [37]. Steroids are often prescribed for chil-
dren with IBD, and a study on 119 children with IBD
treated with corticosteroids at a dose of more than
7.5 mg/day for 12 months revealed a significant
reduction in their bone mass density. A similar study
reported that bone density of the lumbar spine was
lower the higher the cumulative dose of prednisone.
Other studies found no such bone loss correlating
with concurrent or past corticosteroid intake, howev-
er, and osteoporosis has also been observed in IBD
children who have never been exposed to corticos-
teroids.
Corticosteroids may be responsible for loss of
bone mass, but their use may also be indicative of a
more severe disease - which may be the real culprit
[38]. Therapy with corticosteroids is only one of the
many causes of bone loss in IBD. The inflammatory
condition is characterised by an increase in circulat-
ing cytokines, which increases osteoclast activity.
Tumour necrosis factor (TNF) alpha inhibits
osteoblast differentiation and induces osteoclast dif-
ferentiation, increasing osteoclast survival and
decreasing osteoclast apoptosis. A recent study
demonstrated that the TNF-receptor-based interac-
tion between osteoblasts and osteoclasts is the com-
mon pathway of bone metabolism alteration [39].
Although inflammation itself is an important cause
of bone metabolism alteration, malnutrition is com-
mon in IBD patients due to anorexia, malabsorption,
greater loss of nutrients and increased metabolic
demand. In some patients, calcium and vitamin D are
low due to a poor dietary intake and malabsorption,
and any reduction in these elements that are so
important to bone metabolism may contribute to
bone loss. Some studies on the weekly dietary records
of inactive CD patients showed they had a lower vita-
min D intake (1 µg/day) than the recommended daily
amount of 5 µg/day. Similarly, IBD patients had a
Extraintestinal Manifestations of Inflammatory Bowel Disease 65
lower calcium intake than healthy people, and the
active vitamin D levels were found significantly lower
in CD and UC patients than in healthy controls. In
CD patients with extensive ileal disease, bone loss
was related not only to vitamin D deficiency but also
with deficiency of vitamin-K-dependent proteins.
Among these proteins is osteocalcin, the function of
which is dependent on vitamin K; an altered gut
microflora and fat malabsorption can cause vitamin
K deficiency, which contributes to bone mass loss.
There are several pharmacological options for
treating osteoporosis and, since its course varies in
different patients and is not easily predictable, treat-
ment of the bowel disease itself could be a kind of
prophylaxis against bone disease, as inflammatory
cytokines play an important role in altering bone
metabolism [40]. Among treatment options for
osteoporosis in IBD, hormone replacement therapy
(HRT) has only been evaluated in an open study in
postmenopausal women with CD. HRT has been
shown to stop progression of bone loss in post-
menopausal women and increase bone mass density
in the long term although it does not seem to alter
patients’ fracture rate. HRT could be recommended
in postmenopausal women with CD providing they
have no contraindications, such as personal history
or strong family history of breast cancer.
Dietary supplementation with calcium and vita-
min D is one of the front-line therapies for prevent-
ing bone loss but is not enough in patients taking
corticosteroids (such as IBD patients). A randomised
controlled trial involving 103 patients comparing cal-
cium (1,000 mg/qd) and calcitriol (0.6 mg/qd)
showed that calcitriol prevented yearly bone loss
from the lumbar spine more effectively than calcium
alone [41]. Another study showed that long-term oral
vitamin D substitution was able to prevent forearm
bone loss in CD whereas in unsupplemented
patients, bone mass density decreased significantly
(7%). Combined calcium (800–1,000 mg) and vita-
min D (800–1,000 IU) intake increased lumbar spine
bone mineral density by 2.2–3.2% in the first year of
treatment.
Calcitonin is a nonsteroidal hormone that directly
inhibits osteoclast activity: its use seems to increase
bone mass by 4–5% and it is now available in nasal
sprays or rectal suppositories. It has not been
approved for glucocorticoid-induced osteoporosis,
however, and there are no published data available
on its efficacy in this IBD patient population [42].
Sodium fluoride has been found to increase bone
mass density in patients with CD, and its effect
increases over 2 years of treatment whereas calcium
and vitamin D supplementation is only beneficial in
the first year of treatment.
Bisphosphonates are the only effective therapy for
glucocorticoid-induced osteoporosis, and there are
different types of medication that bind tightly to
hydroxyapatite crystals in the bone and inhibit osteo-
clastic bone resorption. Recent meta-analyses
demonstrated that etidronate, alendronate and rise-
dronate increase bone mass density at the hip and
spine in a dose-dependent manner, and their use is
associated with a 30–50% reduction of vertebral frac-
tures. Alendronate and risedronate also reduce rates
of nonvertebral fractures both in women with osteo-
porosis and in adults with corticosteroid-induced
osteoporosis. The efficacy of bisphosphonates
beyond 1 year of treatment and on spinal fractures
remains to be seen, however. Similarly, a recent
review on etidronate demonstrated that it increased
bone mass density in the lumbar spine and femoral
neck, but the beneficial effect was only evident for
vertebral fractures [43].
Adequate use of corticosteroids and agents that
can facilitate their tapering are of fundamental
importance in prevention of osteoporosis in IBD
patients. The latter agents include: mesalamine,
which has been effective in reducing the number of
steroid-dependent CD patients, and azathioprine, 6-
mercaptopurine and infliximab, which are also effec-
tive in reducing the number of steroid-dependent
patients and treating refractory patients.
Many efforts have been made to reduce the use of
conventional steroids, which should be used while
maximising the use of other effective therapies to
contain the risk of severe osteoporosis and fractures.
Clinical evidence suggests that steroid dosage corre-
lates with bone mass density but not with fracture
risk and that ongoing steroid therapy only worsens
bone mass density in cases of UC. There are scant
data on the reversibility of these effects (only one
small study on patients after colectomy), and topical
steroids apparently offer no advantage because they
may be less effective in controlling inflammation.
The most important measures in managing osteo-
porosis are treating intestinal inflammation, identi-
fying patients with osteoporosis and promptly start-
ing adequate therapy. Bone mass density measure-
ments can be recommended at diagnosis and repeat-
ed every 2–3 years. In the event of osteopenia, or if
corticosteroids are needed, then preventive therapy
should be considered.
Skin Manifestations
Erythema nodosum (EN) and pyoderma gangreno-
sum (PG) are the most frequent cutaneous manifes-
tations among skin lesions [44]. EN is the most fre-
quent cause of inflammatory nodules in the lower
extremities and is associated with IBD in 11% of
66 G.C. Sturniolo, M. Barollo, R. D’Incà
cases. It occurs more often in UC than in CD, and it
is three to six times more frequent in women than in
men, with a peak incidence at the age of 20–30 years.
There are several conditions associated with EN.
EN develops in parallel with the colitis whereas PG
may be concomitant or subsequent, even developing
years after colectomy [45]. EN is characterised by
sudden onset of multiple, bilateral, symmetrical,
painful, red and warm nodules arising mainly on the
extensor surfaces of the arms and legs. These nodules
are often associated with systemic symptoms, such as
fever, malaise and joint pain. The typical course of
the disease lasts 3–6 weeks, but the residual bruise-
like lesions may last for months. As for the presence
of different EIM in the same patient (i.e. EN, anky-
losing spondylitis and uveitis), there are numerous
hypotheses to explain overlapping syndromes, one of
which is based on the assumption of a common anti-
gen, an isoform of tropomyosin, in the eyes, skin and
joints. The likely aetiology is a hypersensitive
response due to deposition of immune complex in
and around venules in the septa of connective tissue
in subcutaneous fat. Treatment for EN usually focus-
es on the underlying disease since EN usually
regresses when the bowel disease is brought under
control and recurs when it flares up. Corticosteroids,
5-aminosalicylates (5-ASA), azathioprine, cyclosporine
and other immunosuppressants are the main types of
medication used. Topical hydrocortisone can also be
used symptomatically. Supportive treatment
includes leg elevation, support stockings and bed rest
[46].
PG is a rare, destructive skin lesion characterised
by nodules and pustules, which can lead to formation
of ulcers with necrotic bases (Fig. 2). PG is seen in
1–10% of UC patients and 0.5–20% of CD patients. It
occurs equally in men and women, with a peak inci-
dence between 25 and 54 years of age. From 50% to
78% of patients with PG have underlying disease,
such as IBD, myeloproliferative or rheumatic disease.
PG has been described in four variants: ulcerative,
pustular, bullous and vegetative. Ulcerative and pus-
tular PG are associated with IBD [47]. The pathogen-
esis of PG has not been clearly explained as yet but is
probably due to a vasculitis caused by precipitation
of immunocomplexes. PG is sometimes quite diffi-
cult to treat, depending on severity of the skin lesions
and degree of bowel inflammation. In UC, appropri-
ate treatment for the colonic inflammation is impor-
tant, but neither medical nor surgical treatment can
guarantee results in terms of healing the skin lesions
[48]. It is now well established that topical treatment
is usually insufficient, even in association with sys-
temic treatment, so supportive treatment has to be
combined with systemic therapy. Although measures
to clean the lesions and prevent bacterial overgrowth
are important, in-depth debridement is not encour-
aged because it can cause new lesions. Topical 5-ASA
is not effective, and systemic 5-ASA has limited effect
in treating the associated intestinal disease. Steroids
are the most effective, first-line treatment for acute
PG. High intravenous doses are used for refractory
lesions. Initial doses range from 1 mg to 2 mg/kg per
day. Among the immunosuppressants, cyclosporine
and tacrolimus are effective in the treatment of PG. A
retrospective study reported that 11 steroid-refracto-
ry cases of IBD with associated PG rapidly healed
within 4–5 days of administering cyclosporine thera-
py, irrespective of intestinal disease activity; the
authors suggested using 6-mercaptopurine and aza-
thioprine as maintenance therapy and that long-term
azathioprine is useful in PG for its steroid-sparing
effect [49]. We reported on a case of PG refractory to
cyclosporine that rapidly responded to oral therapy
with tacrolimus (0.1 mg/kg per day), and the patient
remained in remission with azathioprine therapy
alone after discontinuing tacrolimus [50]. The effec-
tiveness of infliximab has been reported in many
studies. A recent randomised placebo-controlled
Fig. 2. A case of extended Pyoderma Gangrenosum (our
experience)
Extraintestinal Manifestations of Inflammatory Bowel Disease 67
study showed that it was superior to placebo in the
treatment of PG. Patients randomised to receive
infliximab were given a dose of 5 mg/kg weekly, and
by the second week, 46% had improved as opposed to
only 6% in the placebo group. There was no differ-
ence in outcome between PG patients with and with-
out associated IBD. Other retrospective studies
demonstrated the efficacy of infliximab in healing PG
skin lesions but found that patients often require
repeated courses of and had to be maintained on
infliximab [51–53]. A recent case report described
the efficacy of leukocyte apheresis (an extracorpore-
al leukocyte removal therapy) in a UC patient with
PG who achieved a rapid and sustained remission of
skin lesions [54].
Ocular Manifestations
Ocular manifestations include anterior uveitis, scleri-
tis and episcleritis. They occur in about 5% of
patients with UC; anterior uveitis is more frequent in
UC whereas milder ocular manifestations are more
frequent in CD. Rare ocular manifestations include
scleromalacia, cataract and retinal vessel problems.
Ocular complications are usually associated with
active bowel disease.
Diagnosis of uveitis is made by slit-lamp examina-
tion and is found in both eyes in 50% of cases. More-
over, uveitis is more frequent in UC patients with
other EIM, such as joint and skin lesions. Uveitis
needs prompt treatment to avoid scarring complica-
tions. The treatment of choice is topical corticos-
teroids associated with systemic corticosteroids, aza-
thioprine or cyclosporine. Colectomy has been
shown to induce remission of ocular disease in half
the cases. The effects of sulphasalazine are discour-
aging while the use of non-steroidal anti-inflamma-
tory drugs is limited by the risk of inducing recurrent
bowel disease [55, 56].
Hepatobiliary Complications
The incidence of hepatobiliary complications ranges
from 5% to 15% in IBD patients. These complications
include steatosis, cholelithiasis and PSC. An Italian
study reported an overall prevalence of hepatobiliary
alterations, e.g. steatosis and altered liver function
test results, in 12% of IBD patients. A recent study by
Bargiggia et al. reported gallstones, liver steatosis and
liver enlargement in about 55% of 511 IBD patients
undergoing abdominal ultrasound (Fig. 3).
Cholelithiasis is reportedly more frequent in
patients with IBD, and the risk of gallstones was
found increased in both CD and UC patients [odds
ratio (OR) 3.6 for CD and 2.5 for UC]. The risk was
also greater in patients with CD localised in the distal
ileum (OR 4.5) and in UC patients with pancolitis
(OR 3.3) [57]. In a study on 251 patients with CD,
Hutchinson et al. found a 28% prevalence of gall-
stones and the only independent risk factor was prior
surgery [58].
The most important and specific hepatobiliary
complication in IBD is PSC, reported in up to 10% of
patients, and 70–90% of PSC patients have associated
UC. The clinically most severe consequence of this
disease is increased risk of cholangiocarcinoma, the
incidence of which is around 15% [59]. PSC is a
chronic progressive disease of the biliary tree that
Fig. 3. Hepatobiliary
abnormalities identified
by ultrasonography in
IBD patients.
* p<0.001 vs. controls
§ p<0.016 vs. controls
(Modified from [57])
45
40
35
30
25
20
15
10
5
0
%
*
*
*
*
§
Steatosis Liver enlargement Gallstones
CD
UC
Controls
68 G.C. Sturniolo, M. Barollo, R. D’Incà
can involve both the intra- and the extrahepatic bile
ducts; it is characterised by duct strictures and dila-
tions and concentric fibrosis of the intrahepatic bile
ducts. Its clinical course does not parallel bowel dis-
ease activity, and it may progress in patients even
years after proctocolectomy. The pathogenesis of
PSC is still not clearly understood, but there is abun-
dant evidence that immune dysregulation plays a
crucial part in the development of this liver disease.
Different studies have reported changes in tissue
lymphocyte population, abnormal cytokine patterns
and aberrant expression of HLA class II molecules on
the bile duct epithelium. This provides indirect evi-
dence that PSC is an immune-mediated disease,
which causes immunological damage to the biliary
tree. PSC also has some features of autoimmune dis-
ease, such as presence of autoantibodies, association
with other autoimmune diseases and strong link with
the haplotype B8-DRB1*0301-DQB1*0201. The
mechanism by which immune tolerance is lost has
yet to be fully understood, however [60]. Genetic sus-
ceptibility to PSC has been investigated, and a num-
ber of studies have reported that a pattern of genetic
polymorphism is involved in generating the predis-
position to develop this disease.
As a possible explanation for the correlation
between intestinal and hepatic disease, some studies
have suggested that the initial event could be passage
of bacterial products through the inflamed mucosa
into the portal circulation. These bacterial products
could be cleared by hepatic macrophages, thus
inducing an immune response that causes peribiliary
duct fibrosis in a susceptible host. Another hypothe-
sis, that is better able to justify the clinical course of
the biliary disease, concerns the presence of entero-
hepatic circulation of lymphocytes between gut and
liver: mucosal lymphocytes produced as a result of
intestinal inflammation would remain as memory
cells, causing hepatic inflammation under certain
circumstances. This theory is supported by the find-
ing that certain lymphocyte homing receptors are
shared by the liver and gut [61]. Moreover, nitric
oxide (NO) synthase overexpression has been found
in biliary cell ducts in advanced PSC. Such synthase
overexpression is not induced by different proin-
flammatory cytokines, and it produces a large
amount of NO, resulting in production of reactive O
species. These highly reactive substances damage
many different cell functions and DNA repair
enzymes and, in the long term, chronic inflammation
may be responsible for the oncological complication
of PSC [62].
Diagnosis of PSC is often incidental during follow-
up of patients with IBD and, in most cases, patients
are asymptomatic but have altered liver function test
results. Symptoms of PSC include pruritus, fatigue,
right upper quadrant pain, jaundice and often
cholangitis. Only few patients present with symp-
toms of advanced liver disease or cholangiocarcino-
ma. Laboratory tests reveal cholestasis with
increased alkaline phosphatase values whereas liver
function test findings may be normal or fluctuate
during the course of the disease, becoming worse in
its advanced stages. Autoantibodies that have the
strongest association with PSC are p-ANCA, found in
33–88% of cases. PSC is diagnosed by finding stric-
tures and dilations of the intra- or extrahepatic bile
ducts on magnetic resonance (MR) cholangiopancre-
atography (which has proved as sensitive as endo-
scopic retrograde cholangiopancreatography)
(Fig. 4). Liver biopsy is also important to determine
the stage of liver disease, rule out any biliary dyspla-
sia and diagnose small-duct PSC. Small duct PSC
affects a subgroup of patients with altered liver func-
tion test results and histological changes typical of
PSC but with negative imaging tests. Recent studies
have reported a better course of this disease, with
only 12% of patients progressing to classical PSC and
no cases of cholangiocarcinoma. A study conducted
in Oslo reported that small-duct PSC is more fre-
quent in CD than in UC.
Treatment for PSC is based on specific agents,
such as immunosuppressants, antifibrogenic drugs
and ursodeoxycholic acid. Cholestatic complications
are treated with cholestyramine, ursodeoxycholic
acid (UDCA) and antihistamines. End-stage liver dis-
ease requires orthotopic liver transplantation [63].
UDCA is a hydrophilic bile acid widely used in
cholestatic liver disease. The positive effect of UDCA
has yet to be fully explained, but it probably contrasts
toxic effects of hydrophobic bile acids on hepatic
cells. Therapeutic actions of UDCA are:
1. protecting cholangiocytes by displacing
hydrophobic bile acid from the bile acid pool.
2. A choleretic effect that prevents retention of
potentially toxic biliary products in the liver.
3. An antiapoptotic effect via activation of epidermal
growth factor receptor and mitogen-activated pro-
tein kinases.
4. A potential immunomodulatory role on cytokine
secretion by monocytes.
Many trials have been performed to understand
the clinical efficacy of UDCA in the context of PSC,
and almost all demonstrated improvement in liver
function test findings while only the small trials by
Stiehl et al. and Beuers et al. and the high-dose trial
by Mitchel et al. have demonstrated improvement in
liver histology. All trials using a standard dose of
UDCA (13–15 mg/kg) failed to demonstrate any sig-
nificant effect on disease progression despite the pos-
itive effect on liver function test findings [64–66]. As
the biliary concentration of UDCA increases with
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