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Relationship Between Hepatitis C Virus Recurrence and De Novo Diabetes After Liver Transplantation: The Hungarian Experience

De novo diabetes mellitus is a common complication after liver transplantation. It is strongly associated with hepatitis C virus (HCV) infection. We analyzed the relationship between HCV recurrence and de novo diabetes among the Hungarian liver transplant population. This retrospective study included cases from 1995 to 2009 on 310 whole liver transplantations. De novo diabetes was defined if the patient had a fasting plasma glucose ≥126 mg/dL permanently after the third month post liver transplantation, and/or required sustained antidiabetic therapy. De novo diabetes occured in 63 patients (20%). The cumulative patient survival rates at 1, 3, 5, and 8 years were 95%, 91%, 88%, and 88% in the control group, and 87%, 79%, 79%, and 64% in the de novo group, respectively (P=.011). The majority of the patients in the de novo group were HCV positive (66% vs 23%). Early virus recurrence within 5 months was associated with the development of diabetes (80% vs 20% non-diabetic controls; P=.017). The fibrosis (2.05 ± 1.5 vs 1 ± 1; P=.039) and Knodell scores (3.25 ± 2 vs 1.69 ± 1.2; P=.019) were higher among the de novo group after antiviral therapy. Rapid recurrence, more severe viremia, and fibrosis showed significant roles in the developement of de novo diabetes after liver transplantation.

New-onset diabetes mellitus after liver transplantation

A de novo diabetes mellitus a majatultetes gyakori szovődmenye. Celkitűzes: A de novo diabetes gyakorisagat, jelentőseget es a kockazati tenyezők szerepet vizsgaltuk. Modszer: 1995 es 2009 kozott 310 majatultetett beteg adatait dolgoztuk fel retrospektiv modszerrel. De novo diabetest allapitottunk meg, ha az ehomi vercukor a 3. posztoperativ honapon tul ismetelten >6,8 mmol/l volt, es/vagy a majatultetes utan tartos, a 3. posztoperativ honapot meghaladoan is fenntartott antidiabetikus terapia indult. Eredmenyek: De novo diabetes a betegek 20%-anal (63 beteg) alakult ki. A de novo es a kontrollcsoport kozott az alabbiakban talaltunk kulonbseget. Donor-testtomegindex (24±3 vs. 22,4±3,6 kg/m 2 , p = 0,003), ferfi nem (58% vs. 33%, p = 0,002). Recipienseletkor (47,6±7,2 vs. 38,3±14,6 ev, p<0,001), -testtomegindex (26,7±3,8 vs. 23,3±5,6 kg/m 2 , p<0,001), ferfi nem (60% vs. 44%, p = 0,031). A de novo diabetesesek csoportjaban a betegek 66%-at HCV talajan kialakult cirrhosis miatt transzplantaltak, a kontrollcs...UNLABELLED New-onset diabetes is a common complication after liver transplantation. AIM We aimed to analyze the incidence and rate of known risk factors and the impact of new-onset diabetes mellitus on postoperative outcome. METHODS We retrospectively evaluated the files of 310 patients who underwent liver transplantation between 1995 and 2009. Definition of new-onset diabetes included: repeated fasting serum glucose >6.8 mmol/l and/or sustained antidiabetic therapy that was present 3 months after transplantation. RESULTS New-onset diabetes occurred in 63 patients (20%). Differences between the new-onset and the control group were the donor body mass index (24+/-3 vs. 22.4+/-3.6 kg/m 2 , p = 0.003), donor male gender (58% vs. 33%, p = 0.002), and recipient age (47.6+/-7.2 vs. 38.3+/-14.6 year, p<0.001), body mass index (26.7+/-3.8 vs. 23.3+/-5.6 kg/m 2 , p<0.001), male gender (60% vs. 44%, p = 0.031). The 66% of patients with new-onset diabetes were transplanted with cirrhosis caused by hepatitis C virus infection, while in the control group the rate was 23% (p<0.001). Cumulative patient survival rates at 1, 3, 5 and 8 year were 95%, 90.6%, 88% and 88% in the control group, and 87%, 79%, 79% and 64% in the de novo group, respectively (p = 0.011). Cumulative graft survival rates at 1, 3, 5 and 8 year in the control group were 92%, 87%, 86% and 79%, in the de novo diabetes group the rates were 87%, 79%, 79%, 65%, respectively (p = NS). In case of early recurrence (in 6 months), majority of patients developed new-onset diabetes (74% vs. control 26%, p = 0.03). More patients had more than 10 times higher increase of the postoperative virus titer correlate to the preoperative titer in the de novo diabetes group (53% vs. 20%, p = 0.028). Mean fibrosis score was higher in new-onset group one year after the beginning of antiviral therapy (2.05+/-1.53 vs. 1.00+/-1.08, p = 0.039). CONCLUSIONS Risk factors for new-onset diabetes after transplantation are older age, obesity, male gender and cirrhosis due to hepatitis C infection. The early recurrence, viremia and more severe fibrosis after antiviral therapy have an impact on the occurrence of new-onset diabetes in hepatitis C positive patients.

The recurrence of hepatitis C virus after liver transplantation

A hazai majatultetesi programban magas a hepatitis C-virus (HCV) okozta vegstadiumu majbetegseg miatt vegzett majatultetesek aranya. Celkituzes: A szerzok dolgozatukban elemzik a C-hepatitis miatt majatultetesen atesett betegek adatait. Modszer: Az 1995 ota vegzett 295 primer majatultetes adatainak retrospektiv elemzese: donor- es recipiens-, valamint perioperativ es tulelesi adatok, szerumvirus-RNS-titer, percutan majbiopsziak szovettani eredmenyei. Eredmenyek: A mutet 111 betegnel tortent HCV-fertozes miatt, ez az elvegzett majatultetesek 37,6%-a. A vizsgalt 111 beteg kozul 22 beteg (20%) a posztoperativ idoszakban, a virus kiujulasanak eszlelese elott, egyeb okbol meghalt. A 89 beteg kozul 16 esetben (18%) a virus visszatereset meg nem eszleltek, 73 betegnel (82%) azonban a virus kiujulasa szovettanilag igazolhato volt. Negyven betegnel (56%) a C-virus okozta hepatitis kiujulasat egy even belul eszleltek, kozuluk 28 esetben (39%) 6 honapon belul, 12 esetben hat honapon tul, de 1 even belul (17%), es 32 betegnel (44%) egy even tul. A vegstadiumu C-cirrhosis miatt majatultetett betegek kumulativ 1, 3, 5 es 10 eves tulelese 73%, 67%, 56% es 49% volt. A HCV-negativ, majatultetett betegeknel ezek az ertekek 80%, 74%, 70% es 70%, a kulonbseg szignifikans. A majgraft kumulativ tulelese HCV-pozitiv betegeknel 72%, 66%, 56% es 49% volt, mig HCV-negativ betegeknel 76%, 72%, 68% es 68%, itt nem szignifikans a kulonbseg. Korai kiujulas eseten szignifikansan magasabb szerumvirus-RNS-titert mertek az elso 6 honapban majatultetes utan. A majatultetes utan 6 honappal vett protokollbiopszia korai kiujulas eseten magasabb Knodell-pontszamot eredmenyezett, mint kesoi kiujulaskor. A fibrosisindex eseteben ez forditva volt. A majatultetestol az elso antiviralis kezelesig eltelt ido 1995–2002 kozott atlagosan 20 honap volt, 2003 ota 8 honap. Kovetkeztetesek: Az idosebb donorokbol szarmazo, marginalis majgraftok magasabb vertranszfuzio-igeny mellett torteno beultetese elorevetiti a hamarabb bekovetkezo virusrekurrenciat. Ezt a tendenciat erositi a posztoperativ akut rejectio es az emiatt adott szteroid boluskezeles. A kombinalt antiviralis kezeles protokollja kulonbozik az altalanosan alkalmazottol: az un. „stopszabaly” nem ervenyes. Virusnegativva a betegek csak kevesebb mint 10%-a valik, melynek a fenntartott immunszuppresszio az oka. A majatultetes utan koran, akar fel even belul elkezdett antiviralis kezeles a beteg- es grafttulelest pozitivan befolyasolja, es feltehetoen csokkenti a HCV-reinfekcio miatti retranszplantaciok szamat. A masodik majatultetesnel akkor varhatok jo eredmenyek, ha idoben tortenik, a recipiens meg megfelelo fizikai allapota mellett. Ennek megiteleseben a MELD-score segit. Kulcsszavak: majatultetes, hepatitis C-virus, interferon, rekurrencia, retranszplantacio, tuleles The recurrence of hepatitis C virus after liver transplantation. The main indication of the Hungarian Liver Transplant Program is liver cirrhosis caused by hepatitis C. Aim: Authors present the results of liver transplantations performed due to HCV infection. Method: The data (donor-, recipient-, perioperative characteristics, survival, serum titer of C RNA, histology) of 111 HCV positive recipients were evaluated, that are 37.6% of the 295 patients, who were transplanted since 1995 till the closure of this report. Results: Twenty-two (22) of them (20%) died in the early postoperative period, for other reasons, before the recurrence of the HCV was detectable. Among the 89 HCV-positive patients the recurrence of the HCV is still not detected in 16 cases (18%), and there is a histology-proven recurrence in 73 cases (82%). In 40 cases (56%) the viral recurrence was proven within 1 year after OLT, while in 32 cases (44%) over 1 year. The cumulative 1, 3, 5, and 10 years patient survival is 73%, 67%, 56% and 49%, among HCV-positive patients and 80%, 74%, 70% and 70% among HCV-negatives. The difference is significant. The cumulative graft survival at the same time points is 72%, 66%, 56% and 49% among HCV-positives and 76%, 72%, 68% and 68% among HCV-negatives, which is a non-significant difference. The serum titer of HCV-RNA was significantly higher among those HCV-patients who had an early viral recur

Can a Cutoff Value for Cystatin C in the Operative Setting Be Determined to Predict Kidney Function After Liver Transplantation

Correct assessment and follow-up of kidney function is essential in liver transplant recipients. Glomerular filtration rate (GFR) represents the functional capacity of the kidney. The GFR is generally determined on the basis of creatinine clearance using several methods. It has been suggested that cystatin C be used rather than GFR. Production of cystatin C is not dependent on the same factors as creatinine. It is filtered and completely metabolized in the glomeruli, and is not secreted by the kidney tubules. The objective of this study was to determine a preoperative cutoff value for cystatin C based on kidney function estimated after liver transplantation. At prefixed times before and after orthotopic liver transplantation (OLT), serum cystatin C and creatinine concentrations were measured, and GFR was calculated using the Cockroft-Gault equation. Patients were divided into 2 groups according to GFR on postoperative days 1 to 5. Group 1 (healthy recipients) included patients with post-OLT GFR greater than 70 mL/min; and group 2 (kidney-impaired recipients), post-OLT GFR less than 70 mL/min. Group 2 demonstrated greater risk of postoperative complications, abnormal postoperative creatinine concentrations and GFR values, and worse patient and graft survival. Based on the preoperative cystatin C concentration, postoperative kidney function can be assessed. The cutoff value for preoperative cystatin was determined using receiver operating characteristics analysis. When the preoperative cystatin C concentration exceeded 1.28 mg/L, the postoperative GFR was less than 70 mL/min in the first 5 days after OLT. These findings suggest that if the cystatin C concentration exceeds the cutoff point preoperatively, there will be deterioration of kidney function after OLT. Along with other researchers, we suggest that cystatin C is a sensitive marker of post-OLT kidney function.

Examination of Claudin-1 Expression in Patients Undergoing Liver Transplantation Owing to Hepatitis C Virus Cirrhosis

The cell adhesion molecule claudin-1 (CLDN-1) is a well known co-factor for the cell entry of hepatitis C virus (HCV). We examined 24 hepatic biopsies from liver transplant patients. Reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry were performed according to standard procedures. RT-PCR results were shown as relative expression (ΔCT) with beta-actin as the reference gene. Immunohistochemistry results are shown by morphometry. The CLDN-1 mRNS expression rate was significantly lower when the patient displayed favorably with an unsatisfactory to antiviral therapy 0.756 ± 0.249 versus 1.304 ± 0.28 (P=.012). There was also a strong positive correlation between CLDN-1 protein expression and liver fibrosis (Pearson correlation coefficients: r=0.476; P=.034).

Surgical aspects of pediatric liver transplantation. Living donor liver transplant program in Hungary

Because of the long waiting time for pediatric liver transplantation, new techniques of liver transplantation were invented. Split and living-donor related liver transplantation are common today and the Kaplan-Meier (3 years) overall survival is over 80%. By splitting the liver, two recipients can be transplanted. In general, the left lobe is used for the pediatric, the right lobe for the adult recipient. There are a lot of combinations depending on the donor and recipient weight. The accepted liver volume is approx. 1% of the recipient body weight. The results of the Hungarian pediatric program improve, 27 transplantations were done using 14 partial liver grafts and living donor program was started. Using strict protocols and improving surgical skills, the overall pediatric survival was over 80% in the last 5 years.

The role of marginal donors in liver transplantation. The Hungarian experience

UNLABELLED Availability of suitable donor organs has always limited liver transplantations. Use of marginal donors (Extended Donor Criteria) for liver transplantation is an alternative to overcome the organ shortage. The aim of this study was to analyze the characteristics of organ donation in Hungary with special regard to marginal donors. METHODS We reviewed data from donors and recipients between January 2003 and December 2008 retrospectively. Extended donor criteria were adopted from international recommendations. RESULTS During this period, 1078 donors were reported to the clinic. 835 (77.4%) donors were excluded from liver transplantation and 243 (22.6%) were implanted. From the 243 transplantations 40 recipients (16%) received marginal graft, 203 (84%) received non-marginal graft. Extended Donor Criteria status had no negative impact on the patient and graft survival, postoperative graft dysfunction, and other complications. Recurrence of Hepatitis C occurred earlier in those patients who received marginal graft. CONCLUSION There is an increasing number of patients waiting for liver transplantation in Hungary. There is no significant difference in morbidity and mortality of patients receiving marginal or non-marginal graft. Use of marginal grafts should be avoided in Hepatitis C virus positive recipients. Acceptance of older donors for liver transplantation should be considered.

Recurrence of primary sclerosing cholangitis after liver transplantation - The Hungarian experience.

INTRODUCTION Recurrence of primary sclerosing cholangitis (rPSC) after liver transplantation (OLT) significantly affects long-term graft survival. We aimed to evaluate the incidence of rPSC and clinical data of these patients in Hungary. PATIENTS AND METHODS We retrospectively analyzed data of 511 whole liver transplantations from 1995 to 2011. During the study period, 49 OLTs were performed in 43 adult patients with end-stage PSC (10%). RESULTS Out of 49 OLT, 24 cases were excluded, rPSC was diagnosed in six patients (12%). Patients with rPSC had significantly higher mortality (p = 0.009) and graft loss (p = 0.009) in comparison to patients without recurrent disease. Younger recipient age, higher donor BMI was observed in the rPSC group. One patient was diagnosed with de novo IBD, the remaining five patients had worsening IBD activity in the posttransplant period. PreOLT colectomy was performed in 21% of the control and none of the rPSC group. PostOLT colectomy was performed in two rPSC patients due to severe therapy resistant colitis. CONCLUSIONS Recurrent PSC significantly affects long-term mortality and graft loss. Younger age at OLT, higher donor BMI and severe active IBD may be associated with PSC recurrence. PreOLT total colectomy might have protective effect against rPSC.

Hepatitis C virus recurrence after liver transplantation in Hungary. Trends over the past 10 years

INTRODUCTION Management of hepatitis C virus recurrence is a challenge after liver transplantation. AIM The aim of the authors was to analyse the outcome of liver transplantation performed in hepatitis C virus positive patients during the past ten years and to compare recent data with a previous report of the authors. METHOD The authors retrospectively evaluated the data (donors, recipients, perioperative characteristics, patient and graft survival, serum titer of hepatitis C virus RNA, histology) of 409 patients who underwent liver transplantation between 2003 and 2012. RESULTS 156 patients were transplanted due to hepatitis C virus associated liver cirrhosis (38%). Worse outcome was observed in these patients in comparison to hepatitis C virus negative recipients. The cumulative patient survival rates at 1, 5, and 10 year were 80%, 61%, 51% in the hepatitis C virus positive group and 92%, 85%, 79% in the hepatitis C virus negative group, respectively (p<0.001). The cumulative graft survival rates at 1, 5 and 10 year were 79%, 59% and 50% in hepatitis C virus positive and 89%, 80% and 70% in hepatitis C virus negative patients (p<0.001). Hepatitis C virus recurrence was observed in the majority of the patients (132 patients, 85%), mainly within the first year (83%). The authors observed recurrence within 6 months in 71 patients (56%), and within 3 months in 26 patients (20%). The mean hepatitis C virus recurrence free survival was 243 days. Higher rate of de novo diabetes was detected in case of early recurrence. The cumulative patient survival rates at 1, 3, 5, 10 years were 98%, 89.5%, 81% and 65% when hepatitis C virus recurrence exceeded 3 months and 64%, 53%, 30.5% and 30.5% in patients with early recurrence (p<0.001). CONCLUSIONS Poor outcome of liver transplantation in hepatitis C virus positive patients is still a challenge. Hepatitis C virus recurrence is observed earlier after liver transplantation in comparison with a previous report of the authors. De novo diabetes occurs more frequently in case of early recurrence. Despite an immediate start of antiviral treatment, early recurrence has a significant negative impact on the outcome of transplantation.

Kidney function and liver transplantation

INTRODUCTION In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. AIM The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. METHOD Retrospective data analysis was performed after primary liver transplantations (n = 319). RESULTS impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). CONCLUSIONS Selection of personalized immunosuppressive medication has a positive effect on renal function.