Andrès E.

Bywaters E.G.

Coffernils M.

Cush J.J.

Fautrel B.

Ishikawa M.

Kadar J.

Linde B.

Mehrpoor G.

Mert A.

Motoo Y.

Nemes B.

Ogata A.

Singh S.

Still G.F.

Taccone F.S.

Takami A.

Teran A.

Yamaguchi M.

Zhu G.

Interventional Medicine and Applied Science

Zsófia Müller

Imre Fehérvári

Gergely Zádori

Attila Doros

Balázs Nemes

János Fazakas

András Gelley

Fanni Gelley

Tamás Micsik

AKJournals (Akadémiai Kiadó)

Acute liver transplantation in a 41-year-old male patient presenting symptoms of adult-onset Still's disease

Gelley Fanni

Doros Attila

Micsik Tamás

Fazakas János

Fehérvári Imre

Zádori Gergely

Müller Zsófia

Gelley András

Nemes Balázs

Semmelweis Repository

ISSN 2061-1617 © 2011 Akadémiai Kiadó, Budapest9CASE REPORTInterventional Medicine & Applied Science, Vol. 3 (1), pp. 9–13 (2011)IntroductionAdult-onset Still’s disease (AOSD) is one of the aetio-logic categories of fever of unknown origin (FUO). It isclassified as a connective tissue disorder. According to theliterature, 4% of patients that suffered from FUO hadAOSD (54/1329 patients); however, the incidence ofAOSD is underestimated [1]. The clinical presentationof AOSD is heterogeneous, but its clinical course is typ-ical [2]. It consists of mild or moderate liver dysfunction[3, 4], acute liver failure (ALF) being a rare manifesta-tion [5].In this report, we present a patient with undiagnosedAOSD who underwent orthotopic liver transplantation(OLT) due to ALF and survived 6 months after OLT.Case reportA 41-year-old man was admitted to our clinic on 25 Jan-uary 2009, in an unconscious condition due to ALF ofunknown aetiology. He had been healthy until October2008, when sore throat, high spiking fever (with spikes inthe afternoons), arthralgia (wrist, elbow, knee) and mac-ulopapular rash occurred suddenly. The clinical coursewith relevant laboratory data and treatment are summa-rized in Fig. 1. At first, he was treated on outpatient set-tings with amoxicillin/clavulanate (875/125 mg/day)and diclofenac (2×50 mg) for 1 week. Based on the pos-itive Chlamydia pneumoniae serology results (IgM 23NTU, IgA 13 NTU, IgG 38.8 NTU), his drug coursewas changed first to doxycycline (2×200 mg daily) andthen to clarythromycine (500 mg/day). Rash and arthral-gia were permanently present during the fever spikes de-spite sustained antibiotic therapy. Serology tests includingEpstein–Barr virus (EBV), cytomegalovirus (CMV),My-coplasma pneumoniae, Toxoplasma, Leptospira,Chlamydiapsittaci, HIV-1, -2, hepatitis B virus (HBV) and hepatitisC virus (HCV) were negative. Total immune panel in-cluding rheumatoid factor (RF) was negative. Anti-nu-clear antibody (ANA) was 1:40 positive (aspecific level).All aetiologic factors of liver damage were definitely ruledout pre-operatively. Repeated throat culture and chest X-ray were normal. On the 11 January 2009, he was admit-ted to the Department of Infectology with high spikingfever and weight loss (15–20 kg in 3 months). The pa-tient was treated with ceftriaxon (for 4 days), and thenDOI: 10.1556/IMAS.3.2011.1.3Acute liver transplantation in a 41-year-oldmale patient presenting symptoms ofadult-onset Still’s diseaseFANNI GELLEY1*, ATTILA DOROS1, TAMÁS MICSIK2, JÁNOS FAZAKAS1, IMRE FEHÉRVÁRI1,GERGELY ZÁDORI1, ZSÓFIA MÜLLER3, ANDRÁS GELLEY4, BALÁZS NEMES11Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary21st Department of Pathology and Experimental Cancer Research, Budapest, Hungary3Department of Infectology, Saint George Hospital, Székesfehérvár, Hungary4Polyclinic of Hospitaller Brothers of Saint John of God, Budapest, Hungary*Corresponding author: Fanni Gelley MD; Department of Transplantation and Surgery, Semmelweis University, Baross u. 23–25, H-1082Budapest, Hungary; Phone: +36-1-267-6000; Fax: +36-1-3170-964; E-mail: fanni.gelley@gmail.comFunding sources: the authors have no funding or conflicts of interest on this study.(Received: March 4, 2011; Accepted after revision: April 11, 2011)Abstract: Adult-onset Still’s disease is a rare systemic non-infectious inflammatory disease of unknown aetiology. It is characterized by high spik-ing fever, sore throat, arthralgia, transient maculopapular rash, hepatosplenomegaly, liver cytolysis, weight loss, leukocytosis, neutrophilia, lym-phadenopathy, myopathia and polyserositis. Mild or moderate liver involvement is common but fulminate liver failure is a rare manifestation. Wereport a 41-year-old male with undiagnosed adult Still’s disease who underwent liver transplantation due to acute fulminate liver failure. He died6 months after the liver transplantation in a septic condition. To date, six patients with adult Still’s disease-related liver failure have been reportedwho required liver transplantation. We emphasize that adult Still’s disease should be considered in the differential diagnosis of fulminate liver fail-ure, especially in young adults with fever of unknown aetiology or typical features in the history.Keywords: adult-onset, fever, fulminate liver failure, liver transplantation, Still’s disease, unknown aetiologyISSN 2061-1617 © 2011 Akadémiai Kiadó, Budapest 10 Interventional Medicine & Applied ScienceGelley et al.with amikacin, meropenem (for 7 days) and metronida-zole (for 3 days) (Fig. 1).Ultrasonography and computedtomography (CT) found hepatosplenomegaly (Fig. 2) aswell as pleural and pericardial fluid. The results of repeatedblood, urine and throat cultures were negative. Aspecific,reactive leukocytosis was described on peripheral bloodsample. It is worth mentioning that the patient had32,200 µg/L serum ferritine level. From the 22 January,high fever and exanthema relapsed and jaundice devel-oped which progressed daily. Toxic aetiology of ALF wassuggested because the patient was a poor CYP3A4 me-tabolizer. On the 25 January, he was admitted to our clinicand underwent standard OLT (whole-sized donor liverfrom a 41-year-old deceased donor) without any intra-op-erative complication. The patient fulfilled King’s Collegecriteria for ALF having an increase in international nor-malized ratio (INR) of up to 6.87. Fulminant hepaticnecrosis, but no specific aetiology, was described in theexplanted liver (Fig. 3). The patient was admitted to theintensive care unit (ICU) and was treated there for6 months. In the early post-operative period, initial poorfunction developed. Liver biopsy made on the secondpost-operative day showed Banff grade 1/9 acute cellularrejection. Tacrolimus, mycophenolate-mofetil and pred-nisolone were given as immunosuppressive therapy. Onimaging performed post-operatively, pleural fluid and as-cites, but no abscess, were found (CT). Due to clinicalsigns of peritonitis, the patient underwent relaparatomy(drainage-lavage) for three times, and a feeding jejunos-tomy was implanted. Septic episode developed on the 4thweek, without certain focus, despite the fact that Entery-obacter cloacae was verified in the ascites. Relevant antibi-otics were given. The patient was unconscious and in needof sustained respiratory therapy, and suffered of kidneyfailure. Despite an improvement in liver function and in-flammatory markers, persistent polyserositis (ascites, pleu-ral, pericardial), severe myopathy and catabolic state oc-curred. Critical-illness myopathy was described. Themuscle biopsy revealed severe non-infectious myogendamage, as well as T- and B-lymphocyte infiltration (Fig.4). A repeated liver biopsy (in April) revealed non-specificalteration that could have been the sign of either rejectionor other inflammatory processes. Due to this uncertainsituation, no anti-rejection therapy was administered. Hehad taken exercises (passive–active) and took a few stepswith help in June. On the 5 June, the feeding jejunostomywas changed to percutaneous endoscopic gastrostomy(PEG). During the disease, he had lost a total of 33 kgweight. In July, he was transferred to the rehabilitationdepartment but he was turned back to our ICU due toFig. 1. Clinical course of the patient. Typical features, relevant laboratory data and treatment from the first visit to the early post-operative periodfevertreatmentarthralgiaexanthemaOctober November December January February40 °C37 °CsevereDoxycycline 1×100 mg–2×200 mg Clarythromycine 2×500 mg Doxycycline 2×200 mgAmoxicillin/clavulanate 875/125 mg,Diclofenac 2×50 mg Ceftriaxone 1×2 gAmikacin 1×1 gMeropenem 3×1 gMetronidazole 3×100 mlplasmapheresis X3Methyl-prednisolone 125 mgMethyl-prednisolone 125 mgplasmapheresisyes dlimnoout - patient in - patient preOLT postOLTdate 10.14. 12.17 01.11. 01.14. 01.19. 01.22. 01.24. 01.25. 01.27. 02.12.Leu[G/l] 9.36 8.54 14.9 8.9 21.8 13.4 24.1 17.7 16.9 5.7Neu[%] 88.3 78.3 88.1 85.3 71.9 87 89.6 90.7 83.7CRP[mg/l] 54.26 117.5 254.5 205.8 13.6 32.9 21.8INR 1.69 2.88 4.62 3.74 >4 5.84 3.65 1.36GOT[U/l] 78 47 1415 3279 947 299 1465 269 1386 110GPT[U/l] 115 43 1053 1639 880 257 631 244 1261 157GGT[U/l] 124 76 319 183 83 47 38 31 41 302Fig. 2. CT image of the abdomen shows significant hepatospleno-megalyInterventional Medicine & Applied Science 11 ISSN 2061-1617 © 2011 Akadémiai Kiadó, BudapestAcute liver transplantation in a 41-year-old male patientclinical relapse, fever, diarrhoea and vomiting. Multi-com-partment abdominal fluid and severe pleural fluid was de-scribed, and the ascites puncture was suppurosus. He diedon 29 July due to septic shock and multi-organ failure. Atthe autopsy, chronic abdominal abscesses were found.DiscussionStill’s disease is the systemic form of juvenile idiopathicarthritis. It was first described by George Still in 1897 [6].In 1971, Bywaters [7] described a similar presentation ofthe disease in 14 adults and termed it “adult-onset Still’sdisease”. This is a rare disease; about 25 cases have been re-ported in Hungary so far [8]. The mean age is 38.1 yearsin AOSD [8] and it affects slightly more women than men[9]. In the last 40 years, AOSD has become an importantcause of FUO [10]. The pathogenesis is not completelyunderstood, but immunopathomechanisms are responsi-ble for the disease [11]. Rapid diagnosis is difficult becauseno relevant test for the disease exists. The diagnosis is basedon a set of clinical and laboratory criteria [9]. The clinicalcourse is typical as in our case (Fig. 1). The most commonFig. 3. Histology of the explanted liver. Up: fulminate necrosis can be seen on the histological slides from the explanted liver. The trabecularstructure was destroyed (HE-stained slides,×250 magnification). Left down: severe ductular proliferation could be recognized withina necrotic and inflammated tissue (HE-stained slides, ×400 magnification). Right down: only fewer than 10% hepatocytes were rec-ognizable with vacuolated cytoplasm (HE-stained slides, ×400 magnification)ISSN 2061-1617 © 2011 Akadémiai Kiadó, Budapest 12 Interventional Medicine & Applied ScienceGelley et al.features (prevalences) are high spiking fever (95–100%),transient maculopapular rash (50–87%) correlated withfever spikes and arthralgia (92–100%), lymphadenopathy(15–74%), hepatosplenomegaly (25–56%), myalgia(60–84%), polyserositis (5–31%) and weight loss. Leuko-cytosis (90–92%), neutrophilia (88–90%), increasedtransaminases (65–70%), high serum ferritine and negativeANA (80–92%) and RF (93–100%) are the most commonlaboratory features [1, 9].Several classification criteria have been published forAOSD [3, 4]. In our case, all the classification criteriawere met. Infectious diseases, tumours and autoimmunedisorders should be ruled out in the differential diagno-sis. In our case, FUO protocol examinations were all neg-ative. Tumours were ruled out (solid tumours, lympho-proliferative diseases, tumour markers), full autoimmunepanel was negative and no pathogens were detectable inthe pre-transplant setting. A high serum ferritine level(>3000 µg/L) has been reported to be a useful markerand is in good correlation with disease activity [10]. Inour case, 30,000 µg/L was measured (repeated exami-nation).Fig. 4. Histology of the muscular biosy (m. quadriceps femoris). Up: severe impairment of the muscular structure can be seen (HE-stainedslides, ×250 magnification). Left down: high variability of the diameter of the cells with more multinucleated giant cells and degen-erated, necrotized muscle fibres can be seen (HE-stained slides,×400 magnification). Right down: high amount of infiltrating leuko-cytes and fibrosis can be recognized (leukocyte common antigen immunohistochemically stained slides of ×400 magnification)Interventional Medicine & Applied Science 13 ISSN 2061-1617 © 2011 Akadémiai Kiadó, BudapestAcute liver transplantation in a 41-year-old male patientLiver involvement is frequently seen, and it is caused byAOSD itself [10, 12, 13]. Treatment for patients withliver involvement is aimed mainly at AOSD itself andmost of the patients get complete remission with systemiccorticosteroid therapy [12]. The therapy protocol forAOSD is non-steroidal anti-inflammatory drugs(NSAIDs), than corticosteroids combined with disease-modifying anti-rheumatic drugs (DMARDs) or cy-closporine; anti-IL1 or anti-TNF-α agents are also rec-ommended [11]. In our case, the typical symptoms(arthralgy, spiking fever and rash) disappeared after OLTbesides the immunosuppressive therapy. ALF in AOSD israre [5, 14]. To date, six patients with adult Still’s dis-ease-related liver failure have been reported who requiredliver transplantation. One of them died within 48 h, andfive were diagnosed in time and received proper treat-ment [15–17]. The aetiology of severe liver damage inAOSD is heterogeneous. Macrophage activation syn-drome (MAS) is a severe, and potentially life-threateningcomplication of AOSD [18]. Extremely elevated serumferritine levels (>10,000 µg/L) might reflect the pres-ence of MAS [19]. In our case, MAS was also suggested(extremely high serum ferritine level) but the patient didnot have the characteristic laboratory features and we didnot find haemophagocytosis in the explanted liver. Bonemarrow biopsy was not done. We cannot exclude thetoxic aetiology of ALF since the patient was a poor me-tabolizer of CYP 3A4. However, he was not administeredany drugs that would affect CYP 3A4 except for metron-idazole, which was given only for 3 days (January) andclarithromycine for 1 week (November). NSAIDs mightcause ALF in AOSD [10]. Our patient was treated withdiclofenac in October but it was canceled because ofstomach complaints. Rarely, the exacerbation of AOSDcan cause severe liver damage itself [5].In conclusion, we report a patient with AOSD. Ac-cording to our data files, this is the first reported case inour centre since 1995 [20–22]. We emphasize that AOSDshould be considered in the differential diagnosis of acutefulminate liver failure of unknown aetiology, especially inyoung adults and with FUO or typical features describedin the history.References1. Mert A et al.: Fever of unknown origin: a review of 20 patientswith Adult-onset Still’s disease. Clin Rheumatol 22, 89–93 (2003)2. Singh S et al.: Adult-onset Still’s disease: a study of 14 cases. ClinRheumatol 27, 35–39 (2008)3. Yamaguchi M et al.: Preliminary criteria for classification of adult’sStill’s disease. J Rheumatol 19, 424–430 (1992)4. Cush JJ et al.: Adult-onset Still’s disease. Clinical course and out-come. Arthritis Rheum 30(2), 186–194 (1987)5. Takami A et al.: Adult-onset Still’s disease with submassive hepaticnecrosis. Int Med 34, 89–91 (1995)6. Still GF: On a form of chronic joint disease in children. Med ChirTrans 80, 47 (1897)7. Bywaters EG: Still’s disease in the adult. Ann Rheum Dis 30,121–133 (1971)8. Kadar J, Petrovicz E: Adult-onset Still’s disease. Best Pract Res ClinRheumatol 18, 663–676 (2004)9. Mehrpoor G et al.: Adult-onset Still’s disease: a report of 28 casesand review of the literature. Mod Rheumatol 18, 480–485 (2008)10. Motoo Y et al.: Adult-onset Still’s disease: hepatic involvement andvarious serum markers relating to the disease activity. Jpn Med 30,247–250 (1991)11. Fautrel B: Adult-onset Still’s disease. Best Pract Res Clin Rheuma-tol 22, 773–792 (2008)12. Zhu G et al.: Liver abnormalities in adult onset Still’s disease: a ret-rospective study of 77 Chinese patients. J Clin Rheumatol 15,284–288 (2009)13. Andrès E et al.: Adult Still’s disease: an unrecognized cause of acutefebrile hepatic cytolysis. Study of twelve patients. GastroenterolClin Biol 25, 353–355 (2001)14. Linde B et al.: Fulminate liver failure in a 39-year-old female patientwith leukocytosis, unclear fever, and arthralgic pain. Med Klin 102,846–851 (2007)15. Taccone FS et al.: Fulminant hepatitis requiring MARS and livertransplantation is a patient with Still’s disease. Eur J Intern Med19, 26–28 (2008)16. Teran A et al.: Adult-onset Still’s disease with liver failure requiringliver transplantation. Gastroenterol Hepatol 32, 681–686 (2009)17. Ogata A et al.: Interleukin 18 and hepatocyte growth factor in ful-minant hepatic failure of adult onset Still’s disease. J Rheumatol30, 1093–1096 (2003)18. Ishikawa M et al.: A case of hemophagocytic syndrome with severeliver injury manifestating adult Still’s disease. Jpn J Clin Immun20, 447–452 (1997)19. CoffernilsM et al.: Hyperferritinaemia in adult onset Still’s disease andthe haemophagocytic syndrome. J Rheumatol 19, 1425–1427 (1992)20. Nemes B et al.: The demographic, perioperative and mortality char-acteristics of the Hungarian Liver Transplant Program. Orv Hetil146, 1423–1432 (2005)21. Nemes B et al.: Expression pattern of molecular chaperones afterliver transplantation in hepatitis C positive patients. Relation toserum HCV-RNA titers. Interv Med Appl Sci 1, 35–40 (2009)22. Nemes B et al.: Serum hepatitis C virus-ribonucleotide acid mon-itoring after liver transplantation: the Hungarian experience. DigLiv Dis 37, 68–69 (2005)

Gelley, Fanni

Doros, Attila

Micsik, Tamás

Fazakas, János

Fehérvári, Imre

Zádori, Gergely

Müller, Zsófia

Gelley, András

Nemes, Balázs Áron

DEA University of Debrecen Electronic Archive

English

Abstract
        Adult-onset Still's disease is a rare systemic non-infectious inflammatory disease of unknown aetiology. It is characterized by high spiking fever, sore throat, arthralgia, transient maculopapular rash, hepatosplenomegaly, liver cytolysis, weight loss, leukocytosis, neutrophilia, lymphadenopathy, myopathia and polyserositis. Mild or moderate liver involvement is common but fulminate liver failure is a rare manifestation. We report a 41-year-old male with undiagnosed adult Still's disease who underwent liver transplantation due to acute fulminate liver failure. He died 6 months after the liver transplantation in a septic condition. To date, six patients with adult Still's disease-related liver failure have been reported who required liver transplantation. We emphasize that adult Still's disease should be considered in the differential diagnosis of fulminate liver failure, especially in young adults with fever of unknown aetiology or typical features in the history.</jats:p

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http://repo.lib.semmelweis.hu/bitstream/handle/123456789/872/1686907.pdf?sequence=1

Acute liver transplantation in a 41-year-old male patient presenting symptoms of adult-onset Still's disease

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