Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation.

OBJECTIVES: Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. DESIGN: Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. METHODS: TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. RESULTS: Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. CONCLUSION: Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation.

Physical performance and health-related quality of life in men on a liver transplantation waiting list.

Twenty-six men on a liver transplant waiting list (12 had alcoholic cirrhosis, 8 suffered from posthepatitic cirrhosis, and 6 from cirrhosis of other etiologies) were eligible for this observation. Nineteen subjects underwent exercise testing to determine oxygen uptake at anaerobic threshold. In all patients dynamometry was performed to determine isokinetic muscle strength of knee extensor muscles, and handgrip. Quality of life was evaluated in all patients with the MOS SF-36 questionnaire. Child-Pugh A patients showed 54 +/- 8%, Child-Pugh B patients 36 +/- 2%, and Child-Pugh C patients 31 +/- 4% of VO2 max predicted at the anaerobic threshold (Kruskal-Wallis ANOVA, p < 0.05). Isokinetic muscle strength of the quadriceps femoris (left/right) was 149 +/- 20/134 +/- 14 Nm in Child-Pugh A, 108 +/- 16/114 +/- 19 Nm in Child-Pugh B, and 89 +/- 10/81 +/- 11 Nm in Child-Pugh C patients (Kruskal-Wallis ANOVA, p < 0.05). MOS-SF36 revealed a Child-Pugh class dependent reduced functional status (Kruskal-Wallis ANOVA, p < 0.05). No significant differences in target parameters were found when analysed according to the etiology of cirrhosis. Patients on the liver transplant waiting list do have a stage dependent reduction in physical health. These data are the basis for longitudinal studies measuring the effects of preoperative rehabilitation programs in these patients.

Fulminant lethal tuberculous pneumonia (Sepsis tuberculosis gravissima) with ARDS in a non-immunocompromised western European middle-aged man.

We report the case of a 42 years old, non-immunocompromised native Austrian living in Vienna. He presented at home with severe dyspnea and had to be intubated immediately. Shortly after hospital admission, he developed severe adult respiratory distress syndrome (ARDS) and septic shock with massive, bilobar patchy to confluent infiltrations and a need for norepinephrine. A CT-scan revealed severe loss of functional lung tissue with areas of consolidation and multiple communicating cystic spaces. Air leaking into the mediastinum through fistulas produced pneumomediastinum, pneumoperitoneum, and a massive soft tissue emphysema. Bronchoalveolar lavage performed within the first 24 hours of admission revealed + of acid-fast bacilli. Even though appropriate tuberculostatic medication was started immediately, the patient succumbed the next day to ARDS due to massive tuberculous pneumonia and miliary disease (Sepsis tuberculosis gravissima).

Direct evidence for an increase in thrombopoiesis after liver transplantation.

BACKGROUND: In advanced liver cirrhosis, thrombocytopenia results from 'hypersplenism' due to increased platelet sequestration and platelet 'pooling' in the enlarged spleen and/or from reduced platelet production in the bone marrow. We sought to differentiate between these two mechanisms by studying thrombopoiesis before and after orthotopic liver transplantation by the determination of reticulated platelets, direct indicators for the thrombopoietic activity in the bone marrow. METHODS: Reticulated platelets, peripheral platelet counts, mean platelet volumes and platelet-reactive antibodies were determined in 15 patients suffering from advanced liver cirrhosis before and during an observation period of 14 days after orthotopic liver transplantation (OLT). Thrombopoietin levels of ten patients were determined before transplantation and consecutively for 14 days after surgery. RESULTS: All patients except one were thrombocytopenic before transplantation (median count 94 x 10(9) L-1, range 69-114 x 10(9) L-1). Although levels of reticulated platelets rose 2 days after surgery from baseline values of 1.0% (range 0.2-1.6%) to peak values of 4.6% (range 1.7-17.9%, P < 0.05) on day 6, platelet counts declined during the first 5 days after transplantation. When peripheral platelet counts increased to the normal range (median day 11, range day 8-33), reticulated platelets were again at pretransplant levels. Thrombopoietin levels before OLT were within the normal range (< 85 pg mL-1). On day 5 post surgery, a maximum increase of 5.8-fold (range 2.2- to 28-fold) over baseline values was observed. Mean platelet volume did not show any significant deviation from the baseline values and platelet antibodies could not be detected during the observation period. CONCLUSION: Our findings provide direct evidence for an increase in de novo platelet production after orthotopic liver transplantation. As the elevation of reticulated platelets precedes platelet recovery, it could serve as an early indicator to predict thrombopoiesis as a result of reconstituted liver function.

Preoperative TNM-classification is a better prognostic indicator for recurrence of hepatocellular carcinoma after liver transplantation than albumin mRNA in peripheral blood. Liver Transplant Oncology Group.

BACKGROUND/AIM: Survival after orthotopic liver transplantation for hepatocellular carcinoma is limited by a high rate of tumor recurrence. A polymerase chain reaction assay based on the detection of albumin mRNA expression in peripheral blood for detection of hematogenous micrometastasis of hepatocellular carcinoma has been described, which may help to select candidates for orthotopic liver transplantation. METHODS: The prognostic value of a highly sensitive nested reverse transcription-polymerase chain reaction assay was evaluated in comparison with the TNM-classification of the International Union against Cancer in a population of liver transplant candidates. RESULTS: Eighty patients with liver disease and 42 control patients were evaluated. Six of 21 patients with hepatocellular carcinoma and 11 of 59 patients with other diseases of the liver were positive for albumin reverse transcription-polymerase chain reaction, making this assay an indicator of ongoing liver damage without absolute specificity for hepatocellular carcinoma. Twelve patients with hepatoma were followed after liver transplantation and seven of those patients had a tumor recurrence within 12 months. Six of these patients with recurrence had International Union against Cancer stage IV A tumors preoperatively, while only one of them was positive for albumin reverse transcription-polymerase chain reaction before transplantation. Only one patient with a stage I to III tumor had a recurrence within 12 months. CONCLUSIONS: Detection of albumin mRNA in peripheral blood by reverse transcription-polymerase chain reaction seems to be an unreliable marker for assessing hematogenous spread of hepatocellular carcinoma. With International Union against Cancer stage IV A being a much better predictor of tumor recurrence, the practical value of albumin mRNA reverse transcription-polymerase chain reaction for patient selection in liver transplant candidates seems to be very limited.

Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C.

Thrombocytopenia is common in advanced-stage liver disease and is partly caused by inadequate thrombopoietin (TPO) production in the failing liver. Treatment of chronic hepatitis C with interferon alfa (IFN-) often induces thrombocytopenia, sometimes even leading to discontinuation of treatment. TPO regulation in response to IFN--induced thrombocytopenia was studied in patients with chronic hepatitis C with and without cirrhosis (Child A). An in vitro culture system with HepG2 cells was used to demonstrate any direct effects of IFN- on TPO mRNA expression, TPO synthesis, or TPO secretion from liver cells. Thrombocyte count was lower (U test: P < .05) in patients with hepatitis C cirrhosis compared with patients with chronic hepatitis C without cirrhosis before IFN therapy, and decreased in both patient groups (Wilcoxon matched-pairs test: P < . 05) on IFN therapy, the median decrease in both groups being comparable (noncirrhotic patients, 35%; cirrhotic patients, 32%; U test: P = .57). TPO levels rose in noncirrhotic patients (Wilcoxon matched-pairs test: P < .05), but not in patients with cirrhosis (noncirrhotic patients' median increase: 43% vs. cirrhotic patients' median decrease: 5%; U test: P < .001). Even in patients without cirrhosis, the increase in TPO levels was relatively small for the decrease in platelet count. No effect of IFN- could be demonstrated on TPO mRNA expression in vitro, but TPO secretion from liver cells was significantly reduced. Lower platelet counts but similar TPO levels in patients with chronic hepatitis C and cirrhosis compared with noncirrhotic patients and a moderate increase in TPO levels in noncirrhotic patients with a missing increase in cirrhotic patients during IFN--induced thrombocytopenia provide further evidence for an impairment of TPO production in patients with cirrhosis and during IFN therapy. Recombinant human TPO could be of value in patients developing severe thrombocytopenia under IFN- therapy.

Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.

Thrombopoietin (TPO) deficiency has been proposed as an important etiologic factor for thrombocytopenia in advanced-stage liver disease. To clarify the contributions of platelet production, platelet consumption, coagulation activation, and splenic sequestration to thrombocytopenia in liver disease, we studied TPO serum levels and markers of platelet production, platelet activation, and coagulation activation before and 14 days after orthotopic liver transplantation (OLT) in 18 patients with advanced liver cirrhosis. Thrombocytopenia before transplantation occurred with low-normal serum levels of TPO, normal levels of platelet and coagulation activation markers, and no increase in bone marrow production of platelets. TPO serum levels increased significantly on the first day after OLT, preceding the increase of reticulated platelets by 3 days and peripheral platelets by 5 days. Normalization of the peripheral platelet count occurred in most patients within 14 days of OLT, irrespective of the change in spleen size assessed by computed tomography volumetry. Normalization of platelet counts was not hampered by a certain degree of platelet activation observed during the steepest increase in the peripheral platelet count. Bone marrow production of platelets increased significantly within 2 weeks of transplantation. Low TPO serum levels with low platelet counts and without platelet consumption suggests low TPO production in end-stage liver disease. The rapid increase in TPO serum levels after transplantation induces an increase in the bone marrow production of platelets. Decreased TPO production in the cirrhotic liver is an important etiologic factor for thrombocytopenia in liver disease that is rapidly reversed by transplantation.

Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt.

BACKGROUND: In patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), prognostic scores may identify those with a poor prognosis or even those with a clear survival benefit. The Child-Pugh score (CPS) is well established but several drawbacks have led to development of the model of end stage liver disease (MELD). AIM: The aim of the study was to compare the predictive power of CPS and MELD, to validate the original MELD formula, and to assess the predictive value of the determinants used in the two prognostic scores outside of a study setting. PATIENTS: A total of 501 patients underwent elective TIPS placement and 475 patients fulfilled the inclusion criteria. METHODS: Data of all patients undergoing elective TIPS in one university hospital and four community hospitals in Vienna, Austria, between 1991 and 2001, were analysed retrospectively. The main statistical tests were Cox proportional hazards regression model, the log rank test, Kaplan-Meier analysis, and concordance c statistics. RESULTS: Median follow up was 5.2 years and median survival was 4.6 years. During follow up, 230 patients died, 75 within three months after TIPS placement. In stepwise proportional hazards analyses, independent predictors of death were creatinine level, bilirubin level, age, and refractory ascites. MELD was better in predicting survival in a stepwise Cox model but both scores were equally predictive in c statistics for one month, three month, and one year survival. Renal function was the strongest independent predictor of survival. CONCLUSIONS: Although MELD was the primary predictor of overall survival in multivariate analysis, c statistics showed that both scores can be used for patients undergoing TIPS with equal accuracy. For assessing prognosis in patients undergoing TIPS implantation, there seems little reason to replace the well established Child-Pugh score.