MUDr.Petr Kocna CSc. GASTROENTEROLOGY, …ukb.lf1.cuni.cz/ppt/ge_kasu2012_gb.pdfgastroenterology, laboratory diagnostics - cases ... exocrine pancreatic function ... non-invasive hp

Seminář ÚLBLD, listopad 2012SeminSeminářář ÚLBLD, ÚLBLD, listopadlistopad 20201122

GASTROENTEROLOGY,LABORATORY DIAGNOSTICS - CASES

GASTROENTEROLOGGASTROENTEROLOGY,Y,LABORATORYLABORATORY DIAGNOSTIDIAGNOSTICS CS -- CASESCASES

MUDr.Petr Kocna CSc.http://www.lf1.cuni.cz/~kocna/pkweb1.htm

MUDr.Petr Kocna CSc.MUDr.Petr Kocna CSc.http://www.lf1.http://www.lf1.cunicuni..czcz/~/~kocnakocna/pkweb1./pkweb1.htmhtm

Seminar Medical Faculty - Prague, November 2012SeminarSeminar Medical FacultyMedical Faculty -- PraPraguegue, , NovemberNovember 20201212

Institute of Medical Biochemistry and Laboratory Diagnostics1st Faculty of Medicine, Charles University

General Faculty Hospital, Prague

Institute of Medical Biochemistry and Laboratory DiagnosticsInstitute of Medical Biochemistry and Laboratory Diagnostics11st Faculty of Medicine, Charles Universityst Faculty of Medicine, Charles University

General Faculty Hospital, PragueGeneral Faculty Hospital, Prague

22

HELICOBACTER PYLORIPEPSINOGENS, GASTRITIS

COELIAC SCREENING - THERAPYCHRONIC PANCREATITIS

EXOCRINE PANCREATIC FUNCTIONQUANTITATIVE FIT

COLORECTAL CANCER SCREENING

HELICOBACTERHELICOBACTER PYLORIPYLORIPEPSINOGENPEPSINOGENSS, GASTRIT, GASTRITISIS

CCOOELIAELIACC SCREENING SCREENING -- TTHHERAPERAPYYCHRONIC PANCHRONIC PANCCREATITREATITISIS

EXOEXOCCRINRINEE PANPANCCREATREATIC FUNCTIONIC FUNCTIONQUQUANTITATIVANTITATIVEE FITFIT

CCOLOREOLORECCTTAAL L CANCER SCREENINGCANCER SCREENING

BIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGY Kocna P.BIOCHEMICBIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGYAL DIAGNOSTICS IN GASTROENTEROLOGY KocnaKocna P.P.

33










44

GASTRITIS - CARCINOMA SEQUENCESGASTRITGASTRITIS IS -- CCARCINOMARCINOMA SEQUENCESA SEQUENCES

Hp - IARC 19941.class cancerogen

HpHp -- IARC 1994IARC 19941.1.class cclass cancerogenancerogen

NORMAL MUCOSANORMAL MUCOSANORMAL MUCOSA

ATROPHIC GASTRITISATROPHIC GASTRITISATROPHIC GASTRITIS

INTESTINAL METAPLASIAINTESTINAL METAPLASIAINTESTINAL METAPLASIA

GASTRIC CANCERGASTRIC CANCERGASTRIC CANCER


55

Male - J.N. - IT specialist - born 1978in childhood common childhood diseases,

none of injury, none of hospitalization, parents in healthy,severe disease in the family - who do not know.Now does not have any subjective complainrts.

MaleMale -- J.N. J.N. -- ITIT specialisspecialistt -- born born 19719788in childhood common childhood diseasesin childhood common childhood diseases,,

none of injury, none of hospitalizationnone of injury, none of hospitalization,, parents in healthyparents in healthy,,severe disease in the family severe disease in the family -- who do not knowwho do not know..Now does not have any subjective complainrts.Now does not have any subjective complainrts.

CASE: 12-01CASECASE:: 1212--0101

Comes to LG laboratories with requirement for Hp test - UBTComes to LG laboratories with requirement for Hp test Comes to LG laboratories with requirement for Hp test -- UBTUBT

On the internet he found - Hp is cancerogen of the 1.classOn theOn the internetinternet he foundhe found -- HpHp isis ccancerogenancerogen of the of the 11..classclass

On the internet he found - LG laboratory, non-invasive Hp testOn theOn the internetinternet he foundhe found -- LGLG laboratolaboratory, nonry, non--invainvassivivee Hp Hp testtest


66

13C-UBT performed on the individual wish (self-paying)Value of 13C DOB – 14.1 ‰, Hp - positive

( Normal values up to DOB 5 ‰ )

1313CC--UBTUBT performed on the individual wish (selfperformed on the individual wish (self--paying)paying)Value of Value of 1313C DOB C DOB –– 14.1 ‰, 14.1 ‰, HpHp -- popossitivitivee

( ( NormNormaall values up to values up to DOB DOB 55 ‰ )‰ )

Comes to GE ambulance with requirement foreradication therapy, which the alone cannot pay

Comes toComes to GE ambulance GE ambulance with requirement forwith requirement foreradieradication cation tthheraperapyy,, which the alone cannot paywhich the alone cannot pay

On the internet he found - suitable eradication therapyOn theOn the internetinternet he foundhe found -- suitablesuitable eeradiradiccaation therapytion therapy

CASE: 12-01 - laboratory dataCASECASE:: 1212--01 01 -- laboratorlaboratoryy datadata


European Helicobacter Pylori Study GroupCurrent Concepts in the Management of

Helicobacter pylori InfectionThe Maastricht 2-2000 Consensus Report

September 2000

European Helicobacter PyloriEuropean Helicobacter Pylori StudyStudy GroupGroupCurrent Concepts in theCurrent Concepts in the Management ofManagement of

Helicobacter pylori InfectionHelicobacter pylori InfectionTheThe Maastricht 2Maastricht 2--20002000 ConsensusConsensus ReportReport

SeptemberSeptember 20002000

77

WHO TO TREAT - STRONGLY RECOMMENDED INDICATIONSWHO TO TREAT WHO TO TREAT -- STRONGLY RECOMMENDED INDICATIONSSTRONGLY RECOMMENDED INDICATIONS

DU/GU (active or not, including complicated PUD) 1

MALToma 2

Atrophic gastritis 2

Post-gastric cancer resection 3

Patients - first degree relatives of gastric cancer patients 3

Patients wishes (after full consultation with their physician) 4

DUDU//GUGU ((active oractive or not,not, including complicatedincluding complicated PUD)PUD) 11

MALTomaMALToma 22

AtrophicAtrophic gastritisgastritis 22

PostPost--gastric cancer resectiongastric cancer resection 33

PatientsPatients -- first degree relatives of gastric cancer patientsfirst degree relatives of gastric cancer patients 33

Patients wishesPatients wishes ((after full consultation with their physicianafter full consultation with their physician)) 44


HCl HCl

88

HOW TO PREDICT RESULT of Hp INFECTIONHOW TO PREDICT RESULT of Hp INFECTIONHOW TO PREDICT RESULT of Hp INFECTION

HCl HCl

GASTRIN ↑GASTRIN GASTRIN ↑↑ GASTRIN ↑GASTRIN GASTRIN ↑↑

ATROPHYCANCER

ATROATROPHYPHYCANCERCANCER

DUODENALULCER

DUODENDUODENAALLULCERULCER

NODISEASE

NONODISEASEDISEASE

BACTERIAL TRIBE - GENETIC DISPOSITION - ENVIRONMENT - DIETS ?BACTERIAL TRIBE BACTERIAL TRIBE -- GENETIC DISPOSITIONGENETIC DISPOSITION -- ENVIRONMENT ENVIRONMENT -- DIETS ?DIETS ?

H.Pylori + hostH.H.PyloriPylori + + hosthost


99

Suspected - Gastritis - Hp infection - Gastric-cancer Suspected Suspected -- Gastritis Gastritis -- HpHp infecinfection tion -- GastricGastric--cancer cancer


negative Hp,normal PGI/PGII

normal G-17b

negative Hp,normal PGI/PGII

normal G-17b

positive Hp,normal PGI/PGII

normal G-17b

positive Hp,normal PGI/PGII

normal G-17b

Hp +/-,low PGI/PGIIhigh G-17b

Hp +/-,low PGI/PGIIhigh G-17b

positive Hp,low PGI/PGII

low G-17b

positive Hp,low PGI/PGII

low G-17b

No risk of a stomach disease

No risk of No risk of a a sstomachtomach diseasedisease

Increased risk ofgastric or duodenal

ulcer

IncreasedIncreased risk ofrisk ofgastric or duodenalgastric or duodenal

ulcerulcer

Increased risk ofgastric cancer

IncreasedIncreased risk ofrisk ofgastric cancergastric cancer

detection HpPGI/PGII, G-17b

detection HpPGI/PGII, G-17b

H. pylori gastritisH.H. pyloripylori gastritisgastritis Atrophic gastritis Atrophic gastritiAtrophic gastritis s

Eradicate H. pylori infection + consider gastroscopyEradicateEradicate H.H. pylori infectionpylori infection + + cconsider gastroscopyonsider gastroscopy

Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Agréus L, Kuipers EJ, Kupcinskas L, Malfertheiner P, et al.

Scand J Gastroenterol. 2012; 47(2):136-147

Rationale in diagnosis and screeningRationale in diagnosis and screening ofof atrophicatrophic gastritisgastritis with stomachwith stomach--specific specific plasmaplasma biomarkersbiomarkers.. AgréusAgréus L,L, KuipersKuipers EJ,EJ, KupcinskasKupcinskas L,L, MalfertheinerMalfertheiner P,P, et alet al..

ScandScand JJ GastroenterolGastroenterol. 2012; 47(2):136. 2012; 47(2):136--147147

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Hp INFECTION DIAGNOSTICHp INFECHp INFECTION TION DIAGNOSTIDIAGNOSTICC

non-invasive test, gold standard, specificity and sensitivity 95% - 13C UBT, breath test with 13C-urea

non-invasive test, if 13C-UBT not available, Hp antigen in stool

rapid urease test (CLO test) - if the gastroscopy clinically indicated, required bioptic samples from at least three different gastro-duodenal positions

IgA-IgG antibodies determination in serum does not have primary diagnostic importance, as positivity to Hp-antibodiesin subjects > 60 years could be 85%

non-invasive test, gold standard, specificity and sensitivity 95% - 13C UBT, breath test with 13C-urea

non-invasive test, if 13C-UBT not available, Hp antigen in stool

rapid urease test (CLO test) - if the gastroscopy clinically indicated, required bioptic samples from at least three different gastro-duodenal positions

IgA-IgG antibodies determination in serum does not have primary diagnostic importance, as positivity to Hp-antibodiesin subjects > 60 years could be 85%


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1122

Woman - L.J. - born 1972in childhood anemic, asthenic, often in sanatoria,

mother and sister followed for thyreopathyastheny, height 171 cm, weight 52 kg

menarche at 15 years, married,at the time of diagnosis (2005) after 1 spont. abortion 1994

WomanWoman -- L.J. L.J. -- born born 19721972in childhoodin childhood anemicanemic, , asthenicasthenic, , often in sanatoria,often in sanatoria,

mother and sister followed for mother and sister followed for thyreopatthyreopathyhyasthenasthenyy, , heightheight 171171 cm, cm, weightweight 5252 kgkg

menarchmenarchee atat 15 15 yearsyears, , married,married,at the time of diagnosisat the time of diagnosis (2005) (2005) afterafter 1 spont. 1 spont. abortionabortion 19941994

CASE: 12-02CASECASE:: 1212--0202


1313

2005 admitted to gastroenterology clinic

with requiremed of colonoscopy for hypochrome anemia

Colonoscopy - normal findings

Histology of bioptical samples - normal findings

2005 2005 admitted to admitted to gastroenterologgastroenterology cy clinilinicc

with requiremed of colonoscopy for with requiremed of colonoscopy for hypochypochhromromee anemianemiaa

CColoolononossccopopyy -- normnormaal l findingsfindings

Histology of bioptical samplesHistology of bioptical samples -- normnormaal l findingsfindings

CASE: 12-02CASECASE:: 1212--0202

Routine laboratory test indicatedRoutine laboratory test indicatedRoutine laboratory test indicated


1414

haemoglobin 117 g/l, haematocrit 0.352

albumin 46.6 g/lalkaline phosphatase 1.54 ukat/l

alanine aminotransferase 0.52 ukat/laspartate aminotransferase 0.43 ukat/l

gamma-glutamyl transpeptidase 0.16 ukat/lcalcium 2.35 mmol/l

phosphate 1.22 mmol/lferrum 22.9 mmol/l

total cholesterol 3.19 mmol/ltriglycerides 0.65 mmol/l

hhaaemoglobinemoglobin 117117 g/l,g/l, hhaaematoematoccritrit 0.3520.352

albumin albumin 46.646.6 g/lg/lalkalialkalinene phphososphphatatasease 1.1.5454 ukatukat/l/l

alanine aminotransferalanine aminotransferasease 0.0.5252 ukatukat/l/laspartate aminotransferaspartate aminotransferasease 0.0.4343 ukatukat/l/l

gammagamma--glutamyl transpeptidglutamyl transpeptidasease 0.0.1616 ukatukat/l/lccalciumalcium 2.2.3535 mmolmmol/l/l

phphososphatephate 1.1.2222 mmolmmol/l/lferrumferrum 22.922.9 mmolmmol/l/l

totaltotal cholesterol cholesterol 3.193.19 mmolmmol/l/ltriglyceridtriglycerideses 0.650.65 mmolmmol//ll

CASE: 12-02 - laboratory dataCASECASE:: 1212--0202 -- laboratorlaboratoryy datadata


1515

coeliac screening markers - 11/4/05:

IgA anti-transglutaminase 132 U/ml

IgA anti-gliadin 30 U/ml

IgG anti-gliadin 132 U/ml

IgA anti-endomysium - positive

ccooeliaeliac screening markers c screening markers -- 11/4/05:11/4/05:

IgA antiIgA anti--transglutamintransglutaminasease 132 U/ml132 U/ml

IgA antiIgA anti--gliadin 30gliadin 30 U/mlU/ml

IgG antiIgG anti--gliadin 132 gliadin 132 U/mlU/ml

IgA antiIgA anti--endomysium endomysium -- popossitivitivee

Histology - small bowel biopsy:active coeliac, subtotal atrophy, decreased lactase, IEL 50/100

Histology Histology -- small bowel biopsy:small bowel biopsy:active active ccooeliaeliacc, subtot, subtotaal atrol atrophyphy, , decreased decreased lalaccttasease, IEL 50/100, IEL 50/100



ICEBERG HYPOTHESIS OF COELIAC INCIDENCEICEBERG HYPOTHESIS OF COELIAC INCIDENCEICEBERG HYPOTHESIS OF COELIAC INCIDENCE

POTENTIAL CSPOTENTIAL CS

LATENT CSLATENT CS

SILENT CSSILENT CS

CLINICAL CSCLINICAL CS

HLA DQw2, IEL, γ/δ IELHLA DQw2, IEL, HLA DQw2, IEL, γ/δ γ/δ IELIEL

NORMAL MUSOCA, + MARKERYNORMNORMAALL MUSOCAMUSOCA,, + MARKERY+ MARKERY

MUCOSAL DEFECT, ASYMPTOMATICMUCOSAL DEFECT, ASYMPTOMATICMUCOSAL DEFECT, ASYMPTOMATIC

CLINICAL Dg.CCLINICLINICALAL Dg.Dg.

HISTOLOGY Dg.HISTOLOGYHISTOLOGY Dg.Dg.

SEROLOGY Dg.SEROLOGSEROLOGY Y DgDg..

1616

TRANSIENT CSTRANSIENT CS

ATYPICAL CSATYPICAL CS

((NNONON CS)CS)

INCIDENCE 1:1000INCIDENCE 1:1000INCIDENCE 1:1000




Dermatitis herpetiformisOsteoporosis, unexplained fracturesUnexplained anaemiaChronic fatigue syndrome Resistent irritable bowel syndromeSpont. abortion and fetal growth retardationUnexplained anaemia (iron, folic acid)HypertransaminasemiaRecurrent aphthous stomatitisDental enamel hypoplasiaDiabetes mellitus type 1.Autoimmune thyroiditisAutoimmune liver diseaseSystemic lupus erythematosusSjögren syndromePrimary biliary cirrhosis or sclerosing cholangitis

Dermatitis herpetiformisOsteoporosis, unexplained fracturesUnexplained anaemiaChronic fatigue syndrome Resistent irritable bowel syndromeSpont. abortion and fetal growth retardationUnexplained anaemia (iron, folic acid)HypertransaminasemiaRecurrent aphthous stomatitisDental enamel hypoplasiaDiabetes mellitus type 1.Autoimmune thyroiditisAutoimmune liver diseaseSystemic lupus erythematosusSjögren syndromePrimary biliary cirrhosis or sclerosing cholangitis

MAIN RISK GROUPSMAINMAIN RIRISK GROUPSSK GROUPS

CD SUSPECTED SYMPTOMSCCDD SUSPECTEDSUSPECTED SYMPTOMSYMPTOMSS

AUTOIMUNNE DISEASESAUTOIMUNNAUTOIMUNNEE DISEASESDISEASES

1717

TARGETED COELIAC SCREENINGTARGETED COELIAC SCREENINGTARGETED COELIAC SCREENING


1818


C. Briani et al. / Autoimmunity Reviews 7 (2008) 644–650C.C. Briani et alBriani et al. /. / Autoimmunity ReviewsAutoimmunity Reviews 7 (2008) 6447 (2008) 644––650650

Definitive diagnosis of CDDefinitive diagnosis of CD

Gluten free dietGluten free diet

HLA HLA typitypingng,,bbiopsiopsy rey re--evaluationevaluation

IntestinalIntestinalbiopsybiopsy

negative antibodiesnegative antibodiesnegative antibodies

positiveantibodies

popossitivitiveeantibodiesantibodies

IgA deficientIgAIgA deficientdeficient

positiveantibodiespopossitivitivee

antibodiesantibodies

histologichistologic features of CD features of CD

clinical andclinical and histologichistologic improvementimprovement

high clinicalhigh clinicalsuspicionsuspicion

negativebiopsy

negativenegativebiopsybiopsy

Provisional diagnosis of CDProvisional diagnosis of CD

Increased probabilityIncreased probabilityof of ccooeliaeliacscs

Low probabilityLow probabilityof of ccooeliaeliacscs

IgA atTGIgA atTG // IgA EmAIgA EmAaandnd totaltotal IgAIgA

Targeted screeningTargeted screening ofof ccooeliac diseaseeliac disease

IgIgGG atTGatTG ,, IgG EmAIgG EmAoror IgGIgG AGAAGA

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New ESPGHAN guidelines for the diagnosis of Coeliac Disease inChildren and Adolescents - Steffen Husby, Odense University Hospital, Denmark

New ESPGHAN guidelines for the diagnosis ofNew ESPGHAN guidelines for the diagnosis of CoeliacCoeliac Disease inDisease inChildren and Adolescents Children and Adolescents -- SteffenSteffen HusbyHusby,, OdenseOdense University Hospital, DenmarkUniversity Hospital, Denmark

Definitive diagnosis of CDDefinitive diagnosis of CD

IgIgAA atTGatTG2 & total 2 & total IgAIgA

Intestinal biopsyIntestinal biopsy

negative HLAnegative HLAnegative HLA positive HLApositive HLApositive HLA

anti TG2> 3x normal

anti TG2anti TG2> 3x normal> 3x normal

ExcludeExclude IgAIgA deficiencydeficiencyLow gluten intakeLow gluten intake

No risk for CDNo risk for CD

HLA DQ2 HLA DQ2 aandnd/or DQ8/or DQ8

AsymptomaticAsymptomatic person at genetic risk forperson at genetic risk for coeliaccoeliac diseasedisease

negative antibodiesnegative antibodiesnegative antibodies

anti TG2< 3x normal

anti TG2anti TG2< 3x normal< 3x normal

Marsh 2 or 3

Marsh Marsh 2 or 32 or 3

EmAnegative

EmAEmAnegativenegative

Marsh 0 or 1Marsh 0 or 1Marsh 0 or 1

Normal dietNormal dietFalse positive testsFalse positive tests

Potential CDPotential CD

Transient falseTransient false pozitpozit..anti TG2anti TG2

Normal dietNormal dietFurther serology testingFurther serology testing

IgA EmAIgA EmA

EmA positiveEmAEmA positivepositive

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Old and new serological tests for celiac disease screening.Volta U., Fabbri A., Parisi C. et al. Expert Rev. Gastroenterol. Hepatol. 2010, 4(1)

Old and new serological testsOld and new serological tests forfor celiac disease screeningceliac disease screening..Volta U.,Volta U., FabbriFabbri A., Parisi C.A., Parisi C. et alet al. Expert. Expert RevRev.. GastroenterolGastroenterol.. HepatolHepatol. 2010, 4(1). 2010, 4(1)

ACTUALACTUAL PROTOPROTOCCOLOLANTIBODIES DETERMINATIONANTIBODIES DETERMINATION

(EVIDENCE (EVIDENCE -- BASED)BASED)

PERSPEPERSPECCTIVTIVEE PROTOPROTOCCOLOLANTIBODIES DETERMINATIONANTIBODIES DETERMINATION

((WORKINGWORKING HYPOTHYPOTHESISHESIS))

IgA atTGIgA atTGIgA atTG IgA atTGIgA atTGIgA atTG

+ IgA EmA++ IgA EmAIgA EmA

+ IgG atTG++ IgG atTGIgG atTG

+ IgA AGA++ IgAIgA AGAAGA

+ IgG DGP++ IgGIgG DGPDGP

INCREASE OF IgA atTG SPECIFICITYINCREASEINCREASE OFOF IgA atTGIgA atTG SPECIFICITYSPECIFICITY INCREASE OF IgA atTG SPECIFICITYCOELIAC DETECTION WITH IgA DEFFICIENCYCOELIAC DETECTION IN CHILDRENS < 2 YR

INCREASE INCREASE OFOF IgA atTGIgA atTG SPECIFICITYSPECIFICITYCOELIAC DETECTION WITHCOELIAC DETECTION WITH IgAIgA DEFDEFFICIENCYFICIENCYCOELIAC DETECTIONCOELIAC DETECTION IN CHILDRENSIN CHILDRENS < 2 YR< 2 YR

COELIAC DETECTION WITH IgA DEFFICIENCYCOELIAC DETECTION WITHCOELIAC DETECTION WITH IgAIgA DEFDEFFICIENCYFICIENCY

COELIAC DETECTION IN CHILDRENS < 2 YRCOELIAC DETECTIONCOELIAC DETECTION IN CHILDRENSIN CHILDRENS < 2 YR< 2 YR

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INTESTINAL BIOPSY IN THE COELIAC DISEASE DIAGNOSTICSINTESTINAL BIOPSY IN THE COELIAC DISEASE DIAGNOSTICSINTESTINAL BIOPSY IN THE COELIAC DISEASE DIAGNOSTICS

Clinical practice - Coeliac disease - Eur J Pediatr. - online March 2012C. M. Frank Kneepkens & B. Mary E. von Blomberg

ClinicalClinical practicepractice -- Coeliac diseaseCoeliac disease -- EurEur J Pediatr. J Pediatr. -- online Marchonline March 20122012C. M. FrankC. M. Frank KneepkensKneepkens & B. Mary E.& B. Mary E. von Blombergvon Blomberg

Marsh 0 Marsh 1 Marsh 2 Marsh 3a Marsh 3b Marsh 3cMarsh 0 Marsh 1 Marsh 0 Marsh 1 Marsh 2 Marsh 3a Marsh 3b Marsh 3cMarsh 2 Marsh 3a Marsh 3b Marsh 3c

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NORMAL MUCOSANORMNORMAL MUCOSAAL MUCOSA

TOTAL ATROPHYTTOTOTAALL ATROATROPHYPHY

NEGATIVE ANTIBODIESNEGATIVE ANTIBODIESNEGATIVE ANTIBODIES

POSITIVE ANTIBODIESPOPOSSITIVITIVE ANTIBODIESE ANTIBODIES

HEALTHY SUBJECTTRATED COELIAC

HEALTHY SUBJECTHEALTHY SUBJECTTRATED COELIACTRATED COELIAC

FLORID COELIACUNTREATED

FLORID COELIACFLORID COELIACUNTREATEDUNTREATED


GLUTEN FREE DIET (GFD) - SCREENING & DIAGNOSTICS GLUTEN FREE DIETGLUTEN FREE DIET (GFD)(GFD) -- SCREENING & DIAGNOSTICS SCREENING & DIAGNOSTICS

TREATED COELIAC ?OTHER AUTOIMMUNITY ?

TREATED TREATED CCOOELIAELIACC ??OTHER OTHER AUTOIAUTOIMMMUNITMUNITYY ??

2233

ENDOSCOPIC MARKERS OF COELIAC DISEASEENDOSCOPIC MARKERS OF COELIAC DISEASE

Normal duodenalmusoca

NormNormaall duodenalduodenalmusocamusoca

EnterscopyEntersEntersccopopyy Mosaic pattern of duodenal mucosaMoMossaiaic pattern of c pattern of duodenal mucosaduodenal mucosa

Chromoendoscopywith indigocarmineChromoendosChromoendosccopopyywith with indigoindigoccarmarmineine

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2244 http://www.lfhk.cuni.cz/kcvl/stranky/Kapsle/C-CE1.htmlhttp://www.http://www.lfhklfhk..cunicuni..czcz//kcvlkcvl//strankystranky/Kapsle/C/Kapsle/C--CE1.CE1.htmlhtml

CAPSULE ENDOSCOPYCAPSULE ENDOSCOPY

NON-INVASIVE ENDOSCOPICEXAMINATION

NON-INVASIVE ENDOSCOPICEXAMINATION

Normal duodenalmusoca


NormNormaall duodenalduodenalmusocamusoca

Mosaic pattern of duodenal mucosaMoMossaiaic pattern of c pattern of duodenal mucosaduodenal mucosa

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tTGtTG

DEAMIDATION

GASTRIC, PANCREATICPEPTIDASES, PROLYL-ENDOPEPTIDASE

CD4+ TCELL

TH1-CELLTH2-CELL

B-CELL

TISSUETRANSGLUTAMINASE

M. CELLS

INFLAMMATION

MESENCHYMALCELLS

COELIAC VILLUSATROPHY

COELIACCRYPTS HYPERTROPHYANTIBODIESANTIBODIES

IL2, γIFN, TNFIL2, γIFN, TNFIL 4,5,10IL 4,5,10

GLIADINGLIADIN

33-mer PEPTIDE33-mer PEPTIDE WHEAT

according to Mowat AT, Lancet 2003, 361: 1290accordingaccording toto MowatMowat AT, Lancet 2003, 361: 1290AT, Lancet 2003, 361: 1290

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COELIAC COELIAC TTHHERAPERAPYY

1. GLUTEN-FREE DIET1. 1. GLUTENGLUTEN--FREE DIETFREE DIET

xx5. NON-TOXIC WHEAT5. N5. NONON--TOXIC TOXIC WHEATWHEAT

4.HLA BLOCATION4.4.HLA BLOHLA BLOCATIONCATION

2. ENZYMES PEP, EP-B22. ENZYM2. ENZYMESES PEPPEP,, EPEP--B2B2xx

3. TG2 INHIBITOR3.3. TG2TG2 INHIBITORINHIBITOR

xx


2277

COELIAC THERAPY: ENZYMIC HYDROLYSISCCOOELIAELIACC THTHERAPERAPY: ENZYMICY: ENZYMIC HYDROLHYDROLYSISYSIS

INTRAINTRA--DIGESTIVDIGESTIVEEDETOXIFIDETOXIFICCAATIONTION

PREPRE--GASTRONOMICGASTRONOMICDETOXIFIDETOXIFICCAATIONTION

PROLYLPROLYL--ENDOPETIDENDOPETIDASEASELACTOBACILLUSLACTOBACILLUS,, ASPERGILUSASPERGILUS

PROTEPROTEASESASES

BABACCTERITERIAALLPROLYLPROLYL--ENDOPEPTIDENDOPEPTIDASEASE,,

CYSCYS--PEPTIDPEPTIDASE FROMASE FROM BARLEYBARLEY

MODIFICATION OF FOODMODIFICATION OF FOOD

PERORPERORAALL APAPPPLILICATION OFCATION OFENZYMENZYMESES -- HYDROLHYDROLASESASES

Alvine Pharmaceuticals Reports Positive Results With ALV003 In Phase 1 Trial of

Therapy In Development For Celiac DiseaseOctober 30, 2008

Alvine Pharmaceuticals Reports Positive Alvine Pharmaceuticals Reports Positive Results With ALV003 In Phase 1 Trial of Results With ALV003 In Phase 1 Trial of

Therapy In Development For Celiac DiseaseTherapy In Development For Celiac DiseaseOctoberOctober 30, 200830, 2008


2288

WHEAT RYE BARLEY OATS RICE SORGHUM MILLET MAIZEWHEAT RYE BARLEY OATS RICE SORGHUM MILLET MAIWHEAT RYE BARLEY OATS RICE SORGHUM MILLET MAIZEZEGLIADIN SECALIN HORDEIN AVENIN ZEINGLIADIN SECALIN HORDEIN AVENIN GLIADIN SECALIN HORDEIN AVENIN ZEINZEIN

DECREASING PATOGENICITY FOR CS

T cell receptorT cell receptorT cell receptor

DQ2 moleculeDQ2 moleculeDQ2 molecule

DECREASING TEST SENSITIVITY mAb

Gliadinstandard

mAbmAbGliadinGliadin

standardstandard

GLUTEN FREE DIET - CEREALS


GLUTEN FREE DIET GLUTEN FREE DIET -- CEREALSCEREALS

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day amount - mg gliadin/50kg weightday amount day amount -- mgmg gliadingliadin//50kg 50kg weightweight

Therapy errorFood with high gliadin level

Therapy errorTherapy errorFood with highFood with high gliadingliadin levellevel

250 g gluten free foodhigh - 9,9 mg gliadin

250 g 250 g gluten free foodgluten free foodhigh high -- 9,9 mg9,9 mg gliadingliadin

Hodnocení bezpečnosti potravin pro bezlepkovou dietu, Gabrovská D. VÚPP-Praha, 2009 - projekt 1B53002

Hodnocení bezpečnosti potravin pro bezlepkovou dietu, Hodnocení bezpečnosti potravin pro bezlepkovou dietu, Gabrovská D.Gabrovská D. VÚPPVÚPP--Praha, 200Praha, 20099 -- pprojektrojekt 1B530021B53002

GLUTEN FREE DIET - DAY QUANTITYGLUTEN FREE DIET GLUTEN FREE DIET -- DAY QUANTITYDAY QUANTITY

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since 11/2005 complete gluten-free diet2008 gave birth to a healthy daughter, who has not coeliac,

follows the diet - is on remision

sincesince 11/2005 11/2005 completecomplete glutengluten--freefree dietdiet2008 2008 gave birth to agave birth to a healthy daughterhealthy daughter, , who has not coeliac,who has not coeliac,

follows the diet follows the diet -- is on remisionis on remision

coeliac specific antibodies - 24/4/06:

IgA anti-transglutaminase 2 U/ml

IgA anti-gliadin 7 U/ml

IgG anti-gliadin 29 U/ml

IgA anti-endomysium - negative

coeliac specific antibodies coeliac specific antibodies -- 24/4/06:24/4/06:

IgA antiIgA anti--transglutamintransglutaminasease 2 U/ml2 U/ml

IgA antiIgA anti--gliadin 7 U/mlgliadin 7 U/ml

IgG antiIgG anti--gliadin 29 U/mlgliadin 29 U/ml

IgA antiIgA anti--endomysium endomysium -- negativnegativee


CASE: 12-02 - THERAPYCASECASE:: 1212--0202 -- THERAPYTHERAPY


3311

immunological markers - 24/7/12:

interferron gamma, IFNγ 57,7 (normal up tol 31 %)

tumor necrosis factor, TNFα 74,7 (normal up to 44 %)

interleukin, IL2 - 47,9 (normal up to 28 %)

immunologicalimmunological marmarkkerers s -- 24/7/12:24/7/12:

interfeinterferrron gammaron gamma,, IFNIFNγγ 57,757,7 (norma(normall up tolup tol 31 %)31 %)

tumor necrosis factor,tumor necrosis factor, TNFTNFα α 74,774,7 (norma(normall up toup to 44 %)44 %)

interleukin, interleukin, ILIL22 -- 47,947,9 (norma(normall up toup to 28 %)28 %)



LIFELONG DISEASE, PERMANENT INTESTINALINTOLERANCE OF GLUTEN, PROLAMIN PROTEINS

GENETIC FACTORS - HLA-B8, HLA-DR3, HLADQ2

INITIALISING FACTORS - GLIADIN OR SIMILAR PEPTIDES

IMMNOLOGY RESPONSE, AUTOIMMUNE TYPE OFDISEASE

DAMAGE OF SMALL INTESTINAL MUCOSA

MALABSORPTION SYNDROME

RESPONSE TO GLUTEN FREE DIET

LIFELONG DISEASE, PERMANENT INTESTINALINTOLERANCE OF GLUTEN, PROLAMIN PROTEINS

GENETIC FACTORS - HLA-B8, HLA-DR3, HLADQ2

INITIALISING FACTORS - GLIADIN OR SIMILAR PEPTIDES

IMMNOLOGY RESPONSE, AUTOIMMUNE TYPE OFDISEASE

DAMAGE OF SMALL INTESTINAL MUCOSA

MALABSORPTION SYNDROME

RESPONSE TO GLUTEN FREE DIET

COELIAC DISEASE SUMMARYCCOEOELIALIAC DISEASE SUMMARYC DISEASE SUMMARY

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H2 a 13C - BREATH TESTSHH22 aa 1313CC -- BREATH TESTSBREATH TESTS

3333

SMALL BOWEL ABSORPTION - FUNCTION TESTSSMALL BOWEL ABSORPTION - FUNCTION TESTS


Hydrogen analyserHydrogen analyserLacto FANLacto FAN

1313--CC analyseranalyserHeliHeli FANFAN

Regression of lactose malabsorption in coeliac patients after receiving a gluten-free diet.

Scand J Gastroenterol. 2008;43(2):174-177

Regression of lactose malabsorption in coeliac patients Regression of lactose malabsorption in coeliac patients after receiving a glutenafter receiving a gluten--free diet.free diet.

Scand J Gastroenterol. 2008;43(2):174Scand J Gastroenterol. 2008;43(2):174--177177

13C-xylose and 14C-xylose breath tests for the diagnosisof coeliac disease.

Scand J Gastroenterol. 2008;43(2):166-173

13C13C--xylose and 14Cxylose and 14C--xylose breath tests for the diagnosisxylose breath tests for the diagnosisof coeliac disease.of coeliac disease.

Scand J Gastroenterol. 2008;43(2):166Scand J Gastroenterol. 2008;43(2):166--173173

LALACCTTOSEOSE BREATHBREATH TESTTEST20g LA20g LACCTTOSE DOSAGEOSE DOSAGEHYDROGEN DETERMINATIONS HYDROGEN DETERMINATIONS 5 HO5 HOURSURSCUTCUT--OFF OFF VALUEVALUE 20 ppm20 ppm

DD--XYLXYLOSEOSE BREATHBREATH TESTTEST100mg 13C100mg 13C--XYLXYLOSE DOSAGEOSE DOSAGERATIORATIO 12C:13C12C:13C DETERMINATIONDETERMINATIONBREATHBREATH INDEX 30min/210minINDEX 30min/210min

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LACTOSE INTOLERANCE DIAGNOSISLACTOSE INTOLERANCE DIAGNOSIS


HISTOCHEMICAL DETECTIONOF LACTASE ACTIVITY IN THEENTEROCYTE BRUSH BORDERIMMUNOHISTOCHEMICAL TEST

HISTOCHEMICAL DETECTIONHISTOCHEMICAL DETECTIONOF LACTASE OF LACTASE AACCTIVITYTIVITY ININ THETHEENTEROCYTENTEROCYTE BRUSH BORDERE BRUSH BORDERIMIMMMUNOHISTOCHEMICUNOHISTOCHEMICALAL TESTTEST

MODERN RAPID TESTLACTASE ACTIVITY DETECTIONCHROMOGENIC METHOD

MODERNMODERN RAPID TESTRAPID TESTLACTASE LACTASE AACCTIVITYTIVITY DETECTIONDETECTIONCHROMOGENCHROMOGENICIC METMETHHODOD

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Male - A.A. - born 1938history of gallbladder problems - (cholecystolithiasis)

hypertension treatment on Ca blockers, obesityDietary error - goulash, beer

Abdominal pain around the navel broadening in the back, vomitingS-amylase 20,2, C-reactive protein 1.day 5 g/l, calcium 1,85 mmol/l

Abdominal ultrasound - cholecystolithiasa

MMaleale -- AA..AA. . -- bornborn 19381938history of history of gallbladder problemsgallbladder problems -- (cholecystolithias(cholecystolithiasisis))

hypertension treatment on Ca blockers, obesityhypertension treatment on Ca blockers, obesityDietary error Dietary error -- goulash, beergoulash, beer

Abdominal pain around the navel broadening in the back, vomitingAbdominal pain around the navel broadening in the back, vomitingSS--amylase amylase 20,220,2, C, C--reactive protein 1.day 5 g/l, calcium 1,85 mmol/lreactive protein 1.day 5 g/l, calcium 1,85 mmol/l

Abdominal ultrasound Abdominal ultrasound -- cholecystolithiasacholecystolithiasa

CASE: 12-03CASECASE:: 1212--0303

Admitted to surgary clinic – emmergency unitliquid saturation – 5000 ml/24 hrs

Admitted to surgary clinic Admitted to surgary clinic –– emmergency unitemmergency unitliquid saturation liquid saturation –– 5000 ml/24 hrs5000 ml/24 hrs


3377

5.day - CT abdomenSevere acute necrotizing pancreatitis (more than 60%)

ATB administration - cefotaxime 10 days, parenteral nutrition, febricity,

25.day – necrosis drainage under CT Complications:

Renal insufficiency, borderline cardiac compensation

5.d5.dayay -- CT abdomenCT abdomenSevere acute necrotizing pancreatitis (more than 60%) Severe acute necrotizing pancreatitis (more than 60%)

ATB ATB administration administration -- cefotaxime 10 days, parenteral nutrition, cefotaxime 10 days, parenteral nutrition, febrifebricitycity, ,

25.d25.dayay –– necrosis drainage under CT necrosis drainage under CT Complications: Complications:

Renal insufficiency, borderline cardiac compensation Renal insufficiency, borderline cardiac compensation

CASE: 12-03CASECASE:: 1212--0303


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22 33 55 77 4545 9090creatinincreatinin 130130 8888 7979 7373 7575 7575ureaurea 9.29.2 6.66.6 4.34.3 6.96.9 2.52.5 4.74.7albuminalbumin 3939 27.827.8 24.524.5 24.524.5 20.520.5 3838NaNa++ 133133 135135 135135 131 / 135131 / 135 135135 143143KK++ 3.73.7 3.63.6 3.43.4 3.4 / 3.93.4 / 3.9 4.04.0 4.94.9ClCl-- 9898 103103 100100 93 / 9693 / 96 102102 104104pHpH 7.437.43 7.46 / 7.477.46 / 7.47pCOpCO22 5.345.34 6.91 6.91 / 5.58/ 5.58BEBE 2.42.4 10.910.9 / 6.2/ 6.2HCOHCO--

33 26.326.3 34.634.6 / 3.01/ 3.01

1-2 day dehydratation 7 day metabolic alkalosis11--2 day dehydratation 7 day metabolic2 day dehydratation 7 day metabolic alalkkalalosisosis


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CASE: 12-03CASECASE:: 1212--0303

Transfer to metabolic unit of 2nd. medical clinicTransferTransfer toto metabolicmetabolic unit of 2nd. medical cunit of 2nd. medical clinilinicc


45.den abdominal CT native and contrast - enhanced biphasic.In comparison with the presence of 8.9.08 slightly accentuated necrotic deposit in pancreatic body, about 39 x 30 mm, minor

hypodense districts in cauda of the pancreas which is the border width, with unsharp bounded. Pancreatic head not enlarged,

without any deposits. Dc. pankreaticus unextended. Peripancreatical fluid better highlightet, particular cranially

from the pancreas - 100 x 110 mm and anterior to the pancreas 110 x 60 mm, fluid collection up to the front of the left renal fascia.

Cholecystolithiasis. Fluidothrax right posterior 71 x 25 mm.

45.den abdominal CT native and contrast45.den abdominal CT native and contrast -- enhanced biphasic.enhanced biphasic.In comparison with the presence of 8.9.08 slightly accentuated In comparison with the presence of 8.9.08 slightly accentuated necrotic depositnecrotic deposit in pancreatic body, about 39 x 30in pancreatic body, about 39 x 30 mm, minor mm, minor

hypodensehypodense districts in cauda of the pancreas which is the border districts in cauda of the pancreas which is the border widthwidth, , with unsharpwith unsharp bounded. Pancreatic head not enlarged, bounded. Pancreatic head not enlarged,

without any deposits. Dc. pankreaticus unextended. without any deposits. Dc. pankreaticus unextended. Peripancreatical fluid better highlightet,Peripancreatical fluid better highlightet, particular cranially particular cranially

from the pancreas from the pancreas -- 100 x 110 mm and anterior to the pancreas 100 x 110 mm and anterior to the pancreas 110 x 60 mm,110 x 60 mm, fluid collection up to the front of the left renal fascia. fluid collection up to the front of the left renal fascia.

Cholecystolithiasis.Cholecystolithiasis. Fluidothrax right posterior 71 Fluidothrax right posterior 71 x 25 x 25 mmmm..

4040

45.day transfer to metabolic unit of 2nd. medical clinicintroduced naso-jejunal probe, pulled the drain, gradually increased

enteral nutrition to 2200 ml per day (2200 kcal, 85 g protein)Drugs: proton pump inhibitors (omeprazole 2x20 mg),

substituted pancreatic enzymes (Creon 25000j 3 x 1 cps),liquid free, probiotics. Conducted training for home

enteral nutrition and released to home care

45.45.dday transferay transfer toto metabolicmetabolic unit of 2nd. medical cunit of 2nd. medical cliniliniccintroduced nasointroduced naso--jejunal probejejunal probe,, pulled the pulled the drdraiainn, , gradually increased gradually increased

enteralenteral nutrition to 2200 ml per day (2200 kcal, 85 g protein)nutrition to 2200 ml per day (2200 kcal, 85 g protein)Drugs: proton pump inhibitors (omeprazole 2x20 mg),Drugs: proton pump inhibitors (omeprazole 2x20 mg),

substituted pancreatic enzymes (Creon 25000j 3 x 1 substituted pancreatic enzymes (Creon 25000j 3 x 1 cpscps)),,liquid liquid freefree,, probiotics. Conducted training for homeprobiotics. Conducted training for home

enteral nutrition and released to home careenteral nutrition and released to home care

The ICU 52 days, 55 days in the hospital, then home enteralnutrition 93 days, gradual transfer to oral intake.

Proton pump inhibitors discontinued,and patient gradually discontinued probiotics ,

The ICU 52 days, 55 days in the hospital, then home enteralThe ICU 52 days, 55 days in the hospital, then home enteralnutrition 93 days, gradual transfer to oral intakenutrition 93 days, gradual transfer to oral intake..

Proton pump inhibitors discontinued,Proton pump inhibitors discontinued,and and patient gradually discontinued probioticspatient gradually discontinued probiotics ,,


CASE: 12-03CASECASE:: 1212--0303

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Cholecystectomy performed after 5 months.Continued pancreatic enzyme application,

Creon 25000 - 3 x 1 cps, total 1,5 year with good effect.

CCholecysteholecystecctotomy performed after 5 months.my performed after 5 months.Continued Continued panpanccreatic enzymreatic enzyme application,e application,

CCreon 25000reon 25000 -- 3 x 1 3 x 1 cpscps, , total total 1,5 1,5 year with good eyear with good effffeect. ct.


90.day - CT and contrast - enhanced abdominal natively.Conclusion: Compared with the measurement of 19.9.08

increased pancreatic pseudocyst extending peripherally to the mediastinum. Splenic vein thrombosis with colleterals at large

curvature of the stomach. Necrosis of the pancreatic body, relatively less is its head and tail. Small deposit in the liver,

nonspecific appearance. Multiple cholecystolithiasis. Duodenal diverticulum..

90.d90.dayay -- CT and contrastCT and contrast -- enhanced abdominal natively.enhanced abdominal natively.Conclusion: Compared with the measurement of 19.9.08 Conclusion: Compared with the measurement of 19.9.08

increased pancreatic pseudocyst extending peripherally to the increased pancreatic pseudocyst extending peripherally to the mediastinum.mediastinum. Splenic vein thrombosis with colleterals at large Splenic vein thrombosis with colleterals at large

curvature of the stomach.curvature of the stomach. Necrosis of the pancreatic body, Necrosis of the pancreatic body, relatively less is its head and tail.relatively less is its head and tail. Small deposit in the liverSmall deposit in the liver,,

nonspecific appearance.nonspecific appearance. Multiple cholecystolithiasis. Multiple cholecystolithiasis. Duodenal diverticulum..Duodenal diverticulum..

CASE: 12-03CASECASE:: 1212--0303

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After 1,5 year executed exocrine pancreatic secretion tests :

FELA (fecal elastase-1) 378 μg/g (normal above 200 μg/g)13C-MTG breath test, 6hr. cPDR - 51 % (normal above 30 %)

After After 1,5 1,5 yearyear executedexecuted exocrineexocrine panpanccreatic sereatic seccreretion teststion tests ::

FELA (FELA (fecal fecal elastelastasease--1) 378 1) 378 μμg/gg/g (normal above 200(normal above 200 μμg/gg/g))1313CC--MTG MTG breath breath testtest,, 6hr. 6hr. cPDR cPDR -- 51 % 51 % (normal above 30(normal above 30 %%))

Pancreatic enzyme substitution discontinued,at this time gall diet without pancreatic substitution.

PPananccreaticreatic enzymeenzyme substitusubstitution tion discontinueddiscontinued,,at this time gall diet without pancreatic substitutionat this time gall diet without pancreatic substitution..



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CHRONIC PANCREATITIS DIAGNOSTICSCHRONICCHRONIC PANPANCCREATITREATITIS DIAGNOSTICSIS DIAGNOSTICS

EUSEUS ERCPERCP MRCPMRCP

SENSITIVITSENSITIVITYY 56% (4056% (40--72)72) 72% (5872% (58--86)86) 54% (4454% (44--64)64)

SPECIFICITSPECIFICITYY 81% (6881% (68--95)95) 75% (6075% (60--90)90) 78% (7278% (72--83)83)

Diagnosis of mild chronic pancreatitis (Cambridge classification)Sai JK, Suyama M, Kubokawa Y, Watanabe S.

World J Gastroenterol 2008 February 28; 14(8): 1218 - 1221Researchers Test the Value of ERPC for the Detection of Early Chronic Pancreatitis

Frei R. - Gastroent.Endoscop.News 2007, 58, 02

DiagnosisDiagnosis ofof mild chronic pancreatitismild chronic pancreatitis (Cambridge (Cambridge classificationclassification))SaiSai JK,JK, SuyamaSuyama M,M, KubokawaKubokawa Y,Y, WatanabeWatanabe S. S.

WorldWorld JJ GastroenterolGastroenterol 20082008 FebruaryFebruary 28; 14(8): 1218 28; 14(8): 1218 -- 12211221ResearchersResearchers TestTest the Valuethe Value of ERPC forof ERPC for the Detectionthe Detection ofof Early Chronic PancreatitisEarly Chronic Pancreatitis

FreiFrei R. R. -- GastroentGastroent..EndoscopEndoscop..NewsNews 2007, 58, 022007, 58, 02


Diagnostic imaging for mild chronic pancreatitisDiagnostic imaging for mild chronic pancreatitisEndoscopic ultrasound (EUS)Endoscopic ultrasound (EUS)

Endoscopic retrograde cholangiopancreatography (ERCP) Endoscopic retrograde cholangiopancreatography (ERCP) Magnetic resonance cholangiopancreatography (MRCP)Magnetic resonance cholangiopancreatography (MRCP)

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Quantitative MRCP assessment of pancreatic exocrine reserve and itscorrelation with faecal elastase-1 in patients with chronic pancreatitis

Manfredi R. el al. Radiol med. - DOI 10.1007/s11547-011-0774-6

Quantitative MRCP assessment of pancreatic exocrine reserve and Quantitative MRCP assessment of pancreatic exocrine reserve and itsitscorrelation with faecal elastasecorrelation with faecal elastase--1 in patients with chronic pancreatitis1 in patients with chronic pancreatitis

Manfredi R. el al. Radiol med. Manfredi R. el al. Radiol med. -- DOI 10.1007/s11547DOI 10.1007/s11547--011011--07740774--66

MRCP - SECRETION VOLUMEMATHEMATICAL PROCEDUREPANCREATIC FUNCTION TEST

MRCP MRCP -- SESECCRERETION VOLUMETION VOLUMEMATHEMATICAL PROCEDUREMATHEMATICAL PROCEDUREPANPANCCREATIC FUNCREATIC FUNCTION TESTTION TEST


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EXOCRINE PANCRAETIC FUNCTION TESTSEXOEXOCCRINRINEE PANPANCCRAETRAETIC FUNCTION TESTSIC FUNCTION TESTS


STOOL SAMPLING - 72hr.STOOL SAMPLINGSTOOL SAMPLING -- 7272hr.hr.

STANDARD METHOD FOREXOCRINE PANCREATIC FUNCTION

STANDARDSTANDARD METMETHHODOD FORFOREXOEXOCCRINRINEE PANPANCCREATREATIC FUNCTIONIC FUNCTION

S-CCK TESTSS--CCKCCK TESTTEST

FAT 72 hr.FATFAT 72 72 hrhr..

WITHOUT STIMULATION

WITHOUT WITHOUT STIMULATIONSTIMULATION

FECALELASTASE

FECALFECALELASTASEELASTASE

INDIRECTSTIMULATION

INDIRECTINDIRECTSTIMULATIONSTIMULATION STIMULATING

MEALSTIMULASTIMULATINGTING

MEALMEAL SUBSTRATESUBSTRSUBSTRATEATE

SECRETORY CAPACITYGRADING CHP

SECRETORY CAPACITYSECRETORY CAPACITYGRADING CHPGRADING CHP

DIGESTIVE FUNCTIONOF (LIPID) DIGESTIONDIGESTIVE FUNCTIONDIGESTIVE FUNCTIONOF (LIPID) DIGESTIONOF (LIPID) DIGESTION

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250mg13C-MTG250mg250mg

1313CC--MTGMTG

MAIZE BREAD20g FAT

MAIZE BREADMAIZE BREAD20g 20g FATFAT

PANCREATICLIPASE

PANPANCCREATICREATICLIPLIPASEASE

SUBSTITUTIONTHERAPY

SUBSTITSUBSTITUTIONUTIONTTHHERAPERAPYY

PERORAL ADMINISTRATIONPERORAL ADMINISTRATIONPERORAL ADMINISTRATION

DRUGLIPASEDRUGDRUG

LIPLIPASEASE

13C-MARKERANALYSIS

1313CC--MARKERMARKERANALYSISANALYSIS

EXOCRINE PANCRAETIC FUNCTION TESTSEXOEXOCCRINRINEE PANPANCCRAETRAETIC FUNCTION TESTSIC FUNCTION TESTSBIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGY Kocna P.BIOCHEMICBIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGYAL DIAGNOSTICS IN GASTROENTEROLOGY KocnaKocna P.P.

13C- MTG BREATH TEST 1313CC-- MTG BREATH TEST MTG BREATH TEST

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peroraladminitration

peroralperoraladminitrationadminitration

enzymichydrolytic

GIT function

enzymicenzymichydrolytichydrolytic

GIT GIT funcfunctiontion

13C 1313C C

absorptionabsorpabsorptiontion

13C 1313C C

eliminationeliminaeliminationtion

measurementof 13C/12C ratiomeasurementmeasurementof of 1313C/C/1212CC ratioratio

cummulativeCO2 output

ccuummmulmulativeativeCOCO22 outputoutput

cPDRcPDRcPDR

13CO21313COCO22

CO2 excretionCOCO22 excretionexcretion


13C-substrate1313CC--substrsubstraattee

meal = bread + fatmeal = bread + fatmeal = bread + fat

4488 Kahl S., Best Pract.Res.Clin.Gastro. 2004KahlKahl SS., ., Best PractBest Pract..ResRes..ClinClin..GastroGastro. . 20020044


40 - 120 kIU LIPASE

THERAPY OK

THERAPY OK

COMBINATION WITH PPI

THERAPY OK

MALABSORPTIONSYNDROME

OTHER SOURCES

FAILED THERAPY

PABA, PLT, 13C-MTG TESTWITH SUBSTITUTION

FAILED THERAPY

SUBSTITUTION THERAPY

PANCREAS RESECTION

40 - 120 kIU LIPASE

THERAPY OK

THERAPY OK

COMBINATION WITH PPI

THERAPY OK

MALABSORPTIONSYNDROME

OTHER SOURCES

FAILED THERAPY

PABA, PLT, 13C-MTG TESTWITH SUBSTITUTION

FAILED THERAPY

SUBSTITUTION THERAPY

PANCREAS RESECTION

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10152025303540

Control CyFi05

10152025303540

Control CyFi

10 mg/kg 13C-MTGcPDR 6 hours1100 mg/kg mg/kg 1313CC--MTGMTGcPDRcPDR 6 hours6 hours

13Carbon mixed triglyceride breath testand pancreatic enzyme supplementation in cystic fibrosis

Amarri S. et al.: Archives of Disease in Childhood 1997; 76: 349–351

13Carbon13Carbon mixed triglyceride breathmixed triglyceride breath testtestand pancreaticand pancreatic enzymeenzyme supplementation in cystic fibrosissupplementation in cystic fibrosis

AmarriAmarri S.S. et alet al.:.: ArchivesArchives ofof Disease in ChildhoodDisease in Childhood 1997; 76: 3491997; 76: 349––351351

CF without enzyme therapy2400 IU lipase/kg/food4800 IU lipase/kg/food

CFCF without enzyme therapywithout enzyme therapy2400 IU lipase2400 IU lipase//kgkg//foodfood448800 IU lipase00 IU lipase//kgkg//foodfood

cPDR 13CcPDRcPDR 1313CC

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13C-MTG - BREATH TEST WITH MIXED TRIGLYCERIDE13C-MTG - BREATH TEST WITH MIXED TRIGLYCERIDE

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CUT-OFF FELA: 200 μg/gCUTCUT--OFF FELAOFF FELA: 200 : 200 μμg/gg/g

FELA μg/gFELA FELA μμg/gg/g

CUT-OFF MTG: 30 %CUTCUT--OFF MTGOFF MTG: : 3030 %%

PANCREATITISPAPANCREATITISNCREATITIS

100 μg/g100 100 μμg/gg/gcPDR MTG (%)cPDRcPDR MTG (%)MTG (%)

NORMALNORMALNORMALCHP-ACHP-BCHP-CCHP-DNON-CHP

CHPCHP--AACHPCHP--BBCHPCHP--CCCHPCHP--DDNONNON--CHPCHP

246 BREATH TESTS WITH 13C-MTG160 CHP - 73 CONTROLS (NON-CHP)

CONFORMITY MTG & FELA - 80.2 % (191/238)

246 BREATH246 BREATH TESTTESTS WITHS WITH 1313CC--MTGMTG160 CHP 160 CHP -- 7733 CONTROLS (NONCONTROLS (NON--CHP)CHP)

CONFORMITYCONFORMITY MTG & FELA MTG & FELA -- 8080.2.2 % (% (191911/238/238) )


13C-MTG - BREATH TEST & FECAL ELASTASE13C-MTG - BREATH TEST & FECAL ELASTASE

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10,0

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CUT-OFF FELA: 200 μg/gCUTCUT--OFF FELAOFF FELA: 200 : 200 μμg/gg/g

FELA μg/gFELA FELA μμg/gg/g

CUT-OFF MTG: 30 %CUTCUT--OFF MTGOFF MTG: : 3030 %%

100 μg/g100 100 μμg/gg/gcPDR MTG (%)cPDRcPDR MTG (%)MTG (%)

NORMALNORMALNORMAL

GROUP OF 28 CHP OF FTN WITH NORMAL VALUES OF BOTH PANCEATIC TESTS

FELA > 200 mg/g MTG > 30.0 %

GROUP OF 28 CHP OF FTN WITH NORMAL GROUP OF 28 CHP OF FTN WITH NORMAL VALUES OF BOTH PANCEATIC TESTSVALUES OF BOTH PANCEATIC TESTS

FELA > 200 mg/g MTG > 30.0 %FELA > 200 mg/g MTG > 30.0 %

SUBSTITUTION THERARYEXCESSED

IN 93 % PATIENTS

SUBSTITUTION THERARYSUBSTITUTION THERARYEXCESSED EXCESSED

IN 93 % PATIENTS IN 93 % PATIENTS

13C-MTG - BREATH TEST & FECAL ELASTASE13C-MTG - BREATH TEST & FECAL ELASTASEBIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGY Kocna P.BIOCHEMICBIOCHEMICAL DIAGNOSTICS IN GASTROENTEROLOGYAL DIAGNOSTICS IN GASTROENTEROLOGY KocnaKocna P.P.

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13C-breath test provides a comprehensive assessment of MTG digestive process - digestion of lipids

Values of cPDR 13C-MTG test are cummulative data, which includes as well the pancreatic function, as substitution therapy

Cut-off value of cPDR 13C-MTG test, lower limit of normalsestablished by mathematical approximation is 30%

To assess exocrine pancreatic function testing is an appropriatecombination of 13C -MTG breath test and determination of faecal elastase 1, affecting various aspects

Economical benefit of exocrine pancreatic function tests is in possibility to exclude pancreatic substitution therapy in more than three-fourths patients with suspected pancreatic insufficiency.

13C-breath test provides a comprehensive assessment of MTG digestive process - digestion of lipids

Values of cPDR 13C-MTG test are cummulative data, which includes as well the pancreatic function, as substitution therapy

Cut-off value of cPDR 13C-MTG test, lower limit of normalsestablished by mathematical approximation is 30%

To assess exocrine pancreatic function testing is an appropriatecombination of 13C -MTG breath test and determination of faecal elastase 1, affecting various aspects

Economical benefit of exocrine pancreatic function tests is in possibility to exclude pancreatic substitution therapy in more than three-fourths patients with suspected pancreatic insufficiency.

EXOCRINNE PANCREATIC FUNCTION TESTSEXOCRINNE PANCREATIC FUNCTION TESTS


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Colorectal carcinoma is the most common tumor of the GE tractIn the Czech Republic (2008) was diagnosed 8236 subjects with CRC,

on CRC died 4313 patients, more than 50% of the mortality is due to the high proportion of patients diagnosed in advanced stages III and IV

Screening over 50 years - the target population in the Czech Republic includes 3,782,524 subjects

FOBT/TOKS screening test was carried out in 2010 only in 370,905 persons, ie. 9.8%

FOBT/TOKS + indicated colonoscopyin 2009 found only 618 CRC of 8236 diagnosed CRC, which is only 7.5%

Colorectal carcinoma is the most common tumor of the GE tractColorectal carcinoma is the most common tumor of the GE tractIn the Czech Republic (2008) was diagnosed 8236 subjects with CRIn the Czech Republic (2008) was diagnosed 8236 subjects with CRC, C,

on CRC died 4313 patients, on CRC died 4313 patients, more than 50%more than 50% of the mortality is of the mortality is due to the high proportion of patients diagnosed in due to the high proportion of patients diagnosed in advanced advanced stages III and IVstages III and IV

Screening over 50 years Screening over 50 years -- the target population in the Czech Republic the target population in the Czech Republic includes includes 3,782,524 3,782,524 subjectssubjects

FOBT/TOKS FOBT/TOKS screening test was screening test was carried outcarried out in 2010 only in 2010 only in in 370,905 370,905 persons, iepersons, ie. . 9.8% 9.8%

FOBT/TOKS + indicated FOBT/TOKS + indicated colonoscopycolonoscopyin 2009in 2009 found only 618 found only 618 CRCCRC of of 82368236 diagnosed diagnosed CRCCRC, , which is only 7.5% which is only 7.5%

Recommendations for the Ministry of Health Commission proposes a solution which enables

1. increase the number of subjects with FOBT/TOKS2. increase the detection of early CRC with more accurate test TOKS

regional cooperation with general practitionersand offer quantitative FIT for FOBT/TOKS

Recommendations for the Ministry of Health Commission Recommendations for the Ministry of Health Commission proposes a solution which enablesproposes a solution which enables

1. 1. increase the numbeincrease the number of subjectsr of subjects with FOBT/with FOBT/TOKSTOKS2. 2. increase the detection of early increase the detection of early CCRC RC with more accurate testwith more accurate test TOKSTOKS

regional cooperation with general practitionersregional cooperation with general practitionersand offer quantitative and offer quantitative FIT for FOBT/TOKSFIT for FOBT/TOKS


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g-FOBT i-FOBT qi-FOBT0

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g-FOBT i-FOBT qi-FOBTHaemoccultHaemoccult

28,728,7%% 56,856,8%% 83,483,4%%

g-FOBT – GUAJAC TEST, HAEMOCCULTgg--FOBT FOBT –– GUAJAGUAJACC TEST, HAEMOCCULTTEST, HAEMOCCULT

gg--FOBT FOBT WITH SENSITIVITY < WITH SENSITIVITY < 30% 30% USED TILL 31.12. 2012USED TILL 31.12. 2012

Commitee of CRC screening at Ministry of health CR, July 2012Commitee of CRC screening at Ministry of health CR, July 2012Commitee of CRC screening at Ministry of health CR, July 2012


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g-FOBT qi-FOBTi-FOBTRapid Rapid testtest

28,728,7%% 56,856,8%% 83,483,4%%

i-FOBT QUALITATIVE, RAPID TESTii--FOBT FOBT QUQUALITATIVALITATIVEE,, RAPID RAPID TESTTEST

2 TIMES HIGNER SENSITIVITY OF 2 TIMES HIGNER SENSITIVITY OF ii--FOBTFOBTss TO GUAJAC gTO GUAJAC g--FOBTsFOBTs


5757

SAMPLINS SYSTEM - OC SENSOR μSAMPLINS SAMPLINS SYSTSYSTEEMM -- OC SENSOR OC SENSOR μμ


ALUMINIUM FOILPERFORATION

ALUMINIUM FOILALUMINIUM FOILPERFORAPERFORATIONTION

FILTRATIONOF SAMPLE EXTRACT

FILTRATIONFILTRATIONOF SAMPLE EXTRACTOF SAMPLE EXTRACT

25 μl INJECTTO CUVETTE25 25 μμll INJECTINJECTTO CUVETTETO CUVETTE

STOOL SAMPLEINSERT

STOOL SAMPLESTOOL SAMPLEINSERTINSERT

TRANSFER of 10 mgSTOOL SAMPLE

TRANSFER of TRANSFER of 10 mg10 mgSTOOL SAMPLESTOOL SAMPLE

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Levi Z.,Rozen P.,Hazazi R.,Vilkin A.,Waked A.,Maoz E.,Birkenfeld S.,Leshno M.,Niv Y.Ann Intern Med. 2007;146:244-255

A Quantitative Immunochemical Fecal Occult Blood Test for Colorectal Neoplasia

LeviLevi Z.,Rozen P.,Z.,Rozen P.,HazaziHazazi R.,R.,VilkinVilkin A.,A.,WakedWaked A.,A.,MaozMaoz E.,E.,BirkenfeldBirkenfeld S.,S.,LeshnoLeshno M.,Niv Y.M.,Niv Y.Ann InternAnn Intern Med. 2007;146:244Med. 2007;146:244--255255

AA Quantitative Immunochemical Fecal Occult BloodQuantitative Immunochemical Fecal Occult Blood Test forTest for Colorectal NeoplasiaColorectal Neoplasia

ng Hb/mlng Hbng Hb/ml/ml SYMPTOMATIC SUBJECTS FOR COLONOSCOPYSYMPTOMATIC SUBJECTS FOR CSYMPTOMATIC SUBJECTS FOR COLONOSOLONOSCCOPOPYY


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NORMAL ADENOM ADV.ADENOM CANCER

iFOBT - OC Micro - Eikencut-off 75 ng/ml

iFOBT iFOBT -- OC MicroOC Micro -- EikenEikenccutut--offoff 7575 ngng/ml/ml

315 - 654 ng/mlmean 485 ng/ml315 315 -- 654654 ngng/ml/mlmeanmean 485485 ngng/ml/ml


25 - 45 ng/mlmean 35 ng/ml25 25 -- 4545 ngng/ml/ml

meanmean 3535 ngng/ml/ml


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van Rossum, L.G., van Rijn, A.F., Laheij, R.J., van Oijen, M.G., Fockens, P., van Krieken, H.H., Verbeek, A.L., Jansen, J.B., Dekker, E., Random

Comparison Of Guaiac And Immunochemical Fecal Occult Blood Tests ForColorectal Cancer In A Screening Population - Gastroenterology (2008)

vanvan RossumRossum, L.G., van, L.G., van RijnRijn, A.F.,, A.F., LaheijLaheij, R.J., van, R.J., van OijenOijen,, M.G., M.G., FockensFockens, P., , P., vanvan KriekenKrieken, H.H.,, H.H., VerbeekVerbeek, A.L.,, A.L., JansenJansen, J.B.,, J.B., DekkerDekker, E.,, E., RandomRandom

ComparisonComparison OfOf GuaiacGuaiac AndAnd Immunochemical Fecal Occult Blood TestsImmunochemical Fecal Occult Blood Tests ForForColorectalColorectal Cancer InCancer In AA Screening PopulationScreening Population -- GastroenterologyGastroenterology (2008)(2008)

iFOBT - OC Micro - Eikencut-off 100 ng/ml

iFOBTiFOBT -- OCOC MicroMicro -- EikenEikenccutut--offoff 100100 ngng/ml/ml

20 623 SAMPLES20 623 SAMPLESRANDOMIZATIONRANDOMIZATION

gg--FOBTFOBT ii--FOBTFOBTINVIATIONINVIATION 10 30110 301 10 32210 322PARTICIPATIONPARTICIPATION 4 8364 836 6 1576 157POSITIVE FOB TESTPOSITIVE FOB TEST 117117 339339EXAMINATIONEXAMINATION 103103 280280POLYPS AND CANCERPOLYPS AND CANCER 8080 218218ADV.ADENOMAS AND CANCERADV.ADENOMAS AND CANCER 5757 145145COLORECTAL CANCERCOLORECTAL CANCER 1111 2424

DUTCH SCREENING STUDY 2008DUTCHDUTCH SCREENINGSCREENING STUDY 2008STUDY 2008


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Value defined by manufacturer (Eiken): 100 ng/mlValue defined by manufacturerValue defined by manufacturer (Eiken): (Eiken): 100 ng/ml100 ng/ml

OPTIMIZATION OF CUT-OFF VALUE FOR qFITOPTIMIZATION OF CUTOPTIMIZATION OF CUT--OFF VALUE FOR qFITOFF VALUE FOR qFIT

Improvements in colorectal cancer screening programmes – quantitative immunochemical faecal occult blood testing .

Kovářová J.T., Zavoral M., Zima T., Žák A., Kocna P. et al. Biomed Pap 2012, 156:143

Improvements in colorectal cancer screening programmes Improvements in colorectal cancer screening programmes –– quantitative quantitative immunochemical faecal occult blood testing . immunochemical faecal occult blood testing .

Kovářová J.T., Zavoral M., Zima T., Žák A., Kocna P. et al. BiomKovářová J.T., Zavoral M., Zima T., Žák A., Kocna P. et al. Biomed Pap 2012, 156:143ed Pap 2012, 156:143

Cutoff value determines the performance of a semi-quantitative immunochemical faecal occult blood test in a colorectal cancer screening programme.

van Rossum LG, van Rijn AF et al. Br J Cancer. 2009;101:1274

Cutoff value determines the performance of a semiCutoff value determines the performance of a semi--quantitative quantitative immunochemical faecal occult blood test in a colorectal cancer simmunochemical faecal occult blood test in a colorectal cancer screening programme.creening programme.

van Rossum LG, van Rijn AF et al. Br J Cancer. 2009;101:1274van Rossum LG, van Rijn AF et al. Br J Cancer. 2009;101:1274

Pilot study in the Czech Republic: 75 ng/mlPilot studPilot study in they in the CzechCzech RRepublic: epublic: 75 ng/ml75 ng/ml

Dutch study - GE specialization: 75 ng/mlDutchDutch studstudyy -- GE specializationGE specialization: : 75 ng/ml75 ng/ml

Dutch study - economical: 50 ng/mlDutchDutch studstudyy -- eecconomiconomicalal: : 50 ng/ml50 ng/mlCost-effectiveness analysis of a quantitative immunochemical test

for colorectal cancer screening.Wilschut JA, Hol L, Dekker E et al. Gastroenterology. 2011;141:1648

CostCost--effectiveness analysis of a quantitative immunochemical test effectiveness analysis of a quantitative immunochemical test for colorectal cancer screening.for colorectal cancer screening.

Wilschut JA, Hol L, Dekker E et al. Gastroenterology. 2011;141:1Wilschut JA, Hol L, Dekker E et al. Gastroenterology. 2011;141:1648648

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Higher Fecal Immunochemical Test Cutoff LevelsTerhaar sive Droste JS et al. Cancer Epidemiol Biomarkers Prev. 2011; 20(2)

Higher Fecal Immunochemical Test Cutoff LevelsHigher Fecal Immunochemical Test Cutoff LevelsTerhaarTerhaar sive Drostesive Droste JS et al. Cancer JS et al. Cancer EpidemiolEpidemiol Biomarkers Biomarkers PrevPrev. 2011; 20(2) . 2011; 20(2)

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sensitivitysensitivitysensitivity

specificityspecificityspecificity

ngng/ml/ml

Optimization of qFIT cut-off, for indication to colonoscopy: Indicate as much as possible, all pathology - with 15% healthy subjects ?

NOT indicate healthy subjects, but decrease sensitivity about 15% ?

Optimization of qFIT cutOptimization of qFIT cut--off, for indication to off, for indication to colonoscopycolonoscopy: : Indicate as much as possible, all pathology Indicate as much as possible, all pathology -- with with 15% healthy subjects15% healthy subjects ??

NOT indicate healthy subjects, but NOT indicate healthy subjects, but decrease sensitivity about 15%decrease sensitivity about 15% ??

2145 subjects > 40 year2145 subjects > 40 yearwith with colonoscopycolonoscopy

76 x CRC76 x CRC

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Proteomics of colorectal cancer: overview of discovery studies and identification ofcommonly identified cancer-associated proteins and candidate CRC serum markers.

Jimenez CR, Knol JC, Meijer GA, Fijneman RJ. - J Proteomics. 2010;73:1873-1895

ProteomicsProteomics ofof colorectal cancercolorectal cancer:: overviewoverview ofof discovery studies and identificationdiscovery studies and identification ofofcommonly identified cancercommonly identified cancer--associated proteins and candidateassociated proteins and candidate CRCCRC serum markersserum markers. .

JimenezJimenez CR,CR, KnolKnol JC,JC, MeijerMeijer GA,GA, FijnemanFijneman RJ. RJ. -- JJ ProteomicsProteomics. 2010;73:1873. 2010;73:1873--18951895

5 year survival rate (%)5 year survival rate (%)5 year survival rate (%)

normal adenoma progressive locatized CRC lymph node CRC livercolon adenoma CRC metastasis metastasis

normal normal adenoma progressiveadenoma progressive locatized CRC lymph node CRC liverlocatized CRC lymph node CRC livercolon colon adenoma adenoma CRC metastasis metastasisCRC metastasis metastasis

10 - 15 years10 10 -- 15 years15 years

CRC stage: Dukes I-II Dukes III Dukes IVCRC stage: DCRC stage: Dukes Iukes I--II Dukes III Dukes IVII Dukes III Dukes IV

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MOLECULAR BIOLOGYDNA CHIPs FOR COLORECTAL CANCER SCREENING

MOLEMOLECCULULAARR BIOLOGBIOLOGYYDNA DNA CHIPCHIPss FOR CFOR COLOREOLORECCTTAALL CCAANCER SCREENINGNCER SCREENING


PreGen-Plus - DETECTION23 MOLECULAR MARKERS OF CR-CA

21 MUTATIONS - APC, K-ras, p53MIKROSATELLITE INSTABILITY - BAT-26

PreGenPreGen--Plus Plus -- DETECDETECTIONTION23 MOLE23 MOLECCULULAARR MARKERMARKERS OFS OF CCRR--CACA

2121 MUTAMUTATIONS TIONS -- APCAPC, K, K--ras, p53ras, p53MIKROSATELMIKROSATELLITELITE INSTABILITINSTABILITY Y -- BATBAT--2626

http://www1.lf1.cuni.cz/~kocna/glab/glency1.htmhttp://www1.lf1.http://www1.lf1.cunicuni..czcz/~/~kocnakocna//glabglab/glency1./glency1.htmhtm

6644NLM Medline on-line

abstractsNLM Medline onNLM Medline on--lineline

abstractsabstractsDirect link to MZČRNational lab.registryDirect link to MZČRDirect link to MZČRNational lab.registryNational lab.registry

http://gelab.zde.czhttp://http://gegelalab.b.zdezde..czcz


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ON - LINE INTERNET RESOURCESON ON -- LINE INTERNET RESOURCESLINE INTERNET RESOURCES

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http://gweb.zde.czhttp://http://gwebgweb..zdezde..czcz

http://www1.lf1.cuni.cz/~kocna/ge_atlas/ge_frames.htmhttp://wwwhttp://www11.lf1..lf1.cunicuni..czcz/~/~kocnakocna/g/ge_atlase_atlas//gege_frames_frames..htmhtm

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Documents

MUDr.Petr Kocna CSc. GASTROENTEROLOGY, …ukb.lf1.cuni.cz/ppt/ge_kasu2012_gb.pdfgastroenterology, laboratory diagnostics - cases ... exocrine pancreatic function ... non-invasive hp