DISSERTATION - Tele2

DISSERTATION
zur Erlangung des akademischen Grades
Doktor der gesamten Heilkunde
NEUE ERGEBNISSE ZUR DIAGNOSE UND
DIFFERENTIALDIAGNOSE VON HEPATOPATHIEN
UNTER BESONDERER BERÜCKSICHTIGUNG VON
AUTOIMMUNERKRANKUNGEN UND DER
HÄMOCHROMATOSE DER LEBER
von
Rok Kokol
eingereicht bei
Univ. Prof. Dr. G. P. Tilz
Klinische Immunologie – Jean Dausset Laboratorium
Karl - Franzens - Universität Graz
Graz im Juli 2002

ROK KOKOL – DISSERTATION
NEW RESULTS ON DIAGNOSIS AND DIFFERENTIALDIAGNOSIS
OF LIVER DISEASES UNDER SPECIAL CONSIDERATION OF AUTOIMMUNDISEASES AND THE
HEMOCHROMATOSIS OF THE LIVER
ABSTRACT
Mutations in the HFE gene are widespread in the general population. In spite of this
fact, the disease is rarely correctly diagnosed. H63D and S65C mutations hardly ever
lead to a typical clinical case of hemochromatosis. These mutations are often
responsible for abnormal blood values and are difficult to classify, therefore leading to a
wrong diagnosis. For example, patients with elevated transaminase or bilirubin values
might be misdiagnosed as suffering from alcoholism.
74 patients were examined for HFE mutations at the institute of Clinical Immunology
in Graz. Of these, one was homozygote and five were heterozygote for the C282Y
mutation, 17 were heterozygote for the H63D mutation, one was heterozygote for the
S65C mutation and one was heterozygote for the C282Y and H63D mutations.
The higher glucose values of patients with a heterozygote mutation in the HFE gene
were especially noticeable. Diabetes mellitus is a common disease, often related to
overweight and inheritance. Although various other genetic defects play a role in the
inheritance of diabetes mellitus, HFE mutations also often play a role. All of the C282Y
heterozygotes had increased glucose values; this represented 76,92% more cases than in
the control group. 7 of the 17 H63D heterozygotes also had increased glucose values.
That was almost twice as much as in the control group. No conclusions could be draw
concerning the other patients with HFE mutations due to the low patient count.
The statistics for GOT, GPT, γ-GT and other liver values show that patients with HFE
mutations tend to have increases in these values. These patients could be misdiagnosed
if the HFE mutations are not recognised. Acute liver damage resulting from alcohol
abuse might be diagnosed if these elements are not taken into consideration.
II

Der Autor bedankt sich bei:
DANKSAGUNGEN/WIDMUNGEN
Univ. Prof. Dr. G. P. Tilz für die Unterstützung und Betreuung während des Studiums und Hilfe
bei der Dissertation. Vor allem aber möchte ich mich bedanken in ihm ein Vorbild sowohl auf
beruflicher als auch auf menschlicher Ebene gefunden zu haben.
Univ. Prof. Dr. Gilbert Reibnegger für die Unterstützung bei der Dissertation und Motivation am
Anfang des Studiums.
Meiner Verlobten Dr. Michaela Pötscher für die Korrekturen, Unterstützung und Motivation bei
der Arbeit.
Meiner Mutter DI Domina Kokol für die Hilfe bei den englischen Tabellen, Texten, Motivation
und Unterstützung.
Meinem Vater DI Marjan Kokol für die Hilfe beim Layout und Drucken von Farbbildern,
Tabellen, Korrekturen und Unterstützung.
Zum Gedenken an meinen Großvater Jože Kokol, der durch den Ausbruch des Zweiten
Weltkrieges sein Medizinstudium an der Universität Graz abbrechen musste.
III

INHALTSVERZEICHNIS
Kapitel 1
LEBERERKRANKUNGEN – GRUNDLAGEN.......................................................................................................1
INFEKTIONSKRANKHEITEN ..........................................................................................................................................1
AUTOIMMUNERKRANKUNGEN ....................................................................................................................................2
AUTOIMMUNHEPATITIS (AIH) ....................................................................................................................................3
Diagnose der AIH ..................................................................................................................................................4
Klinisches Bild der AIH .........................................................................................................................................4
Laborbefunde bei AIH ...........................................................................................................................................5
Leberhistologie bei AIH.........................................................................................................................................5
Therapie und Prognose der AIH ...........................................................................................................................5
Sonderformen der AIH...........................................................................................................................................7
PRIMÄR BILIÄRE ZIRRHOSE (PBC)..............................................................................................................................7
Diagnose der PBC .................................................................................................................................................8
Therapie und Prognose der PBC ..........................................................................................................................9
PRIMÄR SKLEROSIERENDE CHOLANGITIS (PSC).......................................................................................................10
Epidemiologie der PSC........................................................................................................................................10
Diagnose der PSC................................................................................................................................................10
Therapie und Prognose der PSC.........................................................................................................................10
ERBLICHE KRANKHEITEN..........................................................................................................................................11
TUMORE.....................................................................................................................................................................11
VERGIFTUNGEN .........................................................................................................................................................12
FETTLEBER ................................................................................................................................................................12
LEBERZIRRHOSE ........................................................................................................................................................12
"GELBSUCHT"............................................................................................................................................................14
ANDERE ERKRANKUNGEN.........................................................................................................................................14
Kapitel 2
HÄMOCHROMATOSE UND EISENSTOFFWECHSEL ...................................................................................15
ZUSAMMENFASSUNG.................................................................................................................................................15
GESCHICHTE ..............................................................................................................................................................15
ALLGEMEINES............................................................................................................................................................17
Differentialdiagnose der erhöhten Eisenwerte im Serum...................................................................................17
URSACHEN.................................................................................................................................................................18
PCR - Testsystem für HFE - Mutationen (C282Y, H63D und S65C).................................................................20
ANDERE URSACHEN EINER EISENÜBERLADUNG.......................................................................................................22
Porphyria cutanea tarda......................................................................................................................................22
Afrikanische Eisenüberladung.............................................................................................................................22
Neonatale Hämochromatose ...............................................................................................................................22
Juvenile Hämochromatose ..................................................................................................................................23
Hereditäres Hyperferritinämie - Katarakt Syndrom...........................................................................................23
Friedreich Ataxie .................................................................................................................................................23
Hereditäre Atransferrinämie/Hypotransferrinämie............................................................................................24
Hereditärer Caeruloplasmin - Mangel................................................................................................................24
Sekundäre Eisenüberladung................................................................................................................................24
HÄUFIGKEIT...............................................................................................................................................................25
SYMPTOME ................................................................................................................................................................26
Diabetes mellitus..................................................................................................................................................28
Hautverfärbungen................................................................................................................................................28
Gelenksbeschwerden............................................................................................................................................29
Leberzirrhose und Leberkarzinom ......................................................................................................................29
IV

Herzbeschwerden.................................................................................................................................................29
Endokrine Probleme ............................................................................................................................................30
EISENSTOFFWECHSEL ................................................................................................................................................30
Eisengehalt und relative Bioverfügbarkeit von verschiedenen Nahrungsmitteln ..............................................32
Menstruierende und schwangere Frauen............................................................................................................33
Empfohlene Nahrungs - Eisen - Zufuhr...............................................................................................................34
Oxidativer Stress und Eisenhomöostase..............................................................................................................34
Eisenregulation ....................................................................................................................................................35
DIAGNOSE..................................................................................................................................................................36
Indirekte diagnostische Parameter......................................................................................................................36
Direkte diagnostische Parameter ........................................................................................................................37
Nichtinvasive Messung der Gewebseisenüberladung.........................................................................................38
Typische diagnostische Parameter bei hereditärer Hämochromatose ..............................................................40
Ferritin im Serum.................................................................................................................................................41
Transferrinsättigung ............................................................................................................................................41
Leberbiopsie.........................................................................................................................................................41
Genetischer Hämochromatose - Test ..................................................................................................................42
Ungesättigte Eisenbindungskapazität .................................................................................................................44
Familiäre Studien der Hämochromatose ............................................................................................................44
THERAPIE...................................................................................................................................................................44
POPULATIONSSCREENING FÜR HÄMOCHROMATOSE.................................................................................................46
KOMPLIKATIONEN.....................................................................................................................................................47
PROPHYLAXE.............................................................................................................................................................47
PROGNOSE .................................................................................................................................................................47
Kapitel 3
EIGENE DATEN VON PATIENTEN MIT C282Y -, H63D - UND S56C - MUTATIONEN ..........................48
HINTERGRUND...........................................................................................................................................................48
AUSGANGSWERTE .....................................................................................................................................................48
GOT (GLUTAMAT – OXALAZETAT – TRANSAMINASE) ............................................................................................49
DeRitis – Quotient................................................................................................................................................49
GPT (GLUTAMAT – PYRUVAT – TRANSAMINASE)....................................................................................................50
γ-GT (GAMMA – GLUTAMYLTRANSPEPTIDASE).......................................................................................................51
GLUKOSE IM BLUT (I. S.)...........................................................................................................................................53
Glukosetoleranz – Test.........................................................................................................................................53
GESAMTBILIRUBIN.....................................................................................................................................................55
EISEN .........................................................................................................................................................................56
TRANSFERRIN ............................................................................................................................................................57
CK (KREATINKINASE)...............................................................................................................................................58
CHOLINESTERASE (CHE) ..........................................................................................................................................59
EIWEIß........................................................................................................................................................................60
EIWEIßELEKTROPHORESE ..........................................................................................................................................61
HÄMOGLOBIN ............................................................................................................................................................62
ERYTHROZYTENINDIZES............................................................................................................................................63
LAKTAT – DEHYDROGENASE (LDH) ........................................................................................................................64
DISKUSSION UND INTERPRETATION ..........................................................................................................................66
V