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Silvio Danese,
Stefano Semeraro, Alfredo Papa, Italia Roberto, Franco Scaldaferri,
Giuseppe Fedeli, Giovanni Gasbarrini, Antonio Gasbarrini, Department of Internal Medicine, Catholic University
School of Medicine, L.go Vito 1, Rome 00168, Italy
Supported by an unrestricted grant from Fondazione Ricerca in
Medicina
Correspondence to: Silvio Danese, MD, Department of Internal
Medicine, Catholic University School of Medicine, L.go Vito 1, Rome
00168, Italy. sdanese@hotmail.com
Telephone: -39-3392318230 Fax: +39-06-97606741
Received: 2005-04-25 Accepted: 2005-06-18
Abstract
Inflammatory bowel diseases (IBD) can be really considered to be
systemic diseases since they are often associated with
extraintestinal manifestations, complications, and other autoimmune
disorders. Indeed, physicians who care for patients with ulcerative
colitis and Crohn’s disease, the two major forms of IBD, face a new
clinical challenge every day, worsened by the very frequent rate of
extraintestinal complications. The goal of this review is to provide
an overview and an update on the extraintestinal complications
occurring in IBD. Indeed, this paper highlights how virtually almost
every organ system can be involved, principally eyes, skin, joints,
kidneys, liver and biliary tracts, and vasculature (or vascular
system) are the most common sites of systemic IBD and their
involvement is dependent on different mechanisms.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Crohn's disease; Ulcerative colitis; Inflammatory
bowel disease
Danese S, Semeraro S, Papa A, Roberto I, Scaldaferri F, Fedeli G,
Gasbarrini G, Gasbarrini A. Extraintestinal manifestations in
inflammatory Bowel disease. World J Gastroenterol 2005;
11(46): 7227-7236
http://www.wjgnet.com/1007-9327/11/7227.asp
INTRODUCTION
Inflammatory bowel diseases (IBD) can be really considered to be
systemic diseases since they are often associated with
extraintestinal manifestations, complications, and other autoimmune
disorders. Indeed, physicians who care for patients with ulcerative
colitis (UC) and Crohn’s disease (CD), the two major forms of IBD,
face a new clinical challenge every day, worsened by the very
frequent rate of extraintestinal complications. Virtually almost
every system can be involved, principally eyes, skin, joints,
kidneys, liver and biliary tracts, and vasculature (or vascular
system) are the most common sites of systemic IBD and their
involvement is dependent on different mechanisms.
Extraintestinal IBD-related immune disease can be classified into
two major groups: the first one includes reactive manifestations
often associated with intestinal inflammatory activity and therefore
reflecting a pathogenic mechanism common with intestinal disease
(arthritis, erythema nodosum, pyoderma gangrenosum, aphthous
stomatitis, iritis/uveitis)[1,2] (Table 1); the second
one includes many autoimmune diseases independent of the bowel
disease that reflect only a major susceptibility to autoimmunity.
They are not considered (apart for primary sclerosing cholangitis)
as specific IBD features but only as autoimmune associated diseases
such as ankylosing spondilitis, primary biliary cirrhosis, alopecia
areata, and thyroid autoimmune disease and others[1]
(Table 2).
Table 1 Major
extraintestinal immune-related manifestations of IBD
Table 2
Autoimmune disorders associated to IBD
Moreover, many extraintestinal complications due to metabolic or
anatomical abnormalities caused directly by IBD have been reported
frequently and include osteoporosis, biliary and urinary lithiasis,
and anemia (Table 3).
Table 3
Extraintestinal complications in IBD and principal pathogenetic
mechanisms of arthritis
Aim of this paper is to review the pathogenic mechanisms, frequency,
features, and therapy of the major IBD-associated extraintestinal
manifestations.
Pathogenesis of immune-related extraintestinal manifestation in IBD
Extraintestinal immune-related manifestations in IBD are directly
dependent on intestinal disease, often coexist in the same patients
and have probably the same, even if not completely clarified,
pathogenesis[2]. Evidence coming from many studies in
genetically susceptible animal models of colitis suggests the
crucial role of enteric flora in activating the immune system
against bacterial antigens and contemporary against colonic mucosa
on the basis of an antigenic cross-reactivity (“antigen mimicry”)[3].
The sharing of these colonic antigens by extraintestinal organs,
associated with a genetic susceptibility, would finally lead to an
immune attack to these organs[2]. One of the best example
is represented by primary sclerosing cholangitis occurring in UC: in
a subset of patients, the presence (in sera and colonic mucosa) of
anti-colonic mucosa auto-antibodies that cross react with biliary
epithelium has been identified[4]. Furthermore, recently
a colonic epithelial protein (CEP) and the human tropomyosin isoform
5 (hTM5), which are not only expressed in the colon but also in the
biliary tract, skin, eyes, and joints, have been suspected to be the
major common targets of autoimmune attack in extraintestinal organs
of IBD patients being IgG1 specific auto-antibodies identified in UC
patients presenting multiple extraintestinal manifestations[5].
It remains unclear why the extraintestinal organs are not always
involved at the same time and why these auto-antibodies are absent
in colonic CD. A partial explanation is that genetic factors or
local co-existent damage factors (infections, trauma) could regulate
the display of cryptic antigens and the susceptibility to autoimmune
attack[2].
According to the previously explained mechanism, we can identify an
immune induction site, where T cells are primed, represented by the
colon and the effectors sites that are the extraintestinal organs.
Immune cells infiltrate the effectors sites (where they will
proliferate) with the help of adhesion molecules (α4β7 integrin,
vascular adhesion protein 1) that have a cytokine-mediated
overexpression in specific tissues[6].
It is interesting how autoimmune attack can happen many years after
the removal of the colon. In the case of primary sclerosing
cholangitis (PSC), probably memory lymphocytes that have been primed
in the bowel can recirculate for many years also even after the
removal of the colon without causing damage until the occurrence of
a stimulus in the liver that activates inflammation with the
overexpression of adhesion molecules (MAdCAM and CCL 25) and
consequent persistent lymphocytes recruitment[7].
Interference with adhesion molecules could be useful in the
treatment of extraintestinal manifestation as it has already been
shown for the intestinal inflammatory activity[8].
Genetic susceptibility
Extraintestinal manifestations have certainly a familial
predisposition (83% of concordance between siblings)[9]
and this suggests the existence of a strong genetic influence
leading to the identification of many suspected predisposal genes.
HLA system is considered as one of the major genetic markers
associated with IBD and extraintestinal manifestations, probably a
specific and appropriate antigen presentation that leads to
autoimmune reaction in particular predisposing conditions.
It has been reported that UC patients who display HLA-B8, DR3
phenotype have a 10-fold higher risk of primary sclerosing
cholangitis[10].
Moreover, UC patients who have HLA DRB1*0103 (DR103) have a higher
risk of ocular and articular manifestations[11] and
patients with HLA-B*27 and B*58 have a higher risk of uveitis
(Orchard TR 2002). HLA-B*27 is strongly associated with ankylosing
spondylitis (AS) being present in 90% of these patients but it seems
not to be significantly associated with IBD; anyway IBD patients
with HLA-B*27 positiveness have a higher risk to develop AS and IBD
patients with axial articular involvement are HLA-B*27 positive from
25% to 75%[12]. The polymorphism -1031 C TNF-α has been
associated with erythema nodosum in IBD patients[13]. It
is possible that HLA genes interfere actively in the pathogenesis of
IBD-extraintestinal manifestations or that are in linkage
disequilibrium with other really responsible unknown genes.
Moreover, caspase-activation recruitment domain containing protein
15 (CARD15), a gene found in association with ileocecal CD with a
potential role in the bacterial handling, has been recently
associated with sacroiliitis even if previous results did not agree[14].
Joint involvement in IBD
Inflammatory arthropathies are the most common extraintestinal
manifestations in IBD patients with a prevalence ranging between 7%
and 25%[1,12]. Articular and musculoskeletal manifestations are
included in the spondyloarthropathies (SpAs) that are a group of
seronegative autoimmune related disorders with common
characteristics including: ankylosing spondylitis, reactive
arthritis, psoriatic arthritis, inflammatory bowel disease, some
forms of juvenile arthritis and acute anterior uveitis[15].
Articular involvement (peripheral or axial) can precede, be
synchronous or begin afterward the diagnosis of IBD, it is
characteristically pauciarticular, asymmetrical, transitory,
migrating, prevalently non deforming. The axial involvement can vary
from asymptomatic sacroiliitis to inflammatory lower back pain to
ankylosing spondylitis (that occurs in 3% of IBD patients)[1].
It is interesting that the high incidence of asymptomatic
sacroiliitis (varying from 10% to 52%)[16,17,18] and on the other
hand the equally high incidence (about 50%) of characteristic
inflammatory low back pain in the absence of radiological findings
in IBD patients[12] indicating how history and physical examination
should be the diagnostic tools. Peripheral arthritis, different from
axial involvement, has a significant positive association with the
skin, mouth, and ocular manifestation; it happens more frequently in
CD (and particularly in colonic localization), often accompanies
intestinal activity ameliorating with IBD pharmacological or
surgical treatment[1]. In some patients, despite the amelioration of
gut inflammatory activity, articular disease persists[19].
Arthritis is often associated with enthesitis, tenosynovitis,
dactylitis that can also appear in the absence of arthritis[20];
typically they do not alter inflammatory markers and can compromise
deeply the quality of life.
Conventional treatment of inflamed joints include nonsteroidal
anti-inflammatory drugs and cyclooxygenase-2-inhibitor that should
be used for short-term period because of gastrointestinal side
effect and IBD reactivation risk[21,22] nevertheless at drug
suspension articular relapse can occur. Also local intra-articular
steroid treatment can be useful.
The majority of interventional studies included undifferentiated
spondyloarthropathies- or ankylosing spondilytis patients and no IBD
patients, so that the results can only be extrapolated.
Sulfasalazine has been shown to be effective in peripheral joint
disease in SpAs patients[23,24] and positive but limited results
have been obtained with methotrexate[25].
Interesting results have been obtained with anti TNF-α inhibitors in
resistant SpAs with IBD. In uncontrolled studies, infliximab has
shown efficacy in the treatment of SpAs in CD patients as induction
and maintenance therapy[26-28], also in the absence of acute phase
reactants and intestinal activity; there is also a reported case of
positive results in SpA associated with ulcerative colitis[29].
In limited reports (two cases) etanercept, that is ineffective in
IBD treatment[30], has given good results in the treatment of SpAs
associated to CD[31]. It is not clear at the moment the effect of
anti TNF-α therapies on articular damage evolution, certainly the
early recognition and appropriate treatment can help to limit the
patient’s inability.
Hepatobiliary disease
Hepatobiliary diseases are common in IBD patients; they can or
cannot be immuno-mediated and can also depend on side effects of
medications (see Table 4). Elevation of liver function tests have
been observed from 11% to 49% in IBD patients in observational
studies[32-34]. The most common immuno-mediated hepatobiliary
disease is primary sclerosing cholangitis (PSC) that is a chronic
cholestatic disorder characterized by inflammation and fibrosis of
the intrahepatic and extrahepatic bile ducts. It is more frequent in
male individuals, and the prevalence of IBD (mostly UC) in PSC is
about 70-80%[35]. Conversely about 2-7% of UC patients[35,1] and
0.7-3.4% of MC patients have a diagnosis of PSC[36,1]. Suggestive
symptoms of PSC are fatigue, pruritus, jaundice, and abdominal
discomfort but it is not rare that the isolate finding of
abnormalities in liver biochemical markers (first of all alkaline
phosphatase); in fact 15-70% of PSC patients are asymptomatic[37,1].
There are no specific auto-antibodies and so biopsy or
cholangiography is often necessary for the diagnosis. In PSC
patients, IBD frequently present some specific features: pancolonic
extension with rectal sparing, backwash ileitis, low intestinal
activity, and high pouchitis incidence after colectomy. These
distinguishing features have suggested the existence of an IBD-PSC
specific clinical phenotype[38]. It is well-known that the increased
risk of colonic dysplasia/carcinoma in PSC patients compared to the
general population (10-fold risk)[39] and to other UC patients[35]
it could depend on the long-lasting and asymptomatic colitis
(consequently often underestimated) and by alterations in bile salts
pool or folate deficiency. Similarly it has significantly increased
the risk of bile duct cancer[40] and metabolic bone disease[41,38].
PSC has a median survival time of 9-12 years from the time of
diagnosis; it seems that neither concomitant IBD presence nor
colectomy (in UC patients) alter its natural history. Moreover, the
colorectal cancer risk does not seem to be decreased after liver
transplantation[42].
Table 4 Drugs
and their possible adverse side effects
The therapeutic possibilities in PSC are limited; the best results
have been obtained with UDCA at a high dose (until 20 mg/kg)[43-45]
and the combined use of corticosteroids showed only a little
additive benefit[46,47].
The best clinical approaches to PSC include colonoscopic examination
with a biopsy to identify a possible asymptomatic UC and/or cancer
and a prevention colonoscopy program in patients identified to have
had UC. Association between primary biliary cirrhosis (PBC) and UC
is rare but possible and it has been reported in 15 cases; similarly
to the CSP it seems that colectomy does not alter the progression of
the hepatic disease[48].
Apart from classical immunological liver diseases in IBD patients,
they are often observed for other abnormalities. Liver enlargement
is the most common reported finding and is strictly related to
steatosis grade. Steatosis has been described in more than 30% of
patients and it does not seem to be related to the kind of IBD and
sex. Data about the influence of disease activity and
pharmacological treatment on steatosis are contradictory[49].
Also cholelithiasis is more frequent in IBD patients (about 10%)
than in the general population (7%) and mainly in CD (first of all
in ileal localization); it seems to correlate with female sex,
previous surgery (mainly ileal resection), and old age. In limited
series, it has been shown to be less often symptomatic than in the
general population[49]. Probably cholelithiasis is caused by bile
salt pool alteration for malabsorption.
Rare complications reported in literature are liver abscesses; it is
thought that in most cases portal bacteremia, favorite by mucosal
barrier alterations, can be the principal mechanism; rarely an
ascending acute cholangitis in PSC has been suspected to be the
cause[50]. Portal vein thrombosis and suppurative pylephlebitis has
also been described in rare cases[49].
Cutaneous manifestations
Cutaneous manifestations of IBD are relatively common. The incidence
varies from about 10% at the time of IBD diagnosis to more than 20%
in the course of the disease[1].
Skin lesions can be classified into three principal classes:
granulomatous, reactive, and secondary to nutritional deficiency.
Granulomatous cutaneous lesions have the same histological features
of the bowel disease and include: perianal and peristomal ulcers and
fistulas, metastatic CD, oral granulomatous ulcers.
Perianal disease is very frequent occurring in about 50% of CD
patients during their clinical history, and it varies from perianal
erythema to abscesses and perianal complex fistulae[51].
Other fistulae can be internal or entero-cutaneous; rarely develop
on the abdominal scar of laparotomy or at the umbilicus. Many
efforts have been made to treat fistulizing disease, and the
classical surgical approach has been supported recently by a larger
use of drugs. Antibiotics, azathioprine/mercaptopurine, tacrolimus,
thalidomide showed efficacy in uncontrolled studies[52] but at the
moment only infliximab showed effectiveness as induction[53] and
maintenance therapy[54] in phase III controlled trials; consequently
it has been approved as first line therapy in perianal and
enterocutaneous fistulizing CD by the United States Food and Drug
Administration (FDA) and the European Agency for the Evaluation of
Medicinal Products in Europe. Surgical procedures as colostomy in
the more severe cases of perianal fistulas, fistulotomy, abscesses
drainage, and non-cutting setons placement seem to be very useful,
and the combined medical and surgical approach is probably the best
one[55].
Metastatic CD is a rare complication defined as the occurrence of
specific granulomatous cutaneous lesions remote from the intestinal
disease[56]. It manifests as subcutaneous nodules or ulcers mainly
at the lower extremities with rare case of genital (testicular and
vulvar) localizations. It seems unrelated to the bowel activity.
Corticosteroids, antibiotics, azathioprine, methotrexate[57], and
more recently infliximab[58,59] have been used successfully.
The group of reactive skin manifestations of IBD includes aphthous
stomatitis, erythema nodosum, pyoderma gangrenosum, and the rare
Sweet’s syndrome.
Aphthous stomatitis is observed in about 10% of patients: it occurs
generally during active intestinal disease, often recurs and shows a
good response to intestinal treatment.
The prevalence of erythema nodosum in IBD is 3-8%. It appears more
often in women, in the colonic localization, in concomitance with
arthritis and active intestinal disease[1]; furthermore, there is a
positive response to proctocolectomy[42].
Histological examination shows lympho-histiocytic infiltrate of the
lower derma. On the basis of uncontrolled data, corticosteroids are
generally an effective therapy; also immunosuppressive therapy is
used[56]. Resistant cases have been treated effectively with
infliximab[60].
Pyoderma gangrenosum is a very debilitating ulcerating chronic skin
disorder occurring in about 1-2% of IBD patients. It occurs often on
the extensor surface of the legs, particularly in coincidence with
exacerbation of intestinal disease and in association with other
extraintestinal manifestations (arthritis and erythema
nodosum)[1,61]. Moreover, it is often associated with colonic
involvement and in UC patients it seems to benefit lesser than
erythema nodosum from colectomy[42].
According to disease severity, the treatment (based on
non-controlled evidence) can be local or systemic and includes a
high dose of oral or intralesional corticosteroids,
immunosuppressive/immunomodulatory therapy (cyclosporine,
tacrolimus, mycophenolate mofetil, azathioprine, dapsone)[61].
Infliximab has shown to be very effective in the refractory disease
and can be used as first choice therapy[59,62,63]; also etanercept
has been reported to be effective in a refractory case of pyoderma
gangrenosum[64].
Another rare cutaneous manifestation associated with IBD is the
Sweet’s syndrome. It is a neutrophilic dermatosis probably related
to pyoderma gangrenosum consistent with painful erythematous plaques
or nodules often associated with fever and leukocytosis that usually
responds to corticosteroids[65].
The more frequent nutritional-deficient cutaneous manifestation is
the acrodermatitis enteropathica; it is caused by zinc deficiency
and manifests as a psoriasis form erythema[61].
Furthermore, an association between autoimmune cutaneous disease and
IBD has been reported. The most frequent disease is psoriasis (7-11%
of IBD population vs 1-2% of general population) than vitiligo and
more rarely are polimyositis, lupus erythematosus and
scleroderma[66].
Ocular manifestations of IBD
Ocular manifestations occur in about 10% of IBD patients. They can
be immune-related (episcleritis, scleritis, uveitis, corneal
disease) or related to drug exposure (cataract, glaucoma).
Episcleritis manifests as acute redness, irritation, burning, tender
to palpation; if there is also an impairment of vision, the presence
of a scleritis is possible. In this case, a referral to an
ophthalmologist is mandatory for risk of vision loss. Uveitis can be
anterior and posterior and is often associated with joints and skin
manifestations. Anterior uveitis is the most common and presents
painful eye, visual blurring, and photophobia but can be also
asymptomatic and sometimes precedes the diagnosis of IBD.
Concomitance with IBD activity is typical for episcleritis and
uveitis[1,67].
Corneal disease (potential cause of perforation) has also been
reported; conjunctivitis is frequent in IBD population but probably
does not differ in frequency and etiologic factors from the general
population. Anyway it is important that the clinician is aware that
serious ocular disease can mimic conjunctivitis in IBD patients[67].
Ocular manifestations can benefit first of all by the treatment of
the underlying IBD (particularly for anterior uveitis and
episcleritis).
Treatment of ocular disease can prevent complications such as
retinal detachment or optic nerve swelling in scleritis and
secondary glaucoma and cataracts in uveitis.
Cycloplegics, NSAIDs, topical and systemic steroids are useful.
Immunosuppression can be necessary in case of scleritis;
sulfasalazine/mesalazine seems to prevent anterior uveitis
recurrence[67]. Recently infliximab has shown efficacy in acute
uveitis, in episcleritis, and scleritis[68,69]. Other rare reported
ocular manifestations of IBD are: retinitis, orbital IBD, retinal
arterial and venal occlusion, optic neuritis, retinal vasculitis,
marginal corneal disease, lid margin ulcers[70,67].
Metabolic osteopathy
IBD is also associated with an increased risk of osteoporosis and
osteopenia. The prevalence rates ranges from 2% to 30% for
osteoporosis and from 40% to 50% for osteopenia[71]. The risk of
fractures in IBD patients varies widely in different studies[72-74]
(from an OR of 1.41 to 2.5) the real impact being completely clear
on the IBD population; because of contrasting results, it is also
uncertain if the risk is comparable for UC and MC and for men and
women.
Osteoporosis occurrence is often underestimated as shown in an
observational study conducted in the UK[74] in which women aged 65
years with severe IBD have shown a 10-years probability of hip
fracture of 7%; nevertheless only 13% of patients who had already
sustained a fracture were in bone-sparing therapy.
Furthermore, a significant number of fractures in IBD patients (as
in the general osteoporotic population) are asymptomatic (14.2% in a
study of Stockbrugger) and many fractures will be underreported[75].
Bone loss and consequent fractures are certainly multifactorial
processes. They are significantly dependent on the age (above 60
years), the use of corticosteroids[74-76] and the grade of systemic
inflammation (intestinal disease activity correlates with the risk
of fracture)[74].
Recently the role of the inflammatory-induced osteopenia has been
revaluated and a surface receptor (RANK) localized on osteoclasts
that induces osteoclastogenesis has been identified. Its ligand
(RANKL) is induced by proinflammatory cytokines; its decoy receptor
that prevents ligation of RANKL to RANK is called osteoprotegerin
(OPG), and is produced by osteoblasts and prevents bone loss. Its
production is inhibited by corticosteroids and increased by
bisphosphonates. So OPG-RANKL-RANK system is certainly a pivot in
inflammatory-induced bone loss[77,78]. Initial therapeutical use of
recombinant OPG in inflammation-induced osteoporosis seems to be
promising[79].
On the basis of these findings, the role of nutritional deficiency
could be smaller than previously thought, as also shown in a
preliminary recent observational study that found low intake of
calcium (<1 000 mg/die) and vitamin D (<200 IU/die) in premenopausal
IBD women not to be a predictor of bone loss[80].
Other factors that could favor osteoporosis are the use of
corticosteroids, the hypogonadism, and the immobility.
Also genetic markers have been proposed as determinants of bone loss
in IBD patients. In the future, they could contribute to identify
high-risk patients and support clinical behavior[81].
Definition of a correct clinical approach is difficult because
therapeutic trials on IBD patients with the specific end-point of
fractures prevention are lacking and an extrapolation by the major
clinical trials on osteoporosis is difficult, since these studies
involve postmenopausal patients, certainly older than IBD patients
with osteoporosis.
A small randomized, placebo-controlled trial showed that alendronate
significantly ameliorates spine bone density compared with the
control group after 1-year-long therapy in IBD patients[82]. Also
azathioprine, effective on intestinal activity, seems to have
positive effect on bone loss retardation[83].
The expert recommendations on therapy, in the absence of more
specific evidence, do not significantly differ from that of the
general population. Supplementation of vitamin D for patients above
60 years, therapy with bisphosphonates in case of osteoporosis
(identified with densitometry), osteoporotic fractures and
chronically steroid treatment, use of minimum dosage of
corticosteroids (preferentially non-systemic), correction of early
menopause or male hypogonadism by hormone therapy have also been
reported[84,85]. Recently apart from OPG use, another osteoanabolic
substance, the parathyroid hormone 1-34, is under evaluation for the
steroid-induced osteoporosis[86]; in the future they could show
effectiveness in IBD osteoporosis. More efforts are yet to be taken
in the identification of high-risk patients and in the definition of
the most cost-effective clinical behavior in IBD patients.
Thromboembolism and IBD
Patients with IBD have a well-known increased risk (threefold higher
than in controls) of thromboembolism (TE), which is an important
cause of morbidity and mortality. The incidence ranges from 1.2% to
6.1% according to different studies and in necropsy studies it
reaches 39%[87].
Thrombosis accidents occur prevalently as deep vein thrombosis and
pulmonary thromboembolism; they happen in earlier age than in
non-IBD patients and are more frequent in active or complicated IBD;
the type of IBD and the sex seems not to influence thromboembolic
risk[87,88]. Using the logistic regression model, it has been found
that IBD is an independent risk factor for thrombosis that is a
specific IBD feature. In fact, other inflammatory chronic condition
as rheumatoid arthritis or chronic intestinal malabsorptive
conditions as celiac disease do not show an increased risk of
TE[87].
IBD patients have a frequent exposure to classical thrombosis risk
factors: immobility, surgery, steroid therapy, central venous
catheter, contraceptives/hormone substitution, smoke; nevertheless,
these risk factors do not explain the TE risk increase
completely[87].
It is well-known that in IBD patients there is not a completely
explained imbalance between coagulation and fibrinolysis in favor of
coagulation.
Active intestinal inflammation is not probably the unique risk
determinant since about 30-40%[87,89] of thrombosis occurs during
quiescence of the IBD and proctocolectomy has not shown a very clear
protective effect on recurrent venous thrombosis[90].
Also other factors have been claimed; hyperhomocysteinemia, a
well-known risk factor for venous and arterial thrombosis, occurs
more often in IBD patients than in the general population and seems
to be directly dependent by folate and vitamin B12 deficiency even
if there is not a complete concordance in literature[91-93].
The role of the inherited thrombophilia has been recently
reviewed[94]. The analysis has shown that the most frequent
prothrombotic genetic mutations (factor V Leiden mutation, G20210A
mutation in the gene of prothrombin, homozygous in the gene of
methylenetetrahydrofolate reductase) are not significantly
associated with IBD.
At the same time with the limit of a small number of subjects
participating in the studies, it seems that there is no difference
in the prevalence of genetic mutations in IBD patients with
thrombosis compared with non-IBD subjects with thrombosis. Anyway a
recent study comparing IBD patients with thrombosis and IBD controls
has revaluated the role of genetic factors finding a significant
higher prevalence of factor V Leiden in the thrombosis group (20% vs
0%)[95].
The data regarding the prevalence of antiphospholipid antibodies in
IBD are conflicting, but seem to suggest an increase frequency in
IBD. In limited series, the level of lipoprotein (A) has been found
to be higher than in controls[87]. No evidence exists about treating
thrombotic events differently than in non-IBD patients[87].
Conclusively many factors are suspected to play a role in the
thromboembolic increased risk of IBD patients but further studies
are necessary to identify their specific contribution.
At the moment in IBD patients the elimination of removable risk
factors is recommendable; in case of thrombosis probably is useful
to evaluate the thrombotic risk performing coagulation laboratory
parameters and genetic tests.
Anemia
Anemia is a frequent extraintestinal manifestation in IBD; about
one-third of IBD patients have hemoglobin levels below 12 g/dL[96].
The anemic state correlates strictly with the quality of life and so
is certainly an important problem in the therapeutic management of
chronic patients[97]. Multiple pathogenic mechanisms often coexist
in anemic patients leading to mixed features anemia. Chronic
intestinal bleeding with iron loss (due to bowel inflammation)
causes a hypochromic and microcytic anemia with associated
hypoferremia and hypoferritinemia; the chronic inflammatory disease
(typically characterized by hyperferritinemia) can cause anemia
through the proinflammatory cytokine-dependent diversion of iron
traffic to reticuloendothelial system and erythroid progenitor cell
development interference[98]. The same inflammatory cytokines are
able to inhibit erythropoietin production[99]. Recently, in vitro
anti-TNF-α factors showed positive effects in preventing apoptosis
of erythroid cells[100]. Other mechanisms implied in anemia are iron
malabsorption (in duodenum or upper jejunum disease CD), vitamin B12
malabsorption (in terminal ileum and gastric CD), and folate
deficiency (malabsorption, inadequate diet, and side effects of
sulfasalazine and methotrexate). Vitamin B12 and folate deficient
anemia is characteristically macrocytic. Myelosuppressive direct
effects have been reported frequently for
azathioprine/6-mercaptopurine and sometimes also for sulfasalazine
and 5-aminosalycilic acid[101]. Correction of the anemic state is
useful also in low-grade anemia. It is important to prevent and
treat intestinal flares that are often the cause of anemia and to
reintegrate the lacking of iron, B12, and folate.
In low-ferritin patients, prevention therapy with oral iron can be
sufficient; in overt anemia iron intravenous (preferentially iron
sucrose) supplementation should be preferred to oral route because
of major efficacy and no collateral intestinal side effect. Epo
therapy is useful in patients with no satisfactory response to iron
therapy alone[101]. Low levels of Epo, soluble transferring
receptors or transferrin have shown to predict iron sucrose
resistance[102].
Urinary system manifestations
IBD is a risk factor for renal immune and non-immune mediated
diseases.
The prevalence of nephrolithiasis in IBD varies from 2% to 6% and is
more frequent in CD than in UC[103]. Calcium-oxalate stones are the
most common and are caused by hyperoxaluria due to increased
intestinal absorption of oxalate. In fact in the bowel that does not
absorb fatty acids link calcium preventing calcium-oxalate
precipitation with the consequent increased absorbable oxalate
fraction. More than one lithogenic factors are often present in the
same patient, more frequently during active disease. The main
lithogenic risk factors are: low urinary volume, low urinary PH,
increased excretion of lithogenic substances as oxalate, phosphate,
uric acid, and decreased concentration of anti-lithogenic substances
as citrate and magnesium. Colectomy in UC and ileo-colonic resection
in CD seems to further increase the risk of lithiasis and oxalate
stone formation occurs mainly in ileal CD[104].
Periodic sonographic examination is recommended for early diagnosis
and for the prevention of complications. Furthermore, minimal signs
of tubular damage have been found in about 20% of IBD patients but
rarely they are clinically relevant[105].
A calculus uretheral obstruction, prevalently localized on the
right, is also possible and is related to the mechanisms of
adherence and compression by inflamed bowel (prevalently terminal
ileum)[103]. Urinary tract fistulas occur in about 1.7-7.7% of
patients. They can cause pneumaturia, dysuria, recurrent infections,
and fecaluria. At the moment in most cases, the non-satisfactory
response to medical therapy makes surgery the best option[106].
Clinical relevant renal amyloidosis has been reported in about 1% of
IBD patients (more frequently in ileal CD). It is probably related
to acute phase reaction proteins[107]. In IBD patients, cases of
glomerulonephritis causing nephrotic syndrome and renal failure have
also been reported. They are related to intestinal disease activity,
are quite responsive to IBD therapy and can present many patterns at
histology[108]. Moreover, it seems that mi nimal, clinically non
significant, glomerular inflammatory changes are quite frequent in
IBD patients as shown in a post mortem study (70% of subtle renal
lesions vs 8% of controls)[109] but following data do not exploit
this aspect.
Other rare extraintestinal manifestations
It has been reported in literature about the occurrence of other
rare extraintestinal manifestations of IBD, such as, chronic
recurrent multifocal osteomyelitis (CRMO), myositis[110],
polyneuropathy, Guillain-Barre syndrome[111], lymphocytic
encephalomyeloneuritis[112], myocarditis[113], and
pleuropericarditis[114].
Drug-induced side effects
Many drugs used in IBD treatment can cause side effects involving
various organs (Table 4). These effects that often need drug
interruption enter in differential diagnosis with extraintestinal
manifestations/complications of IBD; their early diagnosis is
facilitated by periodical serum analysis exploring liver,
pancreatic, renal, and hematological system integrity as for example
is recommended in methotrexate and azathioprine use[115].
Furthermore, the limited use to short period of other drugs can
prevent their effect as for example as it often happens for
corticosteroids (Table 4).
CONCLUSION
IBD is a systemic disease, since its clinical manifestations can
affect not only the bowel but also practically any other organ
(eyes, liver, osteoarticular system, kidneys, and so on) through
different (often not completely cleared) mechanisms. At the moment,
awareness of the high incidence of extraintestinal manifestations is
often inadequate. Therefore, prevention, early diagnosis, and
adequate treatment of these pathological conditions, sometimes more
dramatic than the intestinal disease, are necessary to increase
patients’ health. Clinical interventional trials in IBD patients
should consider these conditions with more attention to indicate the
best cost-effective method for clinicians.
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