Johan Friso Lock

Prediction of Postoperative Outcome After Hepatectomy With a New Bedside Test for Maximal Liver Function Capacity

Objective:To validate the LiMAx test, a new bedside test for the determination of maximal liver function capacity based on 13C-methacetin kinetics. To investigate the diagnostic performance of different liver function tests and scores including the LiMAx test for the prediction of postoperative outcome after hepatectomy. Summary Background Data:Liver failure is a major cause of mortality after hepatectomy. Preoperative prediction of residual liver function has been limited so far. Methods:Sixty-four patients undergoing hepatectomy were analyzed in a prospective observational study. Volumetric analysis of the liver was carried out using preoperative computed tomography and intraoperative measurements. Perioperative factors associated with morbidity and mortality were analyzed. Cutoff values of the LiMAx test were evaluated by receiver operating characteristic. Results:Residual LiMAx demonstrated an excellent linear correlation with residual liver volume (r = 0.94, P < 0.001) after hepatectomy. The multivariate analysis revealed LiMAx on postoperative day 1 as the only predictor of liver failure (P = 0.003) and mortality (P = 0.004). AUROC for the prediction of liver failure and liver failure related death by the LiMAx test was both 0.99. Preoperative volume/function analysis combining CT volumetry and LiMAx allowed an accurate calculation of the remnant liver function capacity prior to surgery (r = 0.85, P < 0.001). Conclusions:Residual liver function is the major factor influencing the outcome of patients after hepatectomy and can be predicted preoperatively by a combination of LiMAx and CT volumetry.

Early diagnosis of primary nonfunction and indication for reoperation after liver transplantation

Initial graft function is a major factor influencing the clinical outcome after liver transplantation (LTX), but a reliable method for assessing and predicting graft dysfunction directly after LTX is not available. Ninety‐nine patients undergoing deceased‐donor LTX were studied in a prospective pilot study to evaluate the LiMAx test, the indocyanine green test, and conventional biochemical parameters with respect to their sensitivity and prognostic power for the diagnosis of initial graft dysfunction. Patients suffering from initial graft dysfunction (defined as technical complications or primary nonfunction (n = 8)) had significantly decreased LiMAx readouts (43 ± 18 versus 184 ± 98 μg/kg/hour, P < 0.001) immediately after LTX. Univariate analysis also showed significant differences for serum bilirubin, ammonia, glutamate dehydrogenase, and the international normalized ratio (P < 0.05), but multivariate analysis revealed LiMAx as the single independent predictor of initial dysfunction (P = 0.008) with an area under the receiver operating characteristic curve (AUROC) of 0.960 (95% confidence interval = 0.921‐0.998, P < 0.001). In addition, the diagnosis of primary nonfunction (n = 3) was evaluated with LiMAx and aspartate aminotransferase (AST) activity on the first postoperative day. The calculated AUROC values were 0.992 (0.975‐1.0, P = 0.004) for LiMAx and 0.967 (0.929‐1.0, P = 0.006) for AST. By a combination of test results obtained directly after LTX and on the first day, LiMAx indicated primary nonfunction with a sensitivity of 1.0 (0.31‐1.0) and a positive predictive value of 1.0 (0.31‐1.0), whereas AST classification showed a sensitivity of 0.67 (0.13‐0.98) and a positive predictive value of 0.29 (0.05‐0.70). In conclusion, the assessment of initial graft function using the LiMAx test might be effective for identifying critical complications that could threaten graft survival within 24 hours after LTX. Liver Transpl 16:172–180, 2010.

How to define initial poor graft function after liver transplantation? – a new functional definition by the LiMAx test

Initial poor function (IPF) is a frequent complication after liver transplantation, but there is no consensus on its definition. Ninety‐nine patients undergoing primary deceased‐donor liver transplantation were examined in a prospective clinical trial. A new functional classification for initial graft function was developed based on two LiMAx readouts during 24 h after transplantation with a cutoff LiMAx of 60 and 120 μg/kg/h using a simple algorithm. Patients were classified as non‐ (3/99), poor‐ (23/99) and immediate function (73/99). The functional regeneration of IPF grafts was delayed until day 28 (P < 0.05). Significant differences were observed for postoperative maximal transaminase activity, bilirubin, albumin, coagulation and creatinine. Recipients’ MELD score, the donor risk index and donor age were increased in the IPF group. Incidence of haemodialysis (P = 0.003) and catecholamine support (P < 0.0001) was higher for IPF, resulting in higher therapy costs (P = 0.049). However, IPF did not influence either the length of stay (P = 0.434) or 2‐year recipient (P = 0.415) or graft survival (P = 0.495). In conclusion, the LiMAx test might provide the first adequate functional parameter to assess and classify liver graft performance from the beginning. Patients with IPF frequently suffer from secondary complications, but ultimately develop satisfactory outcome and thus worth intensive and expensive therapy.

Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease.

OBJECTIVE Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective. DESIGN This study was cross-sectional and experimental in design. METHODS Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)). RESULTS Chemerin and CMKLR1 mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R(2)=0.543; P<0.001 and R(2)=0.355; P=0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P<0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P<0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P<0.05). The incubation of PHHs with IL6 significantly increased the expression of CMKLR1 mRNA (P=0.027), while that of chemerin remained unaffected (P>0.05). None of the other metabolites showed an influence (P>0.05). CONCLUSION This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role.

Transforming Growth Factor β1 Polymorphisms and Progression of Graft Fibrosis After Liver Transplantation for Hepatitis C Virus-Induced Liver Disease

Re‐infection with the hepatitis C virus (HCV) is an important development after liver transplantation (LT); it can lead to graft fibrosis. The aim of this study was to assess the role of transforming growth factor β1 (TGF‐β1) polymorphisms in the development of HCV‐related graft disease by evaluating protocol liver biopsies. A total of 192 patients with a recurrence of HCV infection after LT were genotyped for TGF‐β1 codon 10 (C→T) and codon 25 (G→C) using the polymerase chain reaction. Histological evaluation of 614 protocol liver biopsies obtained from these patients was undertaken using the classification of Desmet and Scheuer to stage the degree of fibrosis. Mild stages of fibrosis (0‐2) were compared to advanced stages of fibrosis (3‐4) that developed during the period of infection with the virus. Correlations between the prevalence of TGF‐β1 genotypes and the different degrees of fibrosis that developed were determined. No statistically significant differences were found for genotype distributions (codons 10 and 25) with respect to recipient age, donor sex, occurrence of acute cellular rejection, and response to antiviral therapy. However, the C allele at codon 25 was significantly less frequent in the group with advanced fibrosis (P = 0.001). Furthermore, a positive association was found between progression of fibrosis and male recipient sex (P = 0.024), donor age (P = 0.041), and viral genotype 1b (P = 0.002). In conclusion, this study, in which the evolution of hepatic fibrosis was assessed histologically in a large cohort of patients with HCV re‐infection after LT, has demonstrated that the C allele at codon 25 of the TGF‐β1 gene is a marker for the development of graft fibrosis. Liver Transpl, 2011.

Systemic influence of immunosuppressive drugs on small and large bowel transport and barrier function.

Immunosuppressive drug (ISD)‐associated gastrointestinal disorders are a relevant risk factor for graft loss or patient death. The pathomechanisms and the incidence of post‐transplantation diarrhea remain to be fully understood. The aim of this study was to characterize the impact of cyclosporine A, tacrolimus (TAC), mycophenolate mofetil (MMF), enteric coated mycophenolic acid (EC‐MPA), sirolimus, everolimus (EVE) and fingolimod (FTY 720) on small and large bowel transport and barrier function. Functions of the small bowel and distal colon of Wistar rats treated for 14 days with one of the drug were analyzed using Ussing chamber method. In detail, the glucose and sodium absorption, chloride secretion, and barrier function were compared. Bowel functions were investigated by inhibition or activation of the electrogenic epithelial transport, as well as by measuring transepithelial H3‐lactulose flux. TAC altered glucose absorption; EVE glucose absorption, small bowel barrier function and chloride secretion; MMF small bowel barrier function; and EC‐MPA glucose absorption and the small bowel barrier function. Drug effects were partially dose‐dependent. In conclusion, different ISD, such as TAC, EVE, MMF, or EC‐MPA lead to different and specific patterns of pathophysiologic changes of small and large bowel barrier and transport function.

Initial liver graft function is a reliable predictor of tacrolimus trough levels during the first post‐transplant week

Lock JF, Malinowski M, Schwabauer E, Martus P, Pratschke J, Seehofer D, Puhl G, Neuhaus P, Stockmann M. Initial liver graft function is a reliable predictor of tacrolimus trough levels during the first post‐transplant week.
Clin Transplant 2011: 25: 436–443.

Treatment of recurrent hepatocellular carcinoma confined to the liver with repeated resection and radiofrequency ablation: A single center experience

BACKGROUND Recurrence of hepatocellular carcinoma (HCC) after surgical treatment is a common problem. It can be treated by radiofrequency ablation (RFA) or repeated hepatic resection (HR). This report compares both in a retrospective, single-institution database. PATIENTS AND METHODS A prospectively collected database was retrospectively analyzed. RFA was performed under ultrasound control using two different monopolar devices. All kinds of access were used: open surgical (n=10), percutaneous (n=13) and laparoscopic (n=4). HR was performed using an ultrasound aspiration device. Indication for a particular treatment was allocated on a case-by-case basis; the final decision was often made intraoperatively. RESULTS Survival after RFA (median 40 months) was similar compared to that after HR (48 months, p=0.641, logRank-test). Tumor-free survival was markedly impaired after RFA (15 vs. 29 months). This difference was however not significant (p=0.07, logRank-test). Both groups were different regarding occurrence of cirrhosis, maximal tumor size, time after initial diagnosis and duration of the procedure. CONCLUSION In this non-randomized retrospective trial, survival and disease-free survival was not significantly different when compared between patients treated by RFA and HR. There was however a tendency towards a longer tumor-free survival in the resected patients.

Nonalcoholic steatohepatits and liver steatosis modify partial hepatectomy recovery.

ABSTRACT Background: The impact of nonalcoholic fatty liver disease (NAFLD) comprising simple steatosis (NAFL) and steatohepatitis (NASH) on liver recovery after partial hepatectomy has not been evaluated. This pilot study investigated whether there is an effect of proven NAFLD on liver recovery. Methods: Thirty-one patients elected for partial hepatectomy were characterized and included into a prospective study. Liver samples were staged according to the NAFLD activity score. Liver function was measured by using the LiMAx method on postoperative days (POD) 1, 3, 5, and 10. Results: Nineteen patients were identified to suffer from NAFLD (NAFL, n = 11; NASH, n = 8). In NAFL, preoperative liver function (p = .48) and hepatic recovery on POD 1, 3, and 5 was comparable to controls (p > .05, respectively), while it was impaired on POD 10 (p = .022). NASH patients had preoperative enzymatic function comparable to controls (p = .10), but there was a trend to reduced levels on POD 1 (p = .082) and 5 (p = .062), which became significant on POD 10 (p = .003). Conclusion: This study suggests that NAFLD impairs functional recovery assessed by LiMAx after partial hepatectomy.

Interpretation of non-invasive breath tests using 13C-labeled substrates - a preliminary report with 13C-methacetin

Non-invasive breath tests can serve as valuable diagnostic tools in medicine as they can determine particular enzymatic and metabolic functions in vivo. However, methodological pitfalls have limited the actual clinical application of those tests till today. A major challenge of non-invasive breath tests has remained the provision of individually reliable test results. To overcome these limitations, a better understanding of breath kinetics during non-invasive breaths tests is essential. This analysis compares the breath recovery of a 13C-methacetin breath test with the actual serum kinetics of the substrate. It is shown, that breath and serum kinetics of the same test are significantly different over a period of 60 minutes. The recovery of the tracer 13CO2 in breath seems to be significantly delayed due to intermediate storage in the bicarbonate pool. This has to be taken into account for the application of non-invasive breath test protocols. Otherwise, breath tests might display bicarbonate kinetics despite the metabolic capacity of the particular target enzyme.