Werner J. Mayet

Drug-induced hepatitis: a rare complication of oral anticoagulants

Hepatotoxicity is a rare complication of coumarin anticoagulants. We present the case of a 56-year-old woman who developed a viral-hepatitis-like picture 8 months after mitral valve replacement and oral anticoagulation. Phenprocoumon-induced hepatitis was diagnosed after positive reexposure and improvement following withdrawal of the drug. There appeared to be cross-reactivity to warfarin since this drug led to a similar increase in alkaline phosphatase and gamma-glutamyl transferase after a few days of administration. Liver biopsy showed an acute viral-hepatitis-like picture. Anticoagulation was changed to a subcutaneous low molecular weight heparin and low-dose aspirin. Because of the widespread use of coumarin anticoagulants, physicians should be aware of the hepatotoxic potential of these drugs, which most frequently mimics the clinical presentation of viral hepatitis.

Complete congenital heart block in autoimmune hepatitis (SLA-positive)

Complete congenital heart block is a serious complication of neonatal lupus erythematosus which most often occurs in children of mothers suffering from connective tissue disease. We report the occurrence of complete congenital heart block associated with autoimmune hepatitis (SLA-positive). A 32-year-old woman was treated for more than 10 years for autoimmune hepatitis (SLA-/ANA-positive) and remained in clinical remission under immunosuppressive therapy. She showed an MHC-haplotype typical for autoimmune hepatitis (A1, B8, DR3). After a normal first pregnancy, an emergency caesarean section was performed in the 32nd week of her second pregnancy because of fetal bradycardia. The child died a few hours after delivery of complete congenital AV-block. Retrospective analysis of the maternal serum showed the emergence of SS-A/Ro-antibodies prior to the second pregnancy. The maternal serum antibodies were reactive with the 52 kD SS-A/Ro-antigen, as demonstrated by immunoblot employing recombinant SSA/Ro-antigen. The occurrence of complete congenital heart block has been shown to be associated with the presence of SS-A/Ro antibodies as well as the MHC-haplotype DR3. With respect to this genetic linkage, pregnant patients with autoimmune hepatitis and the MHC-haplotype DR3 should be examined for the presence of SS-A/Ro-antibodies. They should be closely followed during pregnancy to enable early detection of the development of congenital heart block, as prevention by plasmapheresis plus dexamethasone may be possible at an early stage.

In vitro production of anti-neutrophilocyte-cytoplasm-antibodies (ANCA) by Epstein-Barr virus-transformed B-cell lines in Wegener's granulomatosis.

The frequent detection of anti-neutrophilocyte-cytoplasm-antibodies (ANCA) in patients with Wegeners granulomatosis (WG) led to the supposition that this disease might be of autoimmune nature. For some authors assume that Epstein-Barr virus (EBV) infection of human B-lymphocytes besides polyclonal activation could reveal the cryptic immune status against different autoantigens in patients with autoimmune diseases we investigated EBV-transformed B-lymphocytes from patients with Sjögrens syndrome, mixed connective tissue disease, WG and healthy blood donors. Two stable B-cell lines (Ho3, We1) could be established. Inhibition experiments showed that antibodies produced by transformed B-lymphocytes and serum ANCA (C-ANCA type) of 10 WG patients recognized the identical antigen. Stimulation of one clone (Ho3) with interleukin 6 (IL-6) led to a switch from IgM to IgG production. Antibodies produced by this clone also stained glomeruli of human frozen kidney sections. Western blot analysis using immunoaffinity purified antigen prepared from human granulocytes revealed a reaction with a protein of approx. 29 kD MW. Our data underscore some new aspects concerning the direct pathogenicity of C-ANCA confirming the hypothesis that the autoimmune B-cell repertoire in WG not only reflects a polyclonal B-cell activation but is shaped by antigen driven responses.

Fulminanter Verlauf einer diffusen alveolären Hämorrhagie bei systemischem Lupus erythematodes – Ein Fallbericht

Zusammenfassung Ein 31-jähriger Mann mit bekanntem systemischen Lupus erythematodes (SLE) seit dem 10. Lebensjahr war seit ca. 8 Jahren klinisch asymptomatisch und wurde seitdem nicht mehr medikamentös behandelt. Zum Zeitpunkt der Aufnahme bestanden seit zwei Tagen Belastungsdyspnoe und Fieber. Laborchemisch zeigten sich eine mikrozytäre Anämie und erhöhte Entzündungsparameter. Im Röntgen-Thorax fanden sich bihiläre und basale Infiltrate beidseits. Innerhalb weniger Stunden entwickelte der Patient ein Atemnotsyndrom und verstarb 16 Stunden nach der Aufnahme. Bei der Obduktion fiel eine massive Hämorrhagie in allen Lungenabschnitten auf. Mikroskopisch bestätigte sich eine intraalveoläre Hämorrhagie des Lungenparenchyms, wobei keine entzündliche Veränderungen beobachtet wurden. Zusätzlich zeigte sich in den Nieren eine membranöse Glomerulonephritis. Es wurde die Diagnose einer diffusen alveolären Hämorrhagie (DAH) bei bekanntem SLE und einer Lupus-Nephritis gestellt. Todesursache war eine akute Lungenblutung. Die DAH ist eine seltene Manifestation des SLE. Es handelt sich um eine Erkrankung, deren Diagnose durch den rapiden Verlauf sowie durch uneinheitliche und unspezifische Symptome und histologische Veränderungen erschwert ist. Wie der vorliegende Fall zeigt, kann eine DAH auch bei Patienten auftreten, die seit mehreren Jahren asymptomatisch sind. Da eine frühe Therapieeinleitung für eine günstige Prognose entscheidend ist, sollte bei SLE-Patienten mit einem schweren pulmonalem Krankheitsbild die DAH differentialdiagnostisch nicht außer Acht gelassen werden, wobei therapeutisch die Gabe von Kortikosteroiden im Vordergrund steht.Summary A 31-year old male patient had suffered from systemic lupus erythematosus (SLE) for 21 years. During the last 8 years he exhibited no clinical symptoms and did not receive any medical SLE treatment. He was admitted with a two-day history of dyspnea and fever. Laboratory studies revealed microcytic anemia and elevated levels of inflammation markers. Chest X-ray showed pulmonary infiltrates. The respiratory status rapidly deteriorated and the patient died 16 hours after admission. An autopsy was performed and diffuse alveolar hemorrhage in all parts of the lungs were seen, which was confirmed by microscopic examination. In contrast, lung histology did not show evidence of infection or inflammatory lesions. Additionally, membranous glomerulonephritis could be identified by light and electron microscopy. Diffuse alveolar hemorrhage (DAH) and concomittant lupus nephritis as manifestations of the known SLE were diagnosed. Acute pulmonary hemorrhage was determined as the cause of death. DAH is a rare, but serious manifestation of SLE. The diagnosis is difficult since the occurrence is abrupt and both symptoms and histology of the lesion are non-uniform and unspecific. The present case demonstrates that DAH also develops in patients that have not had clinical symptoms for several years. Since the early diagnosis is essential for the outcome, DAH should be considered in every case of SLE patients with severe pulmonary symptoms. Corticosteroids are the recommended form of therapy for this disorder.

Prostatakarzinom-assoziierte spontane Hemmkörperhämophilie

Inhibitors of factor VIII are a rare condition in non-hemophiliacs, but they are frequently responsible for life threatening hemorrhage. Acquired factor VIII:C inhibitors represent the spontaneous development of autoantibodies that partially or completely neutralize the plasma coagulant activity of the clotting factor. The autoantibodies can arise in diverse clinical settings, in older adults they are frequently associated with immunologic disorders or malignancies. We report of a 75-year-old man with acquired factor VIII:C inhibitor associated with adenocarcinoma of the prostate and a successful treatment of a severe bleeding complication with porcine factor VIII. A 75-year-old man was admitted because of a hematoma of his right cheek and an isolated prolonged aPTT. Acquired factor VIII:C inhibitor was identified as the cause and immuno-suppressive therapy was begun. In the clinical course severe hemorrhaging occurred and was successfully treated with porcine factor VIII (Hyate:C). The initially high inhibitor titer of 32 Bethesda Units (BU) disappeared. As the cause of acquired factor VIII:C inhibitor a newly diagnosed adenocarcinoma of the prostate is likely. After complete remission of acquired factor VIII:C inhibitor radiation therapy was begun. Six months after severe hemorrhaging the patient was clinically stable and PSA levels were normal. This case demonstrates the necessity of a precise diagnosis and therapy regimen of this coagulopathy based on clinical and laboratory data. In the absence of hemorrhage immuno-suppressive therapy with corticosteroids is indicated, in a patient with severe bleeding and high inhibitor titer (> or = 5 BU) porcine factor VIII should be administered.ZusammenfassungDie spontane Hemmkörperhämophilie ist eine extrem seltene, aber durch schwere Blutungskomplikationen häufig lebensbedrohliche Erkrankung. Ursächlich sind Autoantikörper gegen den Faktor VIII:C, die zu einer partiellen oder kompletten Inhibierung der Gerinnungsfunktion führen. Bei ungefähr der Hälfte der betroffenen Patienten ist das Auftreten der Autoantikörper mit anderen Erkrankungen assoziiert, bei älteren Patienten sind es häufig Autoimmunerkrankungen oder Malignome. Wir berichten über einen 75jährigen Patienten mit spontaner Hemmkörperhämophilie, der Assoziation mit einem Adenokarzinom der Prostata und der erfolgreichen Therapie einer lebensbedrohlichen Blutungskomplikation mit porzinem Faktor VIII:C (Hyate:C≿). Ein 75 Jahre alter Patient wurde wegen eines Hämatoms der rechten Wange sowie einer isolierten PTT-Verlängerung stationär aufgenommen. Als Ursache fand sich die Hemmkörperhämophilie gegen den Faktor VIII:C. Zunächst wurde eine immunsuppressive Therapie mit Prednisolon und Cyclophosphamid eingeleitet. Im weiteren Verlaufkam es zu lebensbedrohlichen Weichteilblutungen, die schließlich erfolgreich mit porzinem Faktor VIII:C (Hyate:C≿) zum Stillstand gebracht werden konnten. Der initial hohe Inhibitortiter von 32 Bethesda-Einheiten sank auf Null. Als Ursache der Hemmkörperhämophilie ist ein neu diagnostiziertes Adenokarzinom der Prostata anzunehmen. Nach kompletter Remission der Hemmkörperhämophilie wurde eine Strahlentherapie durchgeführt. Ein halbes Jahr nach der schweren Blutungskomplikation ist der Patient weiter gerinnungsstabil und das PSA wieder normwertig. Dieser Fall verdeutlicht die Notwendigkeit einer schnellen Diagnose der Koagulopathie und die Bedeutung der individuelle Auswahl der medikamentösen Therapiestrategie in Abhängigkeit vom Vorliegen oder Fehlen einer aktiven Blutung. Bei fehlender Blutung ist eine immunsuppressive Therapie mit Corticosteroiden angezeigt, bei einer akuten, schweren Blutung mit einem Hemmkörpertiter von ≧5 BU eine initiale Therapie mit porzinem Faktor VIII.SummaryInhibitors of factor VIII are a rare condition in non-hemophiliacs, but they are frequently responsible for life threatening hemorrhage. Acquired factor VIII:C inhibitors represent the spontaneous development of autoantibodies that partially or completely neutralize the plasma coagulant activitiy of the clotting factor. The autoantibodies can arise in diverse clinical settings, in older adults they are frequently associated with immunologic disorders or malignancies. We report of a 75-year-old man with acquired factor VIII:C inhibitor associated with adenocarcinoma of the prostate and a successful treatment of a severe bleeding complication with porcine factor VIII. A 75-year-old man was admitted because of a hematoma of his right cheek and an isolated prolonged aPTT. Acquired factor VIII:C inhibitor was identified as the cause and immunosuppressive therapy was begun. In the clinical course severe hemorrhaging occurred and was successfully treated with porcine factor VIII (Hyate:C≿). The initially high inhibitor titer of 32 Bethesda Units (BU) disappeared. As the cause of acquired factor VIII:C inhibitor a newly diagnosed adenocarcinoma of the prostate is likely. After complete remission of acquired factor VIII:C inhibitor radiation therapy was begun. Six months after severe hemorrhaging the patient was clinically stable and PSA levels were normal. This case demonstrates the necessity of a precise diagnosis and therapy regimen of this coagulopathy based on clinical and laboratory data. In the absence of hemorrhage immunosuppressive therapy with corticosteroids is indicated, in a patient with severe bleeding and high inhibitor titer (≧5 BU) porcine factor VIII should be administered.