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The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism--insights from mathematical modeling.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND: Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme … phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. Here, we used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis. RESULTS: Model simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that control of the hepatic glucose metabolism is mainly exerted by enzymes alone, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects. CONCLUSION: In hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes.

Authors: Sascha Bulik, Hergo Holzhütter, Nikolaus Berndt

Date Published: 2nd Mar 2016

Journal: BMC Biol

A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

The liver responds to elevated plasma concentrations of free fatty acids (FFAs) with an enhanced uptake of FFAs and their esterification to triacylglycerol (TAG). On the long term, this may result in … massive hepatic TAG accumulation called steatosis hepatitis. In hepatocytes, the poor water-soluble TAG is packed in specialized organelles: Lipid droplets (LDs) serving as transient cellular deposit and lipoproteins (LPs) transporting TAG and cholesterol esters to extra-hepatic tissues. The dynamics of these organelles is controlled by a variety of regulatory surface proteins (RSPs). Assembly and export of VLDLs are mainly regulated by the microsomal transfer protein (MTP) and apoprotein B100. Formation and lipolysis of LDs are regulated by several RSPs. The best studied regulators belong to the PAT (Perilipin/Adipophilin/TIP47) and CIDE families. Knockdown or overexpression of SRPs may significantly affect the total number and size distribution of LDs. Intriguingly, a large cell-to-cell heterogeneity with respect to the number and size of LDs has been found in various cell types including hepatocytes. These findings suggest that the extent of cellular lipid accumulation is determined not only by the imbalance between lipid supply and utilization but also by variations in the expression of RSPs and metabolic enzymes. To better understand the relative regulatory impact of individual processes involved in the cellular TAG turnover, we developed a comprehensive kinetic model encompassing the pathways of the fatty acid and triglyceride metabolism and the main molecular processes governing the dynamics of LDs. The model was parametrized such that a large number of experimental in vitro and in vivo findings are correctly recapitulated. A control analysis of the model revealed that variations in the activity of FFA uptake, diacylglycerol acyltransferase (DGAT) 2, and adipose triglyceride lipase (ATGL) have the strongest influence on the cellular TAG level. We used the model to simulate LD size distributions in human hepatoma cells and hepatocytes exposed to a challenge with FFAs. A random fold change by a factor of about two in the activity of RSPs was sufficient to reproduce the large diversity of droplet size distributions observed in individual cells. Under the premise that the same extent of variability of RSPs holds for the intact organ, our model predicts variations in the TAG content of individual hepatocytes by a factor of about 3-6 depending on the nutritional regime. Taken together, our modeling approach integrates numerous experimental findings on individual processes in the cellular TAG metabolism and LD dynamics metabolism to a consistent state-of-the-art dynamic network model that can be used to study how changes in the external conditions or systemic parameters will affect the TAG content of hepatocytes.

Authors: C. Wallstab, D. Eleftheriadou, T. Schulz, Georg Damm, Daniel Seehofer, J. Borlak, Hergo Holzhütter, Nikolaus Berndt

Date Published: 2nd Aug 2017

Journal: FEBS J

Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) … mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD(+), NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.

Authors: G. Kurschner, Q. Zhang, R. Clima, Y. Xiao, J. F. Busch, E. Kilic, K. Jung, N. Berndt, S. Bulik, H. G. Holzhutter, G. Gasparre, M. Attimonelli, M. Babu, D. Meierhofer

Date Published: 1st Dec 2017

Journal: Oncotarget

Prospective Assessment of Liver Function by an Enzymatic Liver Function Test to Estimate Short-Term Survival in Patients with Liver Cirrhosis.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND: MELD attempts to objectively predict the risk of mortality of patients with liver cirrhosis and is commonly used to prioritize organ allocation. Despite the usefulness of the MELD, updated … metrics could further improve the accuracy of estimates of survival. AIMS: To assess and compare the prognostic ability of an enzymatic (13)C-based liver function test (LiMAx) and distinct markers of liver function to predict 3-month mortality of patients with chronic liver failure. METHODS: We prospectively investigated liver function of 268 chronic liver failure patients without hepatocellular carcinoma. Primary study endpoint was liver-related death within 3 months of follow-up. Prognostic values were calculated using Cox proportional hazards and logistic regression analysis. RESULTS: The Cox proportional hazard model indicated that LiMAx (p < 0.001) and serum creatinine values (p < 0.001) were the significant parameters independently associated with the risk of liver failure-related death. Logistic regression analysis revealed LiMAx and serum creatinine to be independent predictors of mortality. Areas under the receiver-operating characteristic curves for MELD (0.86 [0.80-0.92]) and for a combined score of LiMAx and serum creatinine (0.83 [0.76-0.90]) were comparable. CONCLUSIONS: Apart from serum creatinine levels, enzymatic liver function measured by LiMAx was found to be an independent predictor of short-term mortality risk in patients with liver cirrhosis. A risk score combining both determinants allows reliable prediction of short-term prognosis considering actual organ function. Trial Registration Number (German Clinical Trials Register) # DRKS00000614.

Authors: M. Jara, T. Dziodzio, M. Malinowski, K. Luttgert, R. Nikolov, P. V. Ritschl, R. Ollinger, J. Pratschke, Martin Stockmann

Date Published: 9th Nov 2018

Journal: Dig Dis Sci

The predictive value of future liver remnant function after liver resection for HCC in noncirrhotic and cirrhotic patients.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND: Surgical 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. METHODS: Clinicopathological 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. RESULTS: In 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. DISCUSSION: These results suggest the superior value of FLRF to FLRV in predicting postoperative complications as well as PHLF in patients with chronic liver disease.

Authors: E. Bluthner, M. Jara, R. Shrestha, W. Faber, J. Pratschke, Martin Stockmann, M. Malinowski

Date Published: 9th Feb 2019

Journal: HPB (Oxford)

Advanced liver function assessment in patients with intestinal failure on long-term parenteral nutrition.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Authors: E. Bluthner, J. Bednarsch, U. F. Pape, M. Karber, S. Maasberg, U. A. Gerlach, A. Pascher, B. Wiedenmann, J. Pratschke, Martin Stockmann

Date Published: 20th Mar 2019

Journal: Clin Nutr

Predicting liver failure after extended right hepatectomy following right portal vein embolization with gadoxetic acid-enhanced MRI.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

OBJECTIVES: Predicting post-hepatectomy liver failure (PHLF) after extended right hepatectomy following portal vein embolization (PVE) from serial gadoxetic acid-enhanced magnetic resonance imaging … (MRI). METHODS: Thirty-six patients who underwent hepatectomy following PVE were evaluated prospectively with gadoxetic acid-enhanced MRI examinations at predefined intervals during the course of their treatment, i.e., before and 14 days and 28 days after PVE as well as 10 days after hepatectomy. Relative enhancement (RE) and volume of the left and right liver lobes were determined. The study population was divided into two groups with respect to signs of PHLF. Differences between the two groups were assessed using the Mann-Whitney U test, and predictive parameters for group membership were investigated using ROC and logistic regression analysis. RESULTS: RE of the left lobe prior to PVE versus 14 days after PVE was significantly lower in patients with PHLF than in those without PHLF (Mann-Whitney U test p < 0.001) and proved to be the best predictor of PHLF in ROC analysis with an AUC of 0.854 (p < 0.001) and a cutoff value of - 0.044 with 75.0% sensitivity and 92.6% specificity. Consistent with this result, logistic linear regression analysis adjusted for age identified the same parameter to be a significant predictor of PHLF (p = 0.040). CONCLUSIONS: Gadoxetic acid-enhanced MRI performed as an imaging-based liver function test before and after PVE can help to predict PHLF. The risk of PHLF can be predicted as early as 14 days after PVE. KEY POINTS: * To predict the likelihood of post-hepatectomy liver failure, it is important to estimate not only future liver remnant volume prior to extended liver resection but also future liver remnant function. * Future liver remnant function can be predicted by performing gadoxetic acid-enhanced MRI as an imaging-based liver function test before and after portal vein embolization. * A reduction of relative enhancement of the liver in gadoxetic acid-enhanced MRI after portal vein embolization of 0.044 predicts post-hepatectomy liver failure with 75.0% sensitivity and 92.6% specificity.

Authors: D. Theilig, I. Steffen, M. Malinowski, Martin Stockmann, Daniel Seehofer, J. Pratschke, B. Hamm, T. Denecke, D. Geisel

Date Published: 23rd Mar 2019

Journal: Eur Radiol

Identification of serological markers for pre- and postoperative fasting periods.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND & AIMS: Prolonged preoperative fasting periods lead to catabolic states and decelerate recovery after surgery. Valid plasma markers reflecting the patients' metabolic state may improve … tailored nutrition support before surgery. Within this study, we sought to advance the knowledge on fasting time-sensitive plasma markers that allow the metabolic characterisation of surgical patients for an optimised preoperative metabolic preparation. METHODS: Patients scheduled for elective surgery of the upper (n = 23) or lower (n = 27) gastrointestinal tract participated in a prospective observational study. Patients' charateristics and nutritional status were recorded and blood samples were drawn on the day of admission. Further blood samples were collected before skin incision of the surgical procedure, on postoperative day 3 and on the day of discharge. Values of clinical chemistry, electrolytes, hemograms and plasma amino acids were determined and correlated with fasting times. RESULTS: Preoperative fasting times were positively correlated with plasma levels of valine, leucine, serine, alpha-amino butyric acid, free fatty acids, 3-hydroxy butyric acid and significantly negative correlated with chloride and glutamic acid. Postoperative fasting times were correlated with erythrocytes, leukocytes and plasma levels of albumin, CRP, HDL, asparagine and 3-methylhistidine. The multivariate regression analysis revealed glutamic acid and valine as significant independent predictors of preoperative fasting periods. The regression model showed best performance (sensitivity of 90.91% and specificity of 92.31%) to detect patients fasted for >/=20 h. CONCLUSION: Valine and glutamic acid appear as independent metabolic markers for accurate prediction of prolonged fasting periods, independent of the overall nutritional status, age or BMI of patients.

Authors: Tilo Wuensch, J. Quint, V. Mueller, A. Mueller, J. Wizenty, M. Kaffarnik, B. Kern, Martin Stockmann, M. Biebl, J. Pratschke, F. Aigner

Date Published: 25th Mar 2019

Journal: Clin Nutr ESPEN

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

Background: Fibronectin type III domain-containing (FNDC) proteins fulfill manifold functions in tissue development and regulation of cellular metabolism. FNDC4 was described as anti-inflammatory factor, … upregulated in inflammatory bowel disease (IBD). FNDC signaling includes direct cell-cell interaction as well as release of bioactive peptides, like shown for FNDC4 or FNDC5. The G-protein-coupled receptor 116 (GPR116) was found as a putative FNDC4 receptor. We here aim to comprehensively analyze the mRNA expression of FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, and GPR116 in nonaffected and affected mucosal samples of patients with IBD or colorectal cancer (CRC). Methods: Mucosa samples were obtained from 30 patients undergoing diagnostic colonoscopy or from surgical resection of IBD or CRC. Gene expression was determined by quantitative real-time PCR. In addition, FNDC expression data from publicly available Gene Expression Omnibus (GEO) data sets (GDS4296, GDS4515, and GDS5232) were analyzed. Results: Basal mucosal expression revealed higher expression of FNDC3A and FNDC5 in the ileum compared to colonic segments. FNDC1 and FNDC4 were significantly upregulated in IBD. None of the investigated FNDCs was differentially expressed in CRC, just FNDC3A trended to be upregulated. The GEO data set analysis revealed significantly downregulated FNDC4 and upregulated GPR116 in microsatellite unstable (MSI) CRCs. The expression of FNDCs and GPR116 was independent of age and sex. Conclusions: FNDC1 and FNDC4 may play a relevant role in the pathobiology of IBD, but none of the investigated FNDCs is regulated in CRC. GPR116 may be upregulated in advanced or MSI CRC. Further studies should validate the altered FNDC expression results on protein levels and examine the corresponding functional consequences.

Authors: Tilo Wuensch, J. Wizenty, J. Quint, W. Spitz, M. Bosma, Ann-Kristin Becker, A. Adler, W. Veltzke-Schlieker, Martin Stockmann, S. Weiss, M. Biebl, J. Pratschke, F. Aigner

Date Published: 17th May 2019

Journal: Gastroenterol Res Pract

Resection of hepatic and pulmonary metastasis from metastatic esophageal and gastric cancer: a nationwide study.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

The standard of care for gastroesophageal cancer patients with hepatic or pulmonary metastases is best supportive care or palliative chemotherapy. Occasionally, patients can be selected for curative … treatment instead. This study aimed to evaluate patients who underwent a resection of hepatic or pulmonary metastasis with curative intent. The Dutch national registry for histo- and cytopathology was used to identify these patients. Data were retrieved from the individual patient files. Kaplan-Meier survival analysis was performed. Between 1991 and 2016, 32,057 patients received a gastrectomy or esophagectomy for gastroesophageal cancer in the Netherlands. Of these patients, 34 selected patients received a resection of hepatic metastasis (n = 19) or pulmonary metastasis (n = 15) in 21 different hospitals. Only 4 patients received neoadjuvant therapy before metastasectomy. The majority of patients had solitary, metachronous metastases. After metastasectomy, grade 3 (Clavien-Dindo) complications occurred in 7 patients and mortality in 1 patient. After resection of hepatic metastases, the median potential follow-up time was 54 months. Median overall survival (OS) was 28 months and the 1-, 3-, and 5- year OS was 84%, 41%, and 31%, respectively. After pulmonary metastases resection, the median potential follow-up time was 80 months. The median OS was not reached and the 1-, 3-, and 5- year OS was 67%, 53%, and 53%, respectively. In selected patients with gastroesophageal cancer with hepatic or pulmonary metastases, metastasectomy was performed with limited morbidity and mortality and offered a 5-year OS of 31-53%. Further prospective studies are required.

Authors: M. F. J. Seesing, A. van der Veen, H. J. F. Brenkman, Martin Stockmann, G. A. P. Nieuwenhuijzen, C. Rosman, F. J. H. van den Wildenberg, M. I. van Berge Henegouwen, P. van Duijvendijk, B. P. L. Wijnhoven, J. H. M. B. Stoot, M. Lacle, J. P. Ruurda, R. van Hillegersberg

Date Published: 31st Dec 2019

Journal: Dis Esophagus

Dynamic liver function is an independent predictor of recurrence-free survival after curative liver resection for HCC - A retrospective cohort study.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

BACKGROUND: Hepatocellular carcinoma is the fifth most prevalent cancer worldwide. High tumour recurrence is the most common cause of the impaired 5-year survival rate of 26-58% after hepatectomy. The … aim of this study was to investigate the impact of preoperative dynamic liver function on long-term outcome. MATERIALS AND METHODS: A total of 146 patients that underwent curative resection for HCC at our department from 2005 to 2016 were analysed. Univariate analysis was calculated using Kaplan-Meier method. Multivariable analysis was carried out with Cox regression. RESULTS: The cumulative 1-, 3-, 5-year survival rates were 83%, 42% and 14%, respectively. Multivariable Cox regression yielded that overall survival depends on disease recurrence, haemoglobin, number of tumours, liver cirrhosis, lymphatic vessel invasion, UICC stage and postoperative complications. The corresponding 1-, 3-, 5-year disease-free survival rates were 73%, 32% and 10%, respectively. Multivariable analysis yielded preoperative liver function capacity (HR 2.421; p=0.014), vascular invasion (HR 2.116; p=0.034) and UICC stage (HR 2.200; p=0.037) as risk factors associated with disease-free survival. A subanalysis with respect to the degree of functional impairment implicated that severity of liver function impairment is correlated with the disease-free survival rate. CONCLUSION: This study shows that preoperative dynamic liver function assessed by LiMAx test as well as severity of underlying liver disease have a significant impact on recurrence-free survival after curative hepatectomy. Patients presenting with impaired liver function should be evaluated for other treatment e.g. liver transplantation or receive closer oncological follow-up.

Authors: E. Bluthner, J. Bednarsch, M. Malinowski, P. Binder, J. Pratschke, Martin Stockmann, M. Kaffarnik

Date Published: 9th Sep 2019

Journal: Int J Surg

Sensitivity of multifrequency magnetic resonance elastography and diffusion-weighted imaging to cellular and stromal integrity of liver tissue.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

Microscopic structural alterations of liver tissue induced by freeze-thaw cycles give rise to palpable property changes. However, the underlying damage to tissue architecture is difficult to quantify … histologically, and published data on macroscopic changes in biophysical properties are sparse. To better understand the influence of hepatic cells and stroma on global biophysical parameters, we studied rat liver specimens freshly taken (within 30min after death) and treated by freeze-thaw cycles overnight at either -20 degrees C or -80 degrees C using diffusion-weighted imaging (DWI) and multifrequency magnetic resonance elastography (MRE) performed at 0.5T in a tabletop MRE scanner. Tissue structure was analyzed histologically and rheologic data were analyzed using fractional order derivatives conceptualized by a called spring-pot component that interpolates between pure elastic and viscous responses. Overnight freezing and thawing induced membrane disruptions and cell detachment in the space of Disse, resulting in a markedly lower shear modulus mu and apparent diffusion coefficient (ADC) (mu[-20 degrees C]=1.23+/-0.73kPa, mu[-80 degrees C]=0.66+/-0.75kPa; ADC[-20 degrees C]=0.649+/-0.028mum(2)/s, ADC[-80 degrees C]=0.626+/-0.025mum(2)/s) compared to normal tissue (mu=9.92+/-3.30kPa, ADC=0.770+/-0.023mum(2)/s, all p<0.001). Furthermore, we analyzed the springpot-powerlaw coefficient and observed a reduction in -20 degrees C specimens (0.22+/-0.14) compared to native tissue (0.40+/-0.10, p=0.033) and -80 degrees C specimens (0.54+/-0.22, p=0.002), that correlated with histological observations of sinusoidal dilation and collagen distortion within the space of Disse. Overall, the results suggest that shear modulus and water diffusion in liver tissue markedly decrease due to cell membrane degradation and cell detachment while viscosity-related properties appear to be more sensitive to distorted stromal and microvascular architecture.

Authors: A. A. de Schellenberger, H. Tzschatzsch, B. Polchlopek, G. Bertalan, F. Schrank, K. Garczynska, P. A. Janmey, J. Braun, I. Sack

Date Published: 9th May 2019

Journal: J Biomech

Multiparametric Quantitative MRI for the Detection of IgA Nephropathy Using Tomoelastography, DWI, and BOLD Imaging.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

OBJECTIVES: The aim of this study was to noninvasively evaluate changes in renal stiffness, diffusion, and oxygenation in patients with chronic, advanced stage immunoglobulin A nephropathy (IgAN) by … multiparametric magnetic resonance imaging using tomoelastography, diffusion-weighted imaging (DWI), and blood oxygen level-dependent (BOLD) imaging. MATERIALS AND METHODS: In this prospective study, 32 subjects (16 patients with biopsy-proven IgAN and 16 age- and sex-matched healthy controls) underwent multifrequency magnetic resonance elastography with tomoelastography postprocessing at 4 frequencies from 40 to 70 Hz to generate shear wave speed (meter per second) maps reflecting tissue stiffness. In addition, DWI and BOLD imaging were performed to determine the apparent diffusion coefficient in square millimeter per second and T2* relaxation time in milliseconds, respectively. Regions including the entire renal parenchyma of both kidneys were analyzed. Areas under the receiver operating characteristic (AUCs) curve were calculated to test diagnostic performance. Clinical parameters such as estimated glomerular filtration rate and protein-to-creatinine ratio were determined and correlated with imaging findings. RESULTS: Success rates of tomoelastography, DWI, and BOLD imaging regarding both kidneys were 100%, 91%, and 87%, respectively. Shear wave speed was decreased in IgAN (-21%, P < 0.0001), accompanied by lower apparent diffusion coefficient values (-12%, P = 0.004). BOLD imaging was not sensitive to IgAN (P = 0.12). Tomoelastography detected IgAN with higher diagnostic accuracy than DWI (area under the curve = 0.9 vs 0.8) and positively correlated with estimated glomerular filtration rate (r = 0.66, P = 0.006). CONCLUSIONS: Chronic, advanced stage IgAN is associated with renal softening and restricted water diffusion. Tomoelastography is superior to DWI and BOLD imaging in detecting IgAN.

Authors: S. T. Lang, Jing Guo, A. Bruns, M. Durr, J. Braun, B. Hamm, I. Sack, S. R. Marticorena Garcia

Date Published: 2nd Jul 2019

Journal: Invest Radiol

Magnetic resonance elastography quantification of the solid-to-fluid transition of liver tissue due to decellularization.
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract (Expand)

Maintenance of tissue extracellular matrix (ECM) and its biomechanical properties for tissue engineering is one of the substantial challenges in the field of decellularization and recellularization. … Preservation of the organ-specific biomatrix is crucial for successful recellularization to support cell survival, proliferation, and functionality. However, understanding ECM properties with and without its inhabiting cells as well as the transition between the two states lacks appropriate test methods capable of quantifying bulk viscoelastic parameters in soft tissues. We used compact magnetic resonance elastography (MRE) with 400, 500, and 600 Hz driving frequency to investigate rat liver specimens for quantification of viscoelastic property changes resulting from decellularization. Tissue structures in native and decellularized livers were characterized by collagen and elastin quantification, histological analysis, and scanning electron microscopy. Decellularization did not affect the integrity of microanatomy and structural composition of liver ECM but was found to be associated with increases in the relative amounts of collagen by 83-fold (37.4 +/- 17.5 vs. 0.5 +/- 0.01 mug/mg, p = 0.0002) and elastin by approx. 3-fold (404.1 +/- 139.6 vs. 151.0 +/- 132.3 mug/mg, p = 0.0046). Decellularization reduced storage modulus by approx. 9-fold (from 4.9 +/- 0.8 kPa to 0.5 +/- 0.5 kPa, p < 0.0001) and loss modulus by approx. 7-fold (3.6 kPa to 0.5 kPa, p < 0.0001), indicating a marked loss of global tissue rigidity as well as a property shift from solid towards more fluid tissue behavior (p = 0.0097). Our results suggest that the rigidity of liver tissue is largely determined by cellular components, which are replaced by fluid-filled spaces when cells are removed. This leads to an overall increase in tissue fluidity and a viscous drag within the relatively sparse remaining ECM. Compact MRE is an excellent tool for quantifying the mechanical properties of decellularized biological tissue and a promising candidate for useful applications in tissue engineering.

Authors: H. Everwien, A. Ariza de Schellenberger, N. Haep, H. Tzschatzsch, J. Pratschke, I. M. Sauer, J. Braun, K. H. Hillebrandt, I. Sack

Date Published: 17th Mar 2020

Journal: J Mech Behav Biomed Mater

Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer
Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV)

Abstract

Not specified

Authors: Nikolaus Berndt, Antje Egners, Guido Mastrobuoni, Olga Vvedenskaya, Athanassios Fragoulis, Aurélien Dugourd, Sascha Bulik, Matthias Pietzke, Chris Bielow, Rob van Gassel, Steven W. Olde Damink, Merve Erdem, Julio Saez-Rodriguez, Hergo Holzhütter, Stefan Kempa, Thorsten Cramer

Date Published: 10th Dec 2019

Journal: Br J Cancer

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