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A
lthough the gastrointestinal (GI) system and the lower extremities would seem
anatomically separate and distinct, it is not uncommon to encounter lower extremity
manifestationsofprimaryGIdiseases.Forexample,disordersofmalabsorptionmaypresent
withvitamindeficienciesthatleadtoneuropathiesorcutaneousfindings.Inaddition,primary
dermatologic findings on the lower extremities may be first presentations of inflammatory
boweldiseases(IBDs).Forthesereasons,itisimportantforphysicianstobeawareofthelink
betweentheGIsystemandthelowerextremities.ThischapterfocusesonprimaryGIdisorders
and their lower extremity manifestations, specifically neurologic, dermatologic, and
rheumatologicfindingsbecausethesewillbemostencounteredbyclinicians.
NEUROLOGICASSOCIATIONS
DisordersoftheGIsystem,includingluminaldiseasesofthestomachandbowel,aswellas
pancreatic andhepatic disorders, canlead to neurologic complicationsaffecting the central
nervous system (CNS) and the peripheral nervous system, both of which can present with
lowerextremityfindings.
IBDisachronicinflammatoryGIdiseasecomprisedofCrohndisease(CD)andulcerative
colitis(UC),whichcanaffecttheentireGItract,particularlythesmall andlargeintestines.
Thecourseforeachindividualpatientcanbehighlyvariable,andmanywiththediseasehave
relapsing andremittingdisease. The underlyingdrivingforce of thedisease is not entirely
understood,butone’senvironment,genetics,andimmunesystem(T1helpercellsinCDandT
2
helpercells inUC)allplayanimportantrole.Mostpatientspresent betweentheagesof15
and40.CDmaypresentwithabdominalpain,diarrhea,GItractobstruction,perianalfistulas
orabscesses,andweightloss.UCoftenpresentswithbloodydiarrhea,urgency,tenesmus,and
pain with defecation.1 Aside from GI-specific manifestations, IBD can be associated with
extraintestinal manifestations that can affect multiple other organ systems including the
nervous, dermatologic, vascular, orthopedic, and rheumatologic systems.2 Neurologic
involvementinIBDisoneaspectofextraintestinalmanifestationthatcanbeseeninpatients
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withIBD.Peripheralneuropathyisacommonneurologicmanifestation,andmayberelatedto
medications including metronidazole and anti–tumor necrosis factor (TNF) agents, vitamin
deficiencies,andimmune-mediatedchanges.
3
ThereportedincidenceofneurologicmanifestationsinpatientswithIBDisthoughttobe
approximately3%,4ofwhichtheprevalenceofperipheralneuropathyinparticularhasbeen
reportedtobe ashighas13.4%,5withrelativelycomparableincidence inpatientswithUC
andCD.Theseperipheralneuropathiesmaybesensory,motor,mixed,orautonomic.Theymay
be acuteor chronic, axonal or demyelinating, and mayhave variousdistributions.6 Patients
may also experience primary muscle involvement that may be confused with neuropathies;
these can includeinflammatorymyopathies, dermatomyositis, polymyositis, rimmed vacuole
myopathy,andgranulomatousmyositis.
3
Peripheral neuropathies inIBD are not typically related to disease activity, and do not
respond to treatment of the underlying IBD.3 The underlying pathology of peripheral
neuropathiesmaybeimmune-mediated,secondarymanifestationsofvitamindeficiencies(such
aslowvitaminB12orvitaminB6),ormedicationsideeffects(frommetronidazoleoranti-TNF
agents). Patients mayexperience malabsorption secondaryto surgical changes (e.g.,vitamin
B12 deficiency after ileal resections) or disease activity (ileal inflammation leading to
decreased vitaminB12 deficiency).7 Anti-TNF agents have been associated withperipheral
andcentraldemyelination,bothnewcasesandaggravationofoldcases.Natalizumab,whichis
an anti-integrin also approved for use in patients with IBD, has been associated with
progressive multifocal leukoencephalopathy (PML) in patients with John Cunningham (JC)
virus.
8
AnothernotableneurologicconditionassociatedwithIBDismultiplesclerosis(MS).MS
hasbeenmorefrequentlyassociatedwithUCthanCD.TheprevalenceofMSisincreasedin
patientswithconcomitantIBD.9Furthermore,patientswithIBDarealsomorelikelytohave
asymptomaticwhitematterlesions,althoughtheclinicalsignificanceofthesefindingsremains
unclear.10 The pathophysiology of this relationship is unclear, but likely is related to the
underlyinginflammatoryand immunologic pathology that drives bothMS andIBD.Notably,
anti-TNFagentsarecontraindicatedinpatientswithMS,astheyhavebeen associatedwith
newonsetofdemyelinationandaggravationofpreexistingdisease.
11
There have also been rare reports of fistulization from the rectum to the epidural and
subdural spaces, leading to abscess formation and subsequent nerve compression with
development of lower extremity weakness, pain, and other neurologic complications.
12,13
Although rare and uncommon, sudden onset of focal neurologic findings in the lower
extremitiesshouldtriggeranextensiveworkup,examiningforperipheralneurologicconditions
aswellasbrainandspinalcordpathology.
HepatitisCvirus(HCV)infectionisoneoftheleadingcausesofcirrhosis,withsignificant
morbidityandmortalityglobally.14Itisoftenasymptomaticinitially,butcanbecomeachronic
liver infection in over 80% of those infected with the virus.15 HCV can independently be
associated with peripheral neuropathy.16 Itis thoughtthat HCV cantrigger animmunologic
responseincludingproductionofantigangliosideantibodies(1and2),whichmayberelatedto
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the development of neuropathy.17 Individuals infected with hepatitis C may also develop
cryoglobulinemia, which ischaracterizedby significantcryoglobulins (proteinsthat become
insoluble complexes at cold temperatures) in the blood. Cryoglobulinemia can lead to
deposition of immune complexes in small and medium-sized vessels with vascular
inflammation, as well as mononeuropathy or mononeuropathy multiplex in 17% to60% of
patients.3Otherhepatitidesmayalsobeassociatedwithneurologicmanifestations.HepatitisA
virus(HAV)isanacute,oftenself-limitedhepatitischaracterizedbyjaundice,abdominalpain,
fever, nausea, vomiting, and diarrhea. HAV infection can rarely precede Guillain–Barré
syndrome (which most commonly presents with ascending paralysis of the lower
extremities).18 Hepatitis B virus (HBV) is responsible for both acute and chronic hepatitis
infections and may present with jaundice, abdominal pain, nausea, and vomiting. HBV
infectioncanrarelybeassociatedwithGuillain–Barrésyndrome,19aswellasmononeuropathy
multiplex and acute symmetrical vasculitic polyneuropathy (which presents as nonpalpable
purpura,andacute-onsetdistalsymmetricsensorimotorpolyneuropathy).
20,21
IntermsoftheCNS,multipleGIdisorders(includingIBD,HCVinfection,andcirrhosis)
have beenassociatedwithincreased riskof stroke.This maypresent with focal neurologic
deficits(isolatedmotororsensory,ormixed)inthelowerextremities.Forexample,patients
maypresentwithunilaterallowerextremityweakness,numbness,orgaitinstability.Clinicians
shouldhavealowthresholdtoruleoutacerebralvascularaccidentinindividualswhosuffer
fromoneoftheaforementionedGIdisordersandwhopresentwithfocalneurologicfindings.
Cirrhotics often have an imbalance of prothrombotic and antithrombotic factors that are
synthesizedbytheliver,whichcanmaketheseindividualspronetohemorrhageorincreased
clot formation.22 In thosewith IBD, the underlying mechanismdrivingan increased risk of
strokemaybesecondarytoasystemicinflammatorystate,leadingtoincreasedlevelsoffactor
V and VIII, fibrinogen, decreased levels of protein S and antithrombin, leading to a
prothromboticstate.Otherpossibletheoriesthathavebeenproposedtoexplainwhypatients
withIBDhaveanincreasedriskofclotformationincludeplateletdysfunction,increasedvon
Willebrandfactor,andincreasedlevelsofhomocysteine.3ThosewithIBDhaveanincreased
riskofbotharterialandvenousthrombi.
6,23
Autopsyrecordsestimateaprevalenceashighas
30%forthosewith UC,andtheincidenceofthromboticcomplicationsranges from 0.5%to
approximately7%peryear.24TheyarenotrelatedtothedurationortheseverityofIBD,but
cerebrovasculareventsaremorefrequentduringboutsofinflammation.Therehavealsobeen
casereportsofischemicstrokesthoughttobecomplicationsofanti-TNFαtherapy.Therehave
also been reportsofthrombosis ofthe dural sinus and cerebral veins, and this, perhaps,is
morecommoninthepediatricpopulation.
25,26
Acuteliverfailure(ALF,alsoknownasfulminanthepaticfailure)andcirrhosismayboth
be associated with encephalopathy, which can involve lower extremity findings.
EncephalopathyseeninALFis secondarytoastrocyteswellingandprogressiontocerebral
edema,withorwithoutherniation.27Incirrhosis,encephalopathyisoftenthoughttobedriven
byaccumulation oftoxinsnotcleared bytheliver,whichcanbe triggered byinfections,GI
bleeding,andconstipation;inthecaseofcirrhosis,encephalopathyisknownasportosystemic
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encephalopathy(PSE)orhepaticencephalopathy(HE).28EncephalopathysecondarytoALFor
cirrhosiscan manifestwithsubtlefindingssuchasmyoclonusorstarkchangessuchasfrank
coma with posturing.29 Although it would be rare to see isolated lower extremity
manifestations in these conditions, one should still be aware of evensubtle changes in the
lowerextremitiesasthesehelponerecognizeandgradethedegreeofHE.Withresolutionof
liver disease, one would expect resolution ofthe neurologic manifestations. Although rare,
afterseveralepisodesofPSE,cirrhoticpatientscandevelophepaticmyelopathy,oracomplex
movement disorder known as acquired hepatocerebral degeneration. Hepatic myelopathy is
caused by demyelination of the lateral corticospinal tracts and eventual axonal loss. It is
characterized by a subacute progressive bilateral lower extremity weakness and spasticity,
withminimaltonosensoryabnormalities.
30,31
Acquiredhepatocerebraldegenerationpresents
withparkinsonismofpredominantlylowerbodyinvolvement,posturalinstability,andcranial
dyskinesia; there may also be tremors, limb dystonia, and chorea.
32,33
In making these
diagnoses, one must be careful to rule out metabolic etiologies (including hypoglycemia,
hyponatremia), thiamine deficiency, as well as alcohol or recreational drug use. Patients
shouldalsoundergoaCTofthehead/braintoevaluateforevidenceofintracranialbleed,and
anMRItoruleoutanischemicevent.AnMRIcanalsobehelpfulinmakingthediagnosis,asit
mayrevealT1bilateralhigh-signalabnormalitiesinthepallidumandsubstantianigra,related
todepositionofmanganese.
34
Medications
Promotility agents (such as metoclopramide), which may be utilized for patients with
gastroparesis,hasbeenshowntoleadtothedevelopmentofextrapyramidalsideeffects,acute
dyskinesia,akathisia,tremor,parkinsonism,andtardivedyskinesia.35Anti-TNFagents(which
include infliximab, adalimumab, certolizumab, and golimumab), as described earlier, can
rarelycauseoraggravateanunderlyingperipheralorcentraldemyelinatingdisorder(including
peripheralneuropathiesandMS).Theycanbeassociatedwithdysesthesia,paresthesias,and
ataxia;thesesymptomsmayimproveafterdiscontinuationoftheoffendingagent.Natalizumab,
ananti-integrinagent,hasbeenshowntocausePMLviaactivationoftheJCvirusinthosewho
areinfected;thisusuallypresentswithdementiaorconfusion,butmayalsobeassociatedwith
motor weakness.Metronidazole, when usedforprolonged courses (suchas forClostridium
difficile infection or intra-abdominal abscess), can cause ataxia, tremors, and peripheral
neuropathy;theseoftenresolve afterdiscontinuationofthemedication.PatientswithIBDor
autoimmunehepatitismayalsobetreatedwithsteroidsatsomepointduringthecourseoftheir
disease, sometimes for prolonged periods of time; this may lead to a steroid-related
myelopathyandcanoccurwitheitheracuteorchronicuse.Onemayalsoseeproximalmuscle
wastingonphysicalexaminationwithlong-termsteroiduse.Cyclosporine,whichmaybeused
forsevereIBDrefractorytoothermedications,canalsocausetremorsandseizures.
6
DERMATOLOGICASSOCIATIONS
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GI manifestations in the lower extremities often involve both specific and nonspecific
cutaneous findings. IBDs may present with cutaneous manifestations as their presenting
symptom.Severalhereditarypolyposissyndromes(andfamilialcolorectalcancersyndromes)
are associated with cutaneous manifestations that one must be familiar with, as polyposis
syndromes may confer an increased risk of colorectal malignancy. Certain GI-related
malignanciesmayalsobeassociatedwithskinconditions.
Asmentionedearlier,thosewithIBDmaydevelopextraintestinalmanifestations,including
dermatologic conditions. Most commonly, these include erythema nodosum (EN) and
pyodermagangrenosum(PG).TheprevalenceofcutaneousmanifestationsforpatientswithCD
orUCisfairlysimilar(upto23%ofpatientswithCDand19%ofpatientswithUC).
36
EN is a septal panniculitis, typically affecting the extensor surfaces of the lower
extremities.ItisthemostcommoncutaneousmanifestationofIBD,occurringinapproximately
4% of all patients with IBD. Commonlyseeninyoung women with IBD,EN is thought to
reflecttheunderlyingdiseaseactivitywithinthegut.Treatmentisgearedtowardtreatmentof
theunderlyingGIIBDsymptoms.
37
PGis anotherdermatologic conditionthat is often associated with IBD;0.6%to2%of
patientswithIBDmaydevelopPG,37whereas20%ofPGcasesareassociatedwithIBD.38It
typicallyoccursatsitesofprevioustrauma(referredtoaspathergy).UnlikeEN,PGdoesnot
necessarily reflect disease activity in the gut. Treatment ranges from localized to systemic
therapies, and can include topical or intralesional corticosteroids, topical tacrolimus, anti-
TNFagentssuchasinfliximaboradalimumab,orsystemiccorticosteroids.
38,39
Cutaneouspolyarteritisnodosa(CPN)isanothercutaneousmanifestationofIBD,although
much less frequentlyencountered than either ENor PG. It is a chronic vasculitis affecting
smallandmedium-sizedarteries.Itoftenpresentsasatendernoduleonthelowerextremities.
ItcanbedistinguishedfromENandPGbyexcisionalbiopsy,whichshouldshowpanarteritis
and localized perivascular inflammation. CPN activity is not necessarily reflective of
underlyingactiveIBD.Treatmentinvolvesnonsteroidalanti-inflammatorydrugsandlow-dose
corticosteroids.40NecrotizingvasculitismayalsobeseeninassociationwithIBD,againless
commonlythanENorPG.Itcanpresentwithpalpable purpura,orinadvancedcases,even
ulcerations and gangrene. It typically occurs on the lower extremities. Biopsy reveals a
neutrophilicinfiltrateandendothelialenlargementofpostcapillaryvenules.
41,42
Itisimportanttobemindfulthatanti-TNFagents,whichareusedformanypatientswith
IBD, can also be associated with the development of skin lesions. These can include
palmoplantarpustulosis,eczema,xerosiscutis,andpsoriasiformlesions.43PatientswithIBD
may also be at increased risk for the development of skin cancers; anti-TNF agents may
increase the risk of melanoma, whereas immunomodulators (such as azathioprine and
methotrexate) mayincrease theriskofnonmelanoma skincancers.44Individuals taking these
medicationsshouldundergoroutineskinexaminationswithadermatologisttoexamineforany
concerninglesions.
Patients with IBDare at increased riskforthe development of deep venous thrombosis
(DVT) and thromboembolic disease.45 Patients with DVTs may present with unilateral or
bilateral lower extremity swelling and pain. It is important to ensure that all hospitalized
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patientswithIBDbegivensomeformofprophylaxisagainstDVTs.Itisimportanttorecognize
that these patients are at an increased risk for the development of macrovesicular and
microvesicular thrombosis to help prevent and ensure early recognition of these
complications.
46
Dermatitis herpetiformisis a cutaneous manifestationofCeliac disease, animmunologic
disorder driven by antibodies that target gluten, specifically antigliadin and antitissue
transglutaminase antibodies. It leads to changes in the duodenal mucosa, and endoscopy
classically reveals villous atrophy of the duodenal mucosa with increased intraepithelial
lymphocytesonbiopsy(althoughsomecasesmaypresentwithoutthesefindings).Itisalmost
alwaysassociatedwithhumanleukocyteantigenDQ2andDQ8.Theproducedantibodiescan
deposit inthe papillary dermis, which leads to recruitment of neutrophils and neutrophilic
dermal microabscesses.Theselesionstypicallystartoffassmall herpetiformvesicleson an
erythematousbaseandtheyareoftenpruritic.Itistypicallysymmetricandcanbeseenonthe
knees,elbows,andshoulders.Theyarenotresponsivetotopicaltherapies,butrespondbestto
eliminationofallgluteninone’sdiet.
47–49
The four main familial colorectal cancer syndromes include Lynch syndrome, familial
adenomatous polyposis (FAP) syndrome, juvenile polyposis syndrome, and Peutz–Jeghers
syndrome(PJS).Thesecaneachbeassociatedwithskinfindings thata physicianshouldbe
abletorecognizesoastohelpdiagnoseanunderlyingpolyposissyndrome.50Lynchsyndrome
is a hereditarynonpolyposis coloncancer, andis themost common hereditarycancer. It is
caused by inheritable mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and
PMS2. In addition to colon cancer, it is also responsible for hepatobiliary, small bowel,
gynecologic (endometrial, ovarian), urologic, and brain malignancies.
51,52
Most of the skin
manifestationsseeninLynchsyndrome areassociatedwitha specific variantreferred toas
Muir–Torresyndrome.Someofthedermatologicfindingsthatcanbeseenincludesebaceous
adenomas,epitheliomas,carcinomas,andmultiplekeratoacanthomas.53Thesepatientsrequire
surveillancecolonoscopiesaswellasannualdermatologicfollow-upandskinexaminations.
54
FAPischaracterizedbyinnumerableadenomatouspolypsfoundinthecolon,andcarries
an increased risk of colon cancer. It is caused by a mutation in the APC gene located on
chromosome 5.55 Gardner syndrome is a variantof FAP, and is associated with cutaneous
manifestations,including lipomas, desmoid tumors, andepidermoidcysts. Epidermoid cysts
are usually multiple, typically manifesting on the extremities or face, and can predate the
appearanceofintestinalpolyps.Desmoidtumorsmayoccurabdominallyorextra-abdominally,
especially in the inguinal region;these will appear as firm, well-circumscribed, nontender
tumors.SimilartoLS,FAPconfersanincreasedriskforthedevelopmentofcolorectalcancer
aswell as noncolonic malignancies, andthese includeduodenal, liver,adrenal,thyroid,and
brainmalignancies.
56
PJS is caused by a germline mutation in the STK11 gene on chromosome 19. It is
characterized by hamartomatous polyposis, and PJS is associated with colorectal, small
bowel, pancreatic, and gastric malignancies, as well as breast, uterine, and testicular
cancer.
57,58
Cutaneous manifestations can be seenin 95% of patients withPJS and include
mucocutaneoushyperpigmentation,small(1to5mm)melanocyticmacules.Theselesionsmay
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befoundonthemouth,nostrils,aswellasdorsalandvolaraspectsofthehandsandfeet.They
oftenprecedethedevelopmentofGImalignancy.
Cowdensyndrome,knownasmultiplehamartomasyndrome,iscausedbyanabnormality
inthephosphataseandtensinhomolog(PTEN)tumorsuppressorgenelocatedonchromosome
10.59Itischaracterizedbymultiplehamartomas (inmultipleorgans),dermatologicfindings,
andanincreasedriskofcolon,breast,andthyroidcancers.60Thecutaneousfindings include
acralkeratoses,facialpapules,andoralpapillomatosis.Ithasafemalepredominance.Inthe
GItract,ittypicallyaffectsthecolon,stomach,andesophagus.Mucocutaneousfindingscanbe
seeninalmostallpatients.Acralkeratosesandkeratosispunctata(onthepalmsandsoles)are
someofthemorecommonfindingsinthe lower extremities, butmultipleotherskinfindings
can be encountered.61 Juvenile polyposis syndrome is another genetic hamartomatous
polyposissyndrome,relatedtomutationsinSMAD4andBMPR1Agenes.Itcanpresentwith
multiple juvenile polyps as well as hereditary hemorrhagic telangiectasias and digital
clubbing.57Cronkhite–CanadasyndromeisalsocharacterizedbyGIpolyposisandcommonly
involves naildystrophy inupto98%ofall patients.Nail findingscanincludeonycholysis,
onychomadesis, and thinning and splitting of the nail bed. Inaddition, it can cause diffuse
hyperpigmentation, especially in the soles, palms, and face. Additional symptoms include
nausea,vomiting,diarrhea,andweightloss.It istypicallyseeninindividualsintheirfifties
andaffectsthosewithAsianandEuropeandescent.
62,63
ParaneoplasticSyndromesandGIMalignancies
GI malignancies maybe associated with paraneoplastic-related skin manifestations that are
important to recognize, as they may be the first presenting sign of a malignancy.50 Gastric
adenocarcinomahasbeenassociatedwithpalmoplantar keratodermathatischaracterizedby
epidermalthickeningleadingtobroadridgesanddeepsulciinthepalmsandsoles.64Thesign
of Leser–Trélat is the acute onset of multiple, eruptive seborrheic keratoses and may be
secondarytoanunderlyingGImalignancy(colonandstomachmostcommonly)inuptoone-
thirdofcases.Thispresentsinitiallyonthetrunkand canspreadtotheextremities.65 Bazex
syndrome, also referred to as acrokeratosis paraneoplastica, is a rare acral psoriasiform
dermatosisthatmaybeassociatedwithaGImalignancy(includingsquamouscellcarcinoma
of the esophagus and gastric cancer). It can present as erythematous plaques with scaling,
hyperpigmentation,palmoplantarkeratoderma,paronychia,andonycholysis.Onemayalsosee
bulbousenlargementofdistalphalangeswithnaildystrophy.66Tylosisisalsoassociatedwith
palmoplantarhyperkeratosisandtypicallyinvolvesmorethan50%oftheacralsurfaces,and
hasbeenassociatedwithesophagealcarcinoma.
67
Glucagonomas,aglucagon-secretingpancreatictumor,hasawell-knownassociationwith
necrolytic migratory erythema (NME). NME is characterized by painful and pruritic
erythematouslesions,withcentralblistersanderosions,aswellashyperpigmentation.Itcan
also be associatedwith brittle nails. NMEintheabsenceofaglucagonomacanbe seenin
IBD, pancreatitis, nonpancreatic malignancies, cirrhosis, and intestinal malabsorption
syndrome.
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