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rapidlythan individual cells, thus providingahigher ESR.Fibrinogen is the proteinthat is
mostresponsibleforelevationsinESRinacutestatesofinflammation.However,inchronic
inflammation,decreasedserumalbuminandhematocritlevelsalsocontributetoanincreased
ESR. An increase in immunoglobulin (Ig) such as that seen with myeloma or monoclonal
gammopathiescanalsoleadtoanESRelevation,althoughsuchchangesmaynotnecessarily
indicateaninflammatorystate.TheESRisinfluencedbyanemia,polycythemia,andalterations
in the size and shape of erythrocytes. Falsely low levels are seen in sickle cell disease,
anisocytosis,spherocytosis,polycythemia,andheartfailure.Prolongedstorageofbloodbefore
testingor tilting of thecalibrated tube will tend toanincrease in theESR.TheWestergren
method is thought to be the most reliable. This method measures the fall of RBCs in
millimetersperhourinastandardizedtube.Normalisconsidered0to15formalesand0to
20forfemales.However,theESRalsoincreaseswithage;thus,“normal”levelsarevariable.
Levelsupto40mmperhourarecommoninhealthyelderlypeople.Aruleofthumbisthatthe
age-adjustedupperlimitofnormalofESRisagedividedby2formenandageplus10divided
by 2 for women. The ESR is probably most helpful if it is normal. Active inflammatory
disorderssuchasacuterheumaticfever,SLE,rheumatoidarthritis(RA),temporalarteritis,and
infectionstendtohaveelevatedESRs.AlthoughelevationsoftheESRinsepticarthritisand
crystal-inducedarthritisaretherule,anormalESRdoesnotcompletelyruleouttheseentities.
Jointaspirationisrequired.Fromthis,itisclearthattheESRandCRPareneitherdiagnostic
norspecific.Nonetheless,theycanbehelpfulinevaluatingpatientswhenRAorothersystemic
and local inflammatory conditions are being considered. ESR and CRP are a part of the
metrics used to measure and follow disease activity in RA patients along with signs and
symptoms.
AdditionalAcutePhaseReactants
Other acute phase reactants include ferritin, fibrinogen, serum amyloid A, etc. Although
markersofinflammation,theyarenotroutinelymeasuredbecausetheyarenonspecific.
BIOMARKERS
Cytokines like interleukin (IL)-6 increase swiftly and dramatically with inflammation;
however,theyarenotviewedasacutephasereactants.Thereareseveralcytokinepanelsand
multiproteinbiomarkeralgorithmsnowcommerciallyavailabletomonitordiseaseactivityin
diseases like RA and SLE. There is a commercially available test used to assess disease
activity in RA (Vectra DA). It measures the following biomarkers: adhesion molecules
(VCAM-1), growth factors (EGF, VEGF-A), cytokine-related proteins (IL-6 and tumor
necrosis factor [TNF]-R1), matrix metalloproteinases (MMP-1, MMP-2), skeletal-related
proteins(YKL-40),hormones(leptinandresistin),andacutephaseproteins(SAA,CRP).A
complexalgorithmisthenapplied,toprovideadiseaseactivityscalethatrangesfrom1to100
andcategorizesRAintolow(1to29),moderate(30to44),andhighdiseaseactivity(45to
100).DiagnosticbiomarkerpanelsforSLEarealsoavailable.The“AVISE”SLEdiagnostic
panel measures cell-bound complement activation products (CB-CAPs). The current panel,
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whichwilllikelyevolvewithfuturestudy,includesantinuclearantibody(ANA),anti–doublestranded deoxyribonucleic acid (dsDNA), anti–mutated citrullinated vimentin (anti-MCV)
antibody,andtheCB-CAPserythrocyte-boundC4d(E-C4d)andB-cellC4d(B-C4d).Larger
studiesarerequiredtoconfirmthevalidityofthesepanels.
RheumatoidFactor
Rheumatoid factors (RFs) are autoantibodies that are directed against the Fc fragment of
immunoglobulin G. It is believed that they are synthesized in response to immunoglobulins
(Igs) that have been conformationally altered after reaction with antigen. They are most
commonlyassociatedwithRAbutarealsofoundinotherdisorders.
Historically, thetest was performed bycoatingsheep red blood cells or latex particles
with human IgG and measuring the dilution of patient serum that will still aggregate the
particle. Newer methods include radioimmunoassay, enzyme-linked immunoassay (ELISA),
andnephelometry.Thesemethodsincreasesensitivityandspecificity.
RFisoneofthelaboratorytestsmostfrequentlyorderedintheevaluationofpatientswith
jointcomplaints.Thetestispositivein75%to90%ofpatientswithRA.InearlyRA,only
50%ofpatientsmayhaveapositiveRF.However,thesedataaretakenfromhighlyselected
populationsandmightbesubjecttoreferralbias.Thehighspecificitythatisalsoreportedin
studiesfromthesepopulationsmaynotbeobservedinpatientswhohaveweakindicationsfor
thetest,whomaybeelderly,orwhohaveotherdiseasesthatmaycauseafalse-positiveRF.In
fact,theprevalenceoffalse-positiveRFsinpatientsolderthan75yearsisbetween2%and
25%. Although there may be an increased likelihood of developing RA in a RF-positive
asymptomaticindividual,theuseofRFasascreeningtestperformspoorlybecauseofthehigh
frequencyoffalse-positivetestresults.RFsaremostcommoninpatientswithRA,buttheyare
also presentin normal sera as well as in sera of patientswith acquired immunodeficiency
syndrome, hepatitis, various parasitic diseases, chronic bacterial infections such as
tuberculosisandsubacutebacterialendocarditis(SBE),tumors,chroniclymphocyticleukemia,
and other hyperglobulinemic states such as cryoglobulinemia, primary Sjögren syndrome,
chronicliverdiseaseincludingchronichepatitisC,sarcoidosis,andsomechronicpulmonary
diseases. For example, when RF is found in a patient with fever, arthralgia, and a heart
murmur,SBEmaybeamorelikelycauseofapositiveRFthanRA.Whenfoundinpatients
withRA,RFsareusuallyspecificforhumanIgG,areofhighaffinity,andincludenotonlyIgM
RFsbutalsoIgG,IgA,andIgEvariants.
Highlevels ofRFhavebeenassociated with a worse prognosis;there tendtobemore
involved joints when first seen by a physician, more erosions, and greater ligamentous
instability.However,RFtiterdoesnotcorrelatewithdiseaseactivityandthuscannotbeused
toassess disease activity. Ahigh level ofRFisconsidered a riskfactor forRA vasculitis.
OtherlaboratoryfindingsthatarecommoninRAincludeleukocytosis(usuallywithanormal
differential), thrombocytosis, anemia (normochromic, normocytic), normal uric acid (if the
patient is not takingsalicylates,whichcanraise uricacidlevels),anegativeANA andantiDNAantibody,andnormalorelevatedserumcomplement.
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Anti-CyclicCitrullinatedPeptideAntibodies
Anti-cyclic citrullinated peptide (CCP) antibodies are autoantibodies directed against the
acids formed by posttranslational modificationof arginine. Duringinflammation, the amino
acidargininecanbeenzymaticallyconvertedintocitrulline,inproteinssuchasvimentin,ina
processcalledcitrullination.Iftheirshapesaresignificantlyaltered,theproteinsmaybeseen
as antigens by the immune system, thereby generating an immune response. IgG anti-CCP
antibodiesaremeasuredbyELISAusingsyntheticcitrullinatedpeptides.The2010American
College of Rheumatology (ACR)/EULAR Rheumatoid Arthritis Classification Criteria now
includeanti-CCPtesting.Anti-CCPshavethesamesensitivityasRF,buttheadvantageisthat
theyaremorespecific.Alsoanti-CCPscanbedetectedinearlyRAandarebetterpredictors
oferosive disease thanRF.There are patientswhoareboth RFand CCPnegativebuthave
clinicalsignsofRA.They are labeled seronegative RA.As withRF,CCP levels cannotbe
usedtomonitordiseaseactivity.However,RFandCCPcombinedcanhelpinthediagnosisof
RA.Afalse-positive CCPcansometimesbeseenindiseases liketuberculosis, chroniclung
diseases, and other connective tissue diseases. The newer generation assays, anti-CCP
antibody assays (anti-CCP2), have improved sensitivity and specificity compared with the
originalanti-CCPassays.
There have been several other antibodies described for diagnosing RA: 14-3-3η
autoantibodies, alone and in combination with the 14-3-3η protein, RF, and/or anti-CCP
identifiedmostpatientswithearlyandestablishedRA.1Anumberofotherautoantibodieshave
been the subject of investigation in RA—anti – mutated citrullinated vimentin, Ig-binding
protein,glucose-6-phosphateisomerase,type2collagen,mannose-bindinglectin,ferritin,antiRA33,anti-p68, anti-alpha enolase, antibodies tothe enzyme peptidylarginine deiminase 4,
etc.Alloftheserequirefurtherstudiesforthemtobewidelyused.
AntinuclearAntibodies
Lupusis another autoimmune disease whichmayhave major jointmanifestations.It usually
causes a nonerosive, nondeforming symmetric arthropathy. Multiple joints are typically
involved.TheankleandfootarelesscommonlyinvolvedthanwithRA.Inaddition,systemic
features are more common. These include rash, fever, central nervous system involvement,
renaldisease,andserositis. Unlike RA,manytypesofautoantibodies aretypicallyfoundin
SLE and related syndromes. ANAs are a hallmark of SLE. These are antibodies directed
against the cell nucleus. The ANA is positive in 95% to 99% of patients with lupus. The
indirect immunofluorescence ANA is the method most commonly used. It is performed by
dilutingtestseraandincubatingwithsubstratecells.Traditionally,thinsectionsoffrozenrat
kidneyorliver are used.However,cytocentrifugedpreparationsofcellsfrom tissueculture
suchasHep-2cangiveoptimal sensitivityand patterndiscrimination.AnyboundANAsare
thendetectedbyfluorescein-taggedantihuman Ig. The substratecell is then viewedundera
fluorescence microscope. ANAsare reported byeither intensityoffluorescence(i.e., 1+ to
4+)orbymaximaldilutionofserumgivingapositiveresult.Valuesof2+orgreaterortitersof
greater than 1:40 are considered abnormal. The patternof the ANA is also reported (e.g.,
speckled, diffuse, rim, centromere). ANAs have different targets, and the pattern of
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immunofluorescencecanprovidedifferentialdiagnosticinformation.
Homogeneouspatternsareleastspecific,andcanbeseeninupto5%ofnormalpatients,
especiallywomenandtheelderly.Inthissetting,theyareusuallypresentinlowtiters.Therim
pattern is characteristic of SLE. Nucleolar and speckled patterns are also seen and are
associated with scleroderma, CREST (Calcinosis cutis, Raynaud phenomenon, Esophageal
dysmotility,Sclerodactyly,andTelangiectasia),mixedconnectivetissuedisease(MCTD),and
otherdiseases.OnceapatienthasbeendocumentedtohaveapositiveANA,itisusuallynot
necessarytorepeatthetestunless amajorchangeintherapyor statusisdetected.TheACR
recommendstestingforANAonlywhenthereisasuspicionofaconnectivetissuediseaselike
lupus.Positivetestsmustalwaysbeinterpretedincontextwiththehistory,physicalexam,and
otherlaboratorytests.Itshouldbenotedthatsteroidsandotherimmunosuppressantagentsmay
lowerANAtiters.Extractablenuclearantigens(ENAs)sometimeshelpsortthediagnosis.
Many diseases can produce anti–single-stranded DNA antibodies. These include liver
diseases and drug-induced lupus. However, for the most part, only SLE (and MCTD) is
associatedwithhigh-titeranti-dsDNAantibodies. TheseoccurinnearlyallSLE patients.In
contradistinctiontotheANA,levelsofdsDNAantibodiesarefrequentlyusedinmonitoring
diseaseactivity,soitisoftenrepeatedinfrequentintervals.Manyotherlaboratorytestsmay
beabnormalinSLE,andcanbeusedinconjunctionwiththemorespecifictestsforassessing
disease activity. These include a low WBC (usually with neutropenia and lymphopenia),
anemia (sometimes an autoimmune hemolytic anemia with positive Coombs), and
thrombocytopenia. As suggested by the variety of ANA immunofluorescent patterns, ANAs
may be directed against a number of different cellular constituents. Immunodiffusion and
counterimmunoelectrophoresis can be performed using soluble components of cells (i.e.,
ENAs). The ENAs includeanti-Ro, anti-La, anti-Smith and anti-ribonuclear protein (RNP).
Anti-RNPisoftenaccompaniedby aspeckledANA andisseeninpatientswithSLE,oran
overlap disease that is knownas MCTD.Anti-Ro (SSA) andanti-La (SSB)are associated
with Sjögrensyndrome.Inadditiontonucleicacids, other proteinantigensfromboth nuclei
andcytoplasmhavebeenshowntobetargetsofANAs.Theantinuclearspecificitiesthatare
mostcommonwithSLEareanti–double-strandedDNAandanti-Smith.Anti-histoneantibody
andsingle-strandedDNAantibodiesmaybefoundindrug-inducedlupus.
AntiphospholipidSyndrome
Manypatientswithlupusmayhaveconcomitantantiphospholipidsyndrome(APLS).However,
APLSmayexistinpatientswithoutlupustoo.PatientswithAPLSoftenpresentwithischemic
toes, arterial and venous clots, or even emboli, resulting in strokes. It is characterized by
elevated partial thromboplastin time (PTT), false-positive Venereal Disease Research
Laboratoriestest,andantiphospholipidantibodies.
AfactorhasbeenknowntoexistintheserumofsomeSLEpatientsthatprolongsthePTT.
This inhibitor wasfrequentlyassociatedwithfalse-positive serologictestsforsyphilis.The
factor could be absorbed from plasmaby phospholipids. This factor became knownas the
lupus anticoagulant, even though approximately half of the patients with this serologic
abnormality donothave SLE. In addition,although the inhibitoractsas ananticoagulantin
vitro, patients with the lupus anticoagulant were not prone to excess bleeding. In fact, the
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opposite was found: they were prone to both arterial and venous thromboses as well as
thrombocytopeniaandfetallossormiscarriage.
Standard antiphospholipid panels include the lupus anticoagulant, anti-cardiolipin
antibodies, and β-2 glycoprotein. Anti-cardiolipin and anti-β-2-glycoprotein antibodies are
usually ordered in IgG, IgM, and IgA forms. And generally, IgG antibodies have a higher
predictive value than IgM and IgA; also the higher the elevation, the greater the positive
predictivevalueofanassociationwithAPLS.Recently,afewcentersstartedtomeasureantiphosphatidylserine and other negatively charged phospholipids. However, they are not
routinelyusedinclinicalpracticeasthereisnotenoughevidenceintheliteraturetoshowits
utility in diagnosis. Because these patientsdemonstratea procoagulantstate, treatmentwith
anticoagulationisusuallyindicated.
Complement
Thecomplementcascadecontainsatleast18distinctplasmaproteins.Itisoneofthemajor
effector arms of the humoral immune system. Complement activation is thought to occur
primarilybytwomechanisms:theclassicandthealternative.Intheclassicactivationpathway,
antigen–antibody complexes act on C1 and C2 to cause cleavage of C3. In the alternative
pathway,complexpolysaccharidesactonproperdinfactorsdandbtocausecleavageofC3.
OnceC3iscleaved,theterminalcomponents(C5–C9),whicharecommontobothpathways,
are activated. This leads to the lysis of the target cell and cellular membrane injury.
Subsequently,manymediatorsaregeneratedthattriggerinflammationandanaphylaxis.C3and
C4aremeasuredbyELISAassays.CH50isameasureofthetotalhemolyticcomplementand
thusmoreareflectionoftheclassicalpathway.SerumisdilutedandaddedtosheepantibodycoatedRBCs.Thevaluereportedisthereciprocalofthehighestdilutionabletolyse50%of
the RBCs.Whenimmunecomplexesare formed andcleared from thebody, the complement
levelisdecreased.SerialmeasurementsofC3,C4,orCH50areusefulinmonitoringdisease
activity(particularlyrenaldisease)inSLE.Adecreaseincomplementlevelmayprecedethe
disease flare in lupus and related disorders. Decreased complement may also be seen in
poststreptococcal glomerulonephritis or SBE. Genetic absence of complement proteins is
rarely seen. C4 levels that are disproportionately lower than C3 may indicate
cryoglobulinemia.CB-CAPscanbeusedinthediagnosisoflupus;however,itsvalidityneeds
tobedeterminedbyfurtherstudies.
SERONEGATIVESPONDYLOARTHROPATHIES
Anothermajorgroupofrheumaticdiseasesthathavefrequentmanifestationsintheankleand
foot are the seronegative spondyloarthropathies. These include psoriatic arthritis, Reiter
syndrome, ankylosing spondylitis, and the enteropathic arthritides. As with most forms of
rheumaticdisease,thediagnosisismadeclinically.
Psoriatic arthritis has a number of different clinical presentations. These include
spondylitis, RA-like asymmetric distal arthritis, dactylitis that causes sausage digits, and
arthritismutilans.Nailchangesarecommon.Therearenodiagnosticlabfindings,althoughan
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elevated ESRandslightelevationof uric acid are common. Psoriatic arthritis occurs more
commonlyinpatientswithtissuetypehumanleukocyteantigens(HLA)-Cw6andHLA-B27.
Reitersyndromeisassociatedwithpauciarticulararthritis,frequentlyoftheknees,ankles,
metatarsals, and toes. Conjunctivitis, urethritis, prostatitis, sacroiliitis, and a skin rash
(keratoderma blennorrhagicum—which preferentially affects the feet) are frequent clinical
findings.Heretoo,anelevatedESRcanbeseen.PyuriamayalsobeamanifestationofReiter
syndrome when associated with prostatitis or urethritis (which may be asymptomatic).
ChlamydiaisoneoftheorganismsthoughttoinduceReitersyndrome,andaneffortshouldbe
made in the lab to identify this pathogen. Cultures are not reliable. The diagnostic test of
choiceforchlamydialinfectionofthegenitourinarytractisnucleicacidamplificationtesting
ofvaginalswabsforwomenorfirst-catchurineformen.Whenappropriate,urethral,cervical,
andrectal culturesshouldbeperformed.A varietyofentericpathogenssuch as Salmonella,
Shigella, Yersinia, and Campylobacter can also induce Reiter syndrome. These may be
confirmed by stool culture. Patients infected with Chlamydia are often also infected with
gonorrhea, both sexually transmitted diseases. Probably the most important lab test when
evaluatingapatientwithamono-orpauciarticulararthritis,withurethritis,rash,andenteritis,
is to rule out an infectious cause. Joint aspiration and culture can be performed and in
gonorrheainfectionisthebestwaytoestablishdiagnosis.
ArthritisassociatedwithCrohndiseaseandwithulcerativecolitiswillhavenegativestool
andsynovial fluidcultures.Intestinal histopathologyshouldbe helpfulinconfirmingclinical
suspicionsofaninflammatoryboweldisease.Anti–Saccharomycescerevisiaeantibodiesmay
bepositiveinulcerativeandmicroscopiccolitis.Pyodermagangrenosumisanassociatedskin
conditionwithulcerativecolitisandCrohnmainlyinvolvingthelowerextremity.
Human immunodeficiency virus (HIV) infection has also beenassociated with a Reiter
syndrome–like arthritis. Screening ELISA and confirmation with Western blot should be
consideredafterappropriatehistoryandphysicalexaminationandcounseling.
ItiswellknownthatthereisarelationshipbetweenHLA-B27andankylosingspondylitis.
HLAsarepresentonthesurfaceofnucleatedcellsandplayaroleindeterminingthegenetic
predisposition to a variety of immune-mediated processes, including autoimmune diseases.
The sensitivity of this test is approximately 95% in ankylosing spondylitis, 80% in Reiter
syndrome, and 50% in spondylitis associated with inflammatory bowel disease. The
backgroundprevalenceofthis marker(6%to10% inWhites)andthefactthatonlya small
minorityofHLA-B27-positiveindividualswilleverexperienceanarthropathymakethetestof
limiteduse.Accordingtosomeauthors,peoplewithinflammatorylowbackpainhavea40%
pretestprobabilityofapositive HLA-B27.2When thetestis orderedforpatientswithback
painthatisnotclinicallysuggestiveofsacroiliitis,thetestmayyieldmorefalse-positivethan
true-positive results. Thus, a positive HLA-B27 may be of some value, but, as noted
previously,itmayresultinthemisclassificationofdiseasesifitisreliedontooheavily.
URICACIDANDGOUT
Goutisoneofthemorecommonrheumatic diseasesthataffectthefootandankle.Whenthe
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Table16-1.
metatarsal–phalangeal joint at the base of the big toe is affected, it is known as podagra.
Approximately 50% of cases present with involvement of the big toe. However, other
differentialdiagnosesmustbekeptinmindwhendiagnosinggoutonthebasisofpodagra.A
careful assessmentisthusnecessary(Table 16-1).In itsclassic,acutepresentation,itisnot
likelytobeconfused with RA or SLE. However, in its chronictophaceous form, there are
many features that can mimic RA, including polyarthritis, symmetry of joint involvement,
nodules,fusiformswelling,anderosions.Sometimes,goutandRAmaycoexist.Highuricacid
maybeseeninpatientswithRAforreasonsunrelatedtothetypeofarthritispresent.Common
causesofanincreaseinuricacidare:obesity,renalinsufficiency,hypertension,alcoholintake,
psoriasis,andgenetic factors.Inaddition,patientswithpsoriasishave ahigher thannormal
uric acid, attributed to rapid cell turnover in the skin. The use of such common drugs as
salicylates,inlowdoses,immunosuppressive medicationsliketacrolimus,anddiuretics can
alsoprecipitategout.Itshouldbestressedthatanelevationofserumuricacidisnotsufficient
forthe diagnosis of gout. In fact, hyperuricemia withoutjoint/other manifestationshasbeen
described in more than 15% of certain populations. Current recommendations suggest that
asymptomatichyperuricemiashould not betreated.However,iftreatment with allopurinolis
being considered, then obtaining an HLA-B58 should considered, particularly in Asian
subpopulations(notablyinKorean,HanChinese,orThaidescentpatients)becausethisHLA
typeishighlycorrelatedwithdrugreactions.Furthercomplicatingtheuseofaserumuricacid
inthediagnosisofgout is thefactthatserum uric acid isfrequentlynormalduringanacute
attack.Thediagnosisisbestestablishedbyjointaspirationandevaluationwithcompensated
polarized light microscopy. The identification of needle-shaped, negatively birefringent
crystalswithinneutrophilsisdiagnostic.Aword ofcautionisnecessarybecauseithasbeen
establishedthatavarietyofmaterials,includinglipids,particulatematterfrompreviousjoint
replacements, malignant cells, or other crystals such as previously injected intra-articular
steroids,canbeconfusedwiththoseofuricacid.
PodagraMimics
Septicarthritis/osteomyelitis
Rheumatoidarthritis
CPPD
BCPcrystaldisease/hydroxyapatitecrystals
Calciumoxalatecrystaldepositiondisease
Reactivearthritis
Trauma
BCP,basiccalciumphosphate;CPPD,calciumpyrophosphatedepositiondisease.
CALCIUMPYROPHOSPHATEDEPOSITIONDISEASE
Anothercrystaldiseasethatcanaffectthefootandanklemustbedistinguishedfromgout.That
conditioniscalciumpyrophosphatedepositiondisease(CPPD).Thisisthearthritisassociated
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with calcium pyrophosphate. Acute arthritis (or pseudogout) rarely affects the first
metatarsophalangeal (MTP) joint the way gout does. More often, it affects the knees and
wrists,butitmayalsoinvolvetheankleandonoccasionthefirstMTP.Althoughmostoften
associatedwithafamilialpredispositionorwithaging,anumberofotherdiseaseshavebeen
associatedwithCPPD.Manyofthesehavecharacteristiclaboratoryfeatures,includingCPPD
associated with diabetes, hemochromatosis (elevated iron, iron saturation, and ferritin),
hyperparathyroidism (high parathyroid hormone [PTH], hypercalcemia, hyperchloremic
acidosis),hypomagnesemia,hypophosphatasia,orhemosiderosis.Aswithgout,thediagnosis
ofCPPD is confirmed by joint aspirationand crystal search. CPPDcrystals are positively
birefringentwhenseenundercompensatedpolarizedlightmicroscopy.
DIABETES
DiabeteshasbeenassociatedwithCPPD,althoughthisisthoughtmorelikelytobethechance
occurrence oftwocommondiseases.Diabetes,however,doeshavemajor manifestations in
diseasesofthefoot.Theseincludeperipheralneuropathy,Charcotjoints,anddiabeticulcers
withandwithoutunderlyingosteomyelitis.Thelaboratorydiagnosisofdiabetesis,therefore,
germane.Screeningmaybeperformedwithafastingbloodglucose.Stresstestingcaninclude
2-hour postprandial sugars or a full glucose tolerance test. Hemoglobin (Hb)A1C or
glycosylatedhemoglobinmaybeusefulinmonitoringdiabeticcontrolinanindividualpatient.
A HbA1C above 6.5% is considered indicative of diabetes. Usually by the time the foot
complicationsofdiabetesoccur,thediagnosisiswellestablished.
PERIPHERALNEUROPATHY
Therearemanycausesofperipheralneuropathy,otherthandiabetes,andvasculitis,including
metaboliccauses(e.g.,thyroid—measurethyroid-stimulatinghormone),leadand otherheavy
metal poisoning, toxic—both drug and alcohol related, various vitamin deficiencies,
perniciousanemia,inwhichB12levelscan beusedinthediagnosis,infections—Lyme,HIV,
etc.,depositiondiseases—sarcoidosis,amyloidosis,etc.
SYNOVIALFLUIDANALYSIS
Synovial fluid analysis is one of the most useful lab tests that can be performed in the
evaluationofarthritis.It should be performedaspartofthe workup ineverypatientwitha
jointeffusion.Itisparticularlyimportantintheevaluationofsepticarthritis.
Eveninpatientswithanestablisheddiagnosis,itmayprovideevidenceabouttheactivity
ofdisease.Alternatively,itmaydemonstratethecoexistenceofanotherdisease.Forexample,
apatientwithanunderlyinginflammatoryarthritissuchasRAmayalsohaveasuperimposed
infection.Similarly,apatientwithRAorosteoarthritismayalsohavegoutorpseudogout.Joint
fluidhasoftenbeenclassifiedintofivegroupsasmentionedinTable16-2.
AlthoughitispossibletomeasureantibodiesinsynovialfluidsuchasLymeandRF,they
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Table16-2.
arerarelyperformedanymoreduetolackofspecificityandsensitivity.
Evaluationofthespecimenunder compensatedpolarizedlight microscopyis of critical
importance. This is the only reliable method of diagnosing an acute attack of gout or
pseudogout.Monosodiumuratecrystalsareintenselynegativelybirefringentandformneedles
and rods. When found intracellularly, they are virtually diagnostic of gout. Calcium
pyrophosphate dihydrate is weakly birefringent and often rhomboid in shape. Many other
crystalshavebeendescribedandincludethosecomposedofhydroxyapatiteclumps,calcium
oxalate, cholesterol, myeloma cell aggregates, depot steroids (from prior joint injections),
particulate matter (from prior joint replacement), lipids, Charcot–Leyden crystals, and Igs.
Thesecrystalsarefoundinavarietyofclinicalsettingsandmaybeusefulinthediagnosisof
manydiseases.
METABOLICBONEDISEASE
Stressfracturesofthefootarecommoncausesoffootpain.Theymayoccurinpatientswith
normal bone; however, osteoporosis may often contribute. There are many causes and risk
factorsforosteoporosis.Someofthemareassociatedwithlaboratoryabnormalities.Examples
includesteroiduse(associatedwithhypokalemia),estrogenandtestosteronedeficiencystates
(measurement of specific hormone levels), renal disease (blood urea nitrogen, creatinine
clearance),gastrointestinalandliverdisease(liverfunctiontests,testsforparticulartypesof
diseases thatcause hepatitis, ormalabsorption),abnormalities ofvitaminD,phosphate,and
calcium metabolism (Ca2+, PO
4
2−
, 25-OH vitamin D, 24-hour urine for calcium),
hyperthyroidismandhyperparathyroidism (TSH,thyroxine[T4],T4uptake, triiodothyronine,
T7 index, PTH, electrolyte abnormalities, calcium levels, urinary calcium), marrow
replacement, such as with myeloma (serum immunoelectrophoresis, urine
immunoelectrophoresis,ESR,CBC)orleukemia(CBC).
Synovialfluidanalysis
JointFluid Amount Appearance WBCs Characteristics
Normal Lessthan
1mL
Transparent,
colorless,or
strawcolored
Lessthan200
WBCsandless
than25%of
themPMNs
Negativeculture
Noninflammatory Greater
than1
mL
Transparentwith
highviscosity,
colormaybe
moreyellow
50to1,000WBCs
withlessthan
25%PMNs
Negativeculture.Typicallyosteoarthritis
Inflammatory Greater
than1
mL
Lowviscosity,
translucentbut
not
transparent,
yellowish
colored
1,000to75,000
WBCs,PMNs
typicallygreater
than50%
Negativeculture.RA,psoriaticarthritis,Reiter
syndrome,bowel-relatedSLE,scleroderma,
Wegenergranulomatosis,Sjögren
syndrome,sarcoidosis,crystal-induced,etc.
Septic Greater Opaquefluid WBCcountsoften Cultureistypicallypositivefortherespective
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than1
mL
coloredyellow
togreen
higherthan
100,000and
greaterthan
85%arePMNs
organism
Hemarthrosis Variable Grosslyand
diffusely
bloodyfluid
Variablelikely
sameasin
peripheralblood
Negativeculture.Trauma,PVNS,coagulation
defects,andtumors
WBC,whitebloodcell,PVNS,pigmentedvillonodularsynovitis,PMNs,olymorphonuclearleucocytes(neutrophils).
Autoimmune diseases: Like RA and SLE, not only may these illnesses cause an
inflammatoryarthritisthatcaninvolvethefoot,butmostareassociatedwithosteoporosis.
Pagetdiseaseisanothermetabolicdiseaseofbonethatshouldbesuspectedasacauseof
footpainifthereisanelevatedalkalinephosphataseandhighurinaryhydroxyprolinelevels.
Althoughitmostoftenoccursinthespine,pelvis,skull,femur,andtibia,itmayalsooccurin
the smallbonesofthefoot.Similarly,osteomalaciamayalsoaffectthelower extremity,and
characteristiclaboratoryfindingsmaybe sought(e.g.,calciumlevel, phosphorus,vitaminD,
alkalinephosphate).
INFECTION
Itis critical todiagnose infections ofthe footpromptly. Infection may involvethe footin a
numberofways.Theseincludedirectpuncture(with or withoutforeignbody);trauma (e.g.,
motor vehicle accident) in the setting of ulcers (diabetic, vasculitic) as well as via
hematogeneousspread.Itisimperativetoobtainappropriateculturestoidentifythepathogen.
They may involve the soft tissue, the joint, or deeper structures including the bone. Joint
aspirationmay be requiredtorule outseptic arthritis. If there isevidenceofosteomyelitis,
bonebiopsymaybe neededforbothdiagnosisandcultureandsensitivity.Culturing anopen
ulcermaynotbeveryhelpful,becausetheorganismspresentmaysimplybecontaminants,and
notcausative.
Manyorganismscaninfectthefoot.Theseincludethefollowing:
Bacterial:Typicalstaphylococcalandstreptococcalinfectionsaffectthefoot;however,in
diabetics, Pseudomonas and even some anaerobic infections can be seen. Culture
resultswillguidetherapyinthese.Lymediseaseisatick-borneillnesscausedbythe
bacteriaBorreliaburgdorferi.Ittypicallyaffectstheknee,butmayalsoaffecttheankle
andfoot.Inadditiontohistory,ELISAisperformedasascreeningtest,andaWestern
immunoblot is required for confirmation. IgG Lyme titers usuallystay elevated long
after Lymediseaseis treated.Thus,apositive IgGtiteronlyindicatespastexposure
and not necessarily an active infection. Mycobacterium infections in the joints are
mainly seeninimmunocompromised individuals. Mycobacterium marinum typically
causes clusters of superficial nodules or papules in extremities after contaminated
aquatic exposure. Mycobacterium tuberculosis may present as monoarticular joint
swelling—acidfastbacilli(AFB)smearandcultureshouldbeorderedwhenthereisa
suspicion.
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