LiMAx Test Research Articles

Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx)

BackgroundIn critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test.Materials/methodsThe prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured.ResultsPeak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAx < 100 µg/kg/h) when compared to patients with normal liver function (LiMAx > 300 µg/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax.ConclusionsThe present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients.Trial registry DRKS—German clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-2015

Preoperative Liver Function Guiding HCC Resection in Normal and Cirrhotic Liver

Background: Liver resection is the most effective available therapy for patients with hepatocellular carcinoma (HCC). The accurate selection of patients for surgery requires determination of technical resectability and the risk of recurrence, as well as assessment of liver function and functional reserve to avoid postoperative liver failure. Previous studies have underlined the effectiveness and reliability of the LiMAx® test to evaluate liver function preoperatively. Nevertheless, data concerning HCC evaluation are lacking. Methods: From 2014 to 2019, 92 patients with HCC underwent additional assessment of liver function using the LiMAx test prior to decision for or against liver resection. Preoperative LiMAx results were compared between cirrhotic and noncirrhotic liver. The clinical decision for surgery was evaluated applying the various liver function parameters available. Results: Forty-six patients underwent liver resection. The LiMAx results were higher in resected patients (388 vs. 322 µg/kg/h; p = 0.004). LiMAx values were an independent risk factor for the presence of liver cirrhosis in multivariate analysis. In 17 patients, surgical treatment was cancelled due to major impairment of liver function. Only 4 out of 46 resected patients presented with post-hepatectomy liver failure (PHLF) grade ≥B. Histologic assessment revealed liver cirrhosis in 10 resected patients without PHLF. Conclusion: Preoperative determination of liver function by the LiMAx test enables effective and safe patient selection for HCC resection in both cirrhotic and noncirrhotic liver.

Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition-Results from the Prospective PNLiver Trial.

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB–4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests.

A novel variant of the 13C-methacetin liver function breath test that eliminates the confounding effect of individual differences in systemic CO2 kinetics

The principle of dynamic liver function breath tests is founded on the administration of a 13C-labeled drug and subsequent monitoring of 13CO2 in the breath, quantified as time series delta over natural baseline 13CO2 (DOB) liberated from the drug during hepatic CYP-dependent detoxification. One confounding factor limiting the diagnostic value of such tests is that only a fraction of the liberated 13CO2 is immediately exhaled, while another fraction is taken up by body compartments from which it returns with delay to the plasma. The aims of this study were to establish a novel variant of the methacetin-based breath test LiMAx that allows to estimate and to eliminate the confounding effect of systemic 13CO2 distribution on the DOB curve and thus enables a more reliable assessment of the hepatic detoxification capacity compared with the conventional LiMAx test. We designed a new test variant (named "2DOB") consisting of two consecutive phases. Phase 1 is initiated by the intravenous administration of 13C-bicarbonate. Phase 2 starts about 30 min later with the intravenous administration of the 13C-labelled test drug. Using compartment modelling, the resulting 2-phasic DOB curve yields the rate constants for the irreversible elimination and the reversible exchange of plasma 13CO2 with body compartments (phase 1) and for the detoxification and exchange of the drug with body compartments (phase 2). We carried out the 2DOB test with the test drug 13C-methacetin in 16 subjects with chronic liver pathologies and 22 normal subjects, who also underwent the conventional LiMAx test. Individual differences in the systemic CO2 kinetics can lead to deviations up to a factor of 2 in the maximum of DOB curves (coefficient of variation CV ≈ 0.2) which, in particular, may hamper the discrimination between subjects with normal or mildly impaired detoxification capacities. The novel test revealed that a significant portion of the drug is not immediately metabolized, but transiently taken up into a storage compartment. Intriguingly, not only the hepatic detoxification rate but also the storage capacity of the drug, turned out to be indicative for a normal liver function. We thus used both parameters to define a scoring function which yielded an excellent disease classification (AUC = 0.95) and a high correlation with the MELD score (RSpearman = 0.92). The novel test variant 2DOB promises a significant improvement in the assessment of impaired hepatic detoxification capacity. The suitability of the test for the reliable characterization of the natural history of chronic liver diseases (fatty liver—fibrosis—cirrhosis) has to be assessed in further studies.

Dynamic determination of functional liver capacity with the LiMAx test in post-cardiac arrest patients undergoing targeted temperature management-A prospective trial.

Transiently increased transaminases is a common finding after cardiac arrest but little is known about the functional liver capacity (LiMAx) during the post-cardiac arrest syndrome and treatment in the intensive care unit (ICU). The aim of this trial was to evaluate liver function capacity in post-cardiac arrest survivors undergoing targeted temperature management (TTM) in ICU. Thirty-two post-cardiac arrest survivors were prospectively included with all patients undergoing TTM at 33°C for 24hours. Blood samples were collected, and LiMAx testing was performed at days 1, 2, 5, and 10 post-cardiac arrest. LiMAx is a non-invasive, in vivo, dynamic breath test determining cytochrome P450 1A2 (CYP1A2) capacity using intravenous (IV) 13 C-methacetin, thus reflecting maximum liver function capacity. Static liver parameters were determined and compared to LiMAx values. A typical pattern of transiently, mildly increased transaminases was demonstrated without fulfilling the criteria for hypoxic hepatitis (HH). CYP1A2 activity was reduced with slow normalization over 10days (lowest median 48hours after cardiac arrest: 228.5 (25-75 percentile 105.2-301.7μg/kg/h, P<.05). Parameters reflecting the liver synthetic function were not impaired, as assessed by, in standard laboratory testing. Liver functional capacity is impaired in patients after cardiac arrest undergoing TTM at 33°C. More data are needed to determine if liver functional capacity may add relevant information, especially in the context of pharmacotherapy, to individualize post-cardiac arrest care.

Enzymatic liver function measured by LiMAx \u2013 a reliable diagnostic and prognostic tool in chronic liver disease

Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. Non-invasive assessment of hepatic disease severity represents a relevant issue to further improve clinical management and therapeutic treatment. We retrospectively compared the diagnostic and prognostic performance of different non-invasive tools (LiMAx, transient elastography (TE), and biomarkers) in detecting different severity stages during the course of CLD. Patients were divided into four groups based on clinical parameters: (1) patients without CLD (control group), (2) patients suffering from CLD without having cirrhosis, (3) patients with CLD and compensated cirrhosis, and finally, (4) patients with CLD and decompensated cirrhosis. Patients with acute liver failure were excluded from the analysis. A total of 464 patients who underwent LiMAx measurement at the University Clinic of Essen between 10/2016 and 11/2017 were included in this study. Distribution of the different groups were n = 72 patients for group 1, n = 134 patients for group 2, n = 160 patients for group 3, and n = 98 patients for group 4, respectively. Median LiMAx values significantly declined with respect to increasing degree of CLD: (1) 510 µg/h/kg, (2) 390 µg/h/kg, (3) 264 µg/h/kg, and (4) 151 µg/h/kg (p < 0.001). When comparing the diagnostic accuracy of the LiMAx test in detecting patients with presence of cirrhosis (groups 1 and 2 vs. groups 3 and 4), an AUROC of 0.942 was found (cut-off 322 µg/h/kg, sensitivity 86.1%, specificity 91.3%, p < 0.0001). LiMAx was superior to TE and serum biomarkers in predicting patients’ outcome by 90-day mortality (AUROC 0.811, p < 0.001). Enzymatic liver function measured by LiMAx was closely associated with different severity stages of CLD and was a reliable diagnostic and prognostic tool with an accuracy comparable to current standard methods.

Monitoring Liver Function of Patients Undergoing Transarterial Chemoembolization (TACE) by a 13C Breath Test (LiMAx).

Transarterial chemoembolization (TACE) is associated with the risk of deteriorating liver function, especially in patients with preexisting liver damage. Current liver function tests may fail to accurately predict the functional liver reserve. Aim of this study was to investigate whether changes of liver function caused by TACE are associated with detectable changes of LiMAx values. Forty patients with primary or secondary liver cancer underwent TACE and LiMAx test on the day before, the day after, and 4weeks after TACE. LiMAx results were evaluated, referenced to liver volume (CT/MR volumetry), correlated with the respective TACE volume (subsegmental vs. segmental vs. lobar), established liver function tests, and Child-Pugh and ALBI scores. The individual LiMAx values were significantly reduced by 10% (p = 0.01) on the day after TACE and fully recovered to baseline 1month after treatment. Similar changes were observed regarding levels of bilirubin, transaminases, albumin, INR, and creatinine. LiMAx did not correlate significantly with the treated liver volume, but did correlate with the baseline liver volume (< 1200ml vs. > 1200ml; p < 0.01). No significant changes were observed in the Child-Pugh score or ALBI score. LiMAx is capable of detecting changes in liver function, even modulations caused by superselective TACE procedures. Accordingly, it could be used as a tool for patient selection and monitoring of transarterial therapy. In comparison, Child-Pugh and ALBI scores did not reflect any of these changes. Some biochemical parameters also changed significantly after TACE, but they tend to be less specific in providing sufficient information on actual cellular dysfunction.

Porcine model for the study of liver regeneration enhanced by non-invasive 13C-methacetin breath test (LiMAx test) and permanent portal venous access.

IntroductionDespite advances in perioperative management and surgical technique, postoperative liver failure remains a feared complication after hepatic resection. Various supportive treatment options are under current discussion, but lack of structured evaluation. We therefore established a porcine model of major liver resection to study regeneration after partial hepatectomy in a reliable and well-defined pre-clinical setting.MethodsMajor hepatectomy was performed on seven minipigs with the intention to set up a non-lethal but relevant transient impairment of liver function. For steady postoperative vascular access (e.g. for blood withdrawal, measurement of venous pressure), permanent catheters were implanted into the internal jugular and portal veins, respectively. Animals were followed up for 30 days; clinical and laboratory results were recorded in detail. Monitoring was enhanced by non-invasive determination of the maximum liver function capacity (LiMAx test).Results and conclusionsThe established porcine model appeared suitable for evaluation of postoperative liver regeneration. Clinical characteristics and progression of liver function impairment as well as subsequent recovery were comparable to courses known from surgery in humans. Laboratory parameters (e.g. liver enzymes, bilirubin, INR, coagulation factor II) showed relevant derangements during postoperative days (POD) 0 to 3 followed by normalization until POD 7. Application of the LiMAx test was feasible in minipigs, again showing values comparable to humans and kinetics in line with obtained laboratory parameters. The exteriorized portal vein catheters enabled intra- and postoperative monitoring of portal venous pressures as well as easy access for blood withdrawal without relevant risk of postoperative complications.

Hepatic CYP1A2 activity in liver tumors and the implications for preoperative volume-function analysis.

Dynamic liver function assessment by the [13C]methacetin maximal liver function capacity (LiMAx) test reflects the overall hepatic cytochrome P-450 (CYP) 1A2 activity. One proven strategy for preoperative risk assessment in liver surgery includes the combined assessment of the dynamic liver function by the LiMAx test, the volumetric analysis of the liver, and calculation of future liver remnant function. This so-called volume-function analysis assumes that the remaining CYP1A2 activity in any tumor lesion is zero. The here presented study aims to assess the remaining CYP1A2 activities in different hepatic tumor lesions and its consequences for the preoperative volume-function analysis in patients undergoing liver surgery. The CYP1A2 activity analysis of neoplastic lesions and adjacent nontumor liver tissue from resected tumor specimens revealed a significantly higher CYP1A2 activity (median, interquartile range) in nontumor tissues (35.5, 15.9-54.4 µU/mg) compared with hepatocellular adenomas (7.35, 1.2-32.5 µU/mg), hepatocellular carcinomas (0.18, 0.0-2.0 µU/mg), or colorectal liver metastasis (0.17, 0.0-2.1 µU/mg). In nontumor liver tissue, a gradual decline in CYP1A2 activity with exacerbating fibrosis was observed. The CYP1A2 activity differences were also reflected in CYP1A2 protein signals in the assessed hepatic tissues. Volume-function analysis showed a minimal deviation compared with the current standard calculation for hepatocellular carcinomas or colorectal liver metastasis (<1% difference), whereas a difference of 11.9% was observed for hepatocellular adenomas. These findings are important for a refined preoperative volume-function analysis and improved surgical risk assessment in hepatocellular adenoma cases with low LiMAx values. NEW & NOTEWORTHY The cytochrome P-450 (CYP) 1A2-dependent maximal liver function capacity test reflects the overall functional capacity of the liver. To which extent hepatocellular tumors harbor CYP1A2 activity and thus contribute to the maximal liver function capacity test outcome is unknown. We here show that hepatocellular adenomas but not hepatocellular carcinomas or colorectal liver metastasis contain significant residual CYP1A2 activity. These findings are important for an improved preoperative volume-function analysis and an accurate surgical risk assessment in hepatocellular adenoma cases.

Advanced liver function assessment in patients with intestinal failure on long-term parenteral nutrition

Intestinal failure associated liver disease (IFALD) is one of the leading complications and causes of deaths in adult patients receiving home parenteral nutrition for chronic intestinal failure (CIF). Early diagnosis of IFALD is key to alleviate the progression of hepatic dysfunction. The aim of this study was to evaluate the capability of noninvasive liver function tests. 90 adult patients with CIF receiving long-term home parenteral nutrition were included in a prospective cross-sectional study at our department between 2014 and 2017. All participants underwent dynamic liver function assessment (maximum liver function capacity [LiMAx] test, indocyanine green [ICG] test), transient elastography (FibroScan), blood tests and comprehensive nutritional status assessment. Univariate and multivariable analysis were performed to identify predictors of liver function. LiMAx, ICG test, and FibroScan highly correlated with standard liver function tests. Multivariable analysis identified intact ileum (B=520.895; p=0.010), digestive anatomy type 3 (B=75.612; p=0.025), citrulline level (B=3.428; p=0.040), parenteral olive oil intake (B=-0.570; p=0.043), and oral intake (B=182.227; p=0.040) as independent risk factors affecting liver function determined by LiMAx test. ICG test and FibroScan showed no correlation with gastrointestinal and nutrition-related parameters. The LiMAx test is significantly associated with widely accepted risk factors for IFALD by multivariable analysis, whereas ICG test and FibroScan failed to show significant correlations. Liver function assessment by LiMAx test may therefore have the potential to detect alterations in liver function and identify patients at risk for the development of IFALD. Longitudinal studies are needed to investigate the impact of liver function determined by LiMAx test on long-term outcome in patients with CIF.

The predictive value of future liver remnant function after liver resection for HCC in noncirrhotic and cirrhotic patients

BackgroundSurgical procedures in patients with underlying liver disease are still burdened by a high rate of postoperative morbidity, especially posthepatectomy liver failure (PHLF), ranging from 1.2 to 33.8%. The aim of this study was to investigate the prognostic value of volume/function analysis for the prediction of hepatectomy-related morbidity in patients with hepatocellular carcinoma. MethodsClinicopathological data were analysed in 261 patients who underwent liver resection for HCC between 2001 and 2014. Future liver remnant volume (FLRV) and future liver remnant function (FLRF) based on LiMAx test were obtained retrospectively. A subgroup analysis for high-risk patients with impaired liver function was conducted. Univariate and multivariate regression analysis was performed to identify risk factors for major complications, defined by Dindo ≥ IIIb and PHLF grade ≥ B. ResultsIn the total cohort, FLRF was independently associated with major complications. FLRV, resected liver volume, and FLRF were independent risk factors for PHLF. In a subgroup analysis of high-risk patients, FLRF was identified as the only independent risk factor for major complications and PHLF development. DiscussionThese results suggest the superior value of FLRF to FLRV in predicting postoperative complications as well as PHLF in patients with chronic liver disease.

A randomized controlled trial for enhanced recovery in liver surgery: improved perioperative management using the LiMAx test

Background: The LiMAx test can validly determine liver maximal capacity and has been successfully integrated in clinical management in liver surgery. However, no prospective randomized trials have been available to judge its actual clinical impact. Methods: A randomized controlled trial (RCT) was conducted from January 2013 to September 2015 in six recruiting hospitals. Patients prior open liver resection of at least one segment were included. Patients were randomly assigned to LiMAx group (pre-, and postoperative LiMAx test) or control group (standard-of-care). Stable patients with sufficient residual liver function (LiMAx >150 μg/kg/h) were directly transferred to general ward after surgery. Results: A total of 148 patients were randomized. Patients in LiMAx group were more frequently directly transferred to general ward after surgery (62.1% vs. 1.7%; p<0.0001), the risk of severe postoperative complications was lower (≥ grade IIIa; 14% vs. 28%; p<0.02) and the length of post-operative stay was shorter (10 vs. 13 days; p=0.01). No patient in LiMAx group was admitted to intensive care after primary transfer to general ward. Conclusion: The LiMAx test distinctively improves perioperative management in liver surgery. The valid identification of low risk patients skipping intensive care enables enhanced recovery.

A randomized controlled trial for enhanced recovery in liver surgery: Improved perioperative management using the LiMAx test

Background: The LiMAx test can validly determine liver maximal capacity and has been successfully integrated in clinical management in liver surgery. However, no prospective randomized trials have been available to judge its actual clinical impact. Methods: A randomized controlled trial (RCT) was conducted from January 2013 to September 2015 in six recruiting hospitals. Patients prior open liver resection of at least one segment were included. Patients were randomly assigned to LiMAx group (pre-, and postoperative LiMAx test) or control group (standard-of-care). Stable patients with sufficient residual liver function (LiMAx >150 μg/kg/h) were directly transferred to general ward after surgery. Results: A total of 148 patients were randomized. Patients in LiMAx group were more frequently directly transferred to general ward after surgery (62.1% vs. 1.7%; p<0.0001), the risk of severe postoperative complications was lower (≥ grade IIIa; 14% vs. 28%; p<0.02) and the length of post-operative stay was shorter (10 vs. 13 days; p=0.01). No patient in LiMAx group was admitted to intensive care after primary transfer to general ward. Conclusion: The LiMAx test distinctively improves perioperative management in liver surgery. The valid identification of low risk patients skipping intensive care enables enhanced recovery.

Preoperative Evaluation of Liver Function in Patients with Hepatocellular Carcinoma using the LiMAx Test

Background: Besides liver transplantation, resection surgery provides the best long term survival in patients with hepatocellular carcinoma. To properly select patients for surgery an adequate estimation of liver function is of great clinical importance. Methods: We performed a retrospective analysis of patients diagnosed with HCC that had received the LiMAx test for evaluation of surgical treatment in our department. LiMAx is a non-invasive 13C-breath-test for specific measurement of cytochrom P450 capacity by intravenous administration of 2mg/kg 13C-Methacetin. This system can be purchased commercially. Results: A total of 47 patients were identified. After evaluation of liver function 24 patients received resection surgery. The LiMAx results were higher in resected patients (392 vs. 247 μg/kg/h; P=0,022). Patients diagnosed with liver cirrhosis had significantly lower results (242 vs. 450 μg/kg/h; P<0,006). In 10 patients surgical treatment was cancelled due to reduced liver function (mean LiMAx 181 μg/kg/h). After surgery 7 patients presented with postoperative liver failure (5 patients grade A, 1 grade B and 1 grade C). Histologic assessment revealed complete liver cirrhosis in 5 resected patients not influencing their risk for postoperative liver failure. Conclusion: Evaluation of preoperative liver function by the LiMAx test allows patient selection to reduce severe postoperative liver decompensation. In appropriate patients mortality and morbidity remains low, even in the presence of liver cirrhosis.

Preoperative evaluation of liver function in patients with hepatocellular carcinoma using the LiMAx Test

Background: Besides liver transplantation, resection surgery provides the best long term survival in patients with hepatocellular carcinoma. To properly select patients for surgery an adequate estimation of liver function is of great clinical importance. Methods: We performed a retrospective analysis of patients diagnosed with HCC that had received the LiMAx test for evaluation of surgical treatment in our department. LiMAx is a non-invasive 13C-breath-test for specific measurement of cytochrom P450 capacity by intravenous administration of 2mg/kg 13C-Methacetin. This system can be purchased commercially. Results: A total of 47 patients were identified. After evaluation of liver function 24 patients received resection surgery. The LiMAx results were higher in resected patients (392 vs. 247 μg/kg/h; P=0,022). Patients diagnosed with liver cirrhosis had significantly lower results (242 vs. 450 μg/kg/h; P<0,006). In 10 patients surgical treatment was cancelled due to reduced liver function (mean LiMAx 181 μg/kg/h). After surgery 7 patients presented with postoperative liver failure (5 patients grade A, 1 grade B and 1 grade C). Histologic assessment revealed complete liver cirrhosis in 5 resected patients not influencing their risk for postoperative liver failure. Conclusion: Evaluation of preoperative liver function by the LiMAx test allows patient selection to reduce severe postoperative liver decompensation. In appropriate patients mortality and morbidity remains low, even in the presence of liver cirrhosis.

Chemotherapy-associated Liver Injury prior Surgery of Hepatic Colorectal Metastases – Comparison of Functional and Histopathological Damage

Background: Chemotherapy prior liver resection of colorectal liver metastases (CLM) implies the risk of chemotherapy-associated liver injury (CALI) leading to increased postoperative morbidity and mortality. Methods: Retrospective analysis of patients with CLM prior resection. Preoperative assessment of liver function by LiMAx test. Histologic staging of resected tumor-free liver tissue. Analysis of 12-month history of chemotherapy prior surgery including the regime, the number of cycles and the therapy-free interval. Results: A total of 204 patients were analyzed. The majority (n=127; 62 %) had received previous chemotherapy. Impaired LiMAx results were determined in 49% of patients after chemotherapy. The extent of LiMAx impairment was dependent on number of oxaliplatin cycles, therapy-free interval and obesity in multivariate analysis. Patients with impaired LiMAx showed regeneration during chemotherapy cessation. Chemotherapy increased the incidence of steatosis (>33%; 29 vs. 17%) as well as of mild fibrosis (62 vs. 45%). The LiMAx was markedly decreased in steatosis (335 vs. 375 μg/kg/h, P=0.024), steatohepatitis (292 vs. 372 μg/kg/h, P=0.003), and severe fibrosis (318 vs. 395 μg/kg/h, P=0.001). While the degree of steatosis was associated with a short therapy-free interval, the degree of fibrosis was increased by the number of cycles. Conclusion: The LiMAx test enables preoperative assessment of CALI. Acute injury with steatohepatitis deteriorates LiMAx more severely than chronic injury with fibrosis.

Liver maximum capacity (LiMAx) test as a helpful prognostic tool in acute liver failure with sepsis: a case report

BackgroundAcute liver failure (ALF) is a life-threatening entity particularly when infectious complications worsen the clinical course. Urgent liver transplantation (LT) is frequently the only curative treatment. However, in some cases, recovery is observed under conservative treatment. Therefore, prognostic tools for estimating course of the disease are of great clinical interest. Since laboratory parameters sometimes lack sensitivity and specificity, enzymatic liver function measured by liver maximum capacity (LiMAx) test may offer novel and valuable additional information in this setting.Case presentationWe here report the case of a formerly healthy 20-year old male caucasian patient who was admitted to our clinic for ALF of unknown origin in December 2017. Laboratory parameters confirmed the diagnosis with an initial MELD score of 28 points. Likewise, enzymatic liver function was significantly impaired with a value of 147 [> 315] μg/h/kg. Clinical and biochemical analyses for viral-, autoimmune-, or drug-induced hepatitis were negative. Liver synthesis parameters further deteriorated reaching a MELD score of 40 points whilst clinical course was complicated by septic pneumonia leading to severe hepatic encephalopathy grade III-IV, finally resulting in mechanical ventilation of the patient. Interestingly, although clinical course and laboratory data suggested poor outcome, serial LiMAx test revealed improvement of the enzymatic liver function at this time point increasing to 169 μg/h/kg. Clinical condition and laboratory data slowly improved likewise, however with significant time delay of 11 days. Finally, the patient could be dismissed from our clinic after 37 days.ConclusionEstimating prognosis in patients with ALF is challenging by use of the established scores. In our case, improvement of enzymatic liver function measured by the LiMAx test was the first parameter predicting beneficial outcome in a patient with ALF complicated by sepsis.

The Predictive Value of the Maximal Liver Function Capacity Test for the Isolation of Primary Human Hepatocytes.

The need for primary human hepatocytes is constantly growing for basic research, as well as for therapeutic applications. However, the isolation outcome strongly depends on the quality of liver tissue, and we are still lacking a preoperative test that allows the prediction of the hepatocyte isolation outcome. In this study, we evaluated the "maximal liver function capacity test" (LiMAx) as predictive test for the quantitative and qualitative outcome of hepatocyte isolation. This test is already used in clinical routine to measure preoperative and to predict postoperative liver function. The patient's preoperative mean LiMAx was obtained from the patient records, and preoperative computed tomography and magnetic resonance images were used to calculate the whole liver volume to adjust the mean LiMAx. The outcome parameters of the hepatocyte isolation procedures were analyzed in correlation with the adjusted mean LiMAx. Primary human hepatocytes were isolated from partial hepatectomies (n = 64). From these 64 hepatectomies we included 48 to our study and correlated their isolation outcome parameters with volume corrected LiMAx values. From a total of 11 hepatocyte isolation procedures, metabolic parameters (albumin, urea, and aspartate aminotransferase or AST) were assessed during the hepatocyte cultivation period of 5 days. The volume adjusted mean LiMAx showed a significant positive correlation with the total cell yield (p = 0.049; r = 0.242; n = 48). The correlations of volume adjusted LiMAx values with viable cell yield and cell viability did not reach statistical significance. To create a more homogenous study group regarding tumor entities, subgroup analyses were performed. A subgroup analysis of isolations from patients with colorectal metastasis revealed a significant correlation between volume adjusted mean LiMAx and total cell yield (p = 0.012; r = 0.488; n = 21) and viable cell yield (p = 0.034; r = 0.405; n = 21), whereas a subgroup analysis of isolations of patients with carcinoma of the biliary tree showed significant correlations of volume adjusted mean LiMAx with cell viability (r = 0.387; p = 0.046; n = 20) and lacked significant correlations with total cell yield (r = -0.060; p = 0.401; n = 20) and viable cell yield (r = 0.012; p = 0.480; n = 20). The volume-adjusted mean LiMAx did not show a significant correlation with any of the metabolic parameters. In conclusion, the LiMAx test might be a useful tool to predict the quantitative outcome of hepatocyte isolation, as long as underlying liver disease is taken into consideration.

Impact of liver volume and liver function on posthepatectomy liver failure after portal vein embolization- A multivariable cohort analysis.

BackgroundLiver failure remains a life-threatening complication after liver resection, and is difficult to predict preoperatively. This retrospective cohort study evaluated different preoperative factors in regard to their impact on posthepatectomy liver failure (PHLF) after extended liver resection and previous portal vein embolization (PVE).MethodsPatient characteristics, liver function and liver volumes of patients undergoing PVE and subsequent liver resection were analyzed. Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2). Factors associated with the primary end point PHLF (according to ISGLS definition) were identified through multivariable analysis. Secondary end points were 30-day mortality and morbidity.Results95 patients received PVE, of which 64 patients underwent major liver resection. PHLF occurred in 7 patients (11%). Calculated postoperative liver function was significantly lower in patients with PHLF than in patients without PHLF (67 vs. 109 μg/kg/h; p = 0.01). Other factors associated with PHLF by univariable analysis were age, future liver remnant, MELD score, ASA score, renal insufficiency and heart insufficiency. By multivariable analysis, future liver remnant was the only factor significantly associated with PHLF (p = 0.03). Mortality and morbidity rates were 4.7% and 29.7% respectively.ConclusionFuture liver remnant is the only preoperative factor with a significant impact on PHLF. Assessment of preoperative liver function may additionally help identify patients at risk for PHLF.

Kinetic validation of the LiMAx test during 10 000 intravenous 13C-methacetin breath tests

The maximal liver function capacity (LiMAx) test, a novel 13C-methacetin breath test, has proven clinical validity in determining hepatic metabolic capacity. In contrast to prior 13C-methacetin breath test protocols, the LiMAx test is performed by intravenous body-weight-adjusted substrate administration. Furthermore, the DOB kinetics (delta over baseline of the time-dependent exhaled 13CO2/12CO2 ratio) are measured online at the bedside with a high time resolution in order to determine the maximum DOB. The aim of this study was to analyze the recorded DOB kinetics in a large population for further refinement of the test protocol. Two new methods of kinetic analysis are proposed in this article: the time dependency of the DOB kinetics and the time interval until half of the DOB maximum. A total of 10 100 LiMAx tests on 8483 patients performed during routine clinics at eight centers were available. The kinetic analysis revealed a specific pattern of DOB kinetics depending upon LiMAx result. In addition, potential co-factors for DOB kinetics, such as weight, height, gender and age, were analyzed, yielding a potential influence of gender and smoking behavior. Both the specific patterns and the proposed kinetic analysis have the potential to further improve the sensitivity and specificity of the test and its clinical applicability by shortening its duration.