Hepatic Bile Research Articles

Exposure to GenX and Its Novel Analogs Disrupts Hepatic Bile Acid Metabolism in Male Mice.

Due to its wide usage and recent detection in environmental matrices, hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name GenX) has attracted considerable attention. Here, we explored and compared the toxicity of GenX and its novel analogs with that of perfluorooctanoic acid (PFOA) to provide guidance on the structural design and optimization of novel alternatives to poly- and perfluoroalkyl substances (PFASs). Adult male BALB/c mice were continuously exposed to PFOA, GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2HpA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. The PFOA, GenX, and PFMO3NA treatment groups showed an increase in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, as shown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/d PFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondary bile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure to GenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas the hepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

A Donor With Green Kidneys—To Transplant or Not to Transplant: A Case Report

A Donor With Green Kidneys—To Transplant or Not to Transplant: A Case Report

Anatomic Variations of the Hepatic Artery in 5625 Patients.

To analyze the origin and anatomic course of the hepatic arteries by using digital subtraction angiography (DSA) and multidetector CT in a large study sample. This retrospective study included 5625 patients who underwent liver CT and chemoembolization between January 2005 and December 2018 (mean age, 60 years ± 11 [range, 11-99 years]; 4464 males). The CT and DSA images were reviewed to evaluate the visceral arterial anatomy for variations in the celiac axis and hepatic arteries. Aberrant right hepatic arteries (aRHAs) and aberrant left hepatic arteries (aLHAs) were defined on the basis of their origin and anatomic course. Statistical analyses were performed to evaluate the association between aRHAs and aLHAs and the association between variations in the hepatic artery and celiac axis. Right hepatic arteries were categorized as being aRHAs (if originating from the proximal to middle common hepatic artery, gastroduodenal artery, superior mesenteric artery [SMA], celiac axis, aorta, splenic artery, or left gastric artery [LGA]) or as being aLHAs (if arising from the LGA, celiac axis, aorta, or SMA). The prevalence of aRHAs (15.63%; 879 of 5625) and the prevalence aLHAs (16.32%; 918 of 5625) were similar. Patients with an aRHA were more likely to have an aLHA than those without an aRHA (29.01% vs 13.97%; P < .001), and patients with an aLHA were more likely to have an aRHA than those without an aLHA (27.78% vs 13.26%; P < .001). There was no association between the hepatic arterial variations and celiac axis variations. A hypothetical anatomic model summarizing the observed variations was created. A comprehensive list of hepatic arterial variations and a three-dimensional hypothetical model for the observed variations were described.Keywords: CT, Angiography, Liver, Anatomy, Arteries© RSNA, 2021 Supplemental material is available for this article. See also commentary by Sutphin and Kalva in this issue.

Identification of Novel HBV/HDV Entry Inhibitors by Pharmacophore- and QSAR-Guided Virtual Screening

The hepatic bile acid transporter Na+/taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, but the synthetic peptide Hepcludex® of high molecular weight is the only approved HDV entry inhibitor so far. The present study aimed to identify small molecules as novel NTCP inhibitors with anti-viral activity. A ligand-based bioinformatic approach was used to generate and validate appropriate pharmacophore and QSAR (quantitative structure–activity relationship) models. Half-maximal inhibitory concentrations (IC50) for binding inhibition of the HBV/HDV-derived preS1 peptide (as surrogate parameter for virus binding to NTCP) were determined in NTCP-expressing HEK293 cells for 150 compounds of different chemical classes. IC50 values ranged from 2 µM up to >1000 µM. The generated pharmacophore and QSAR models were used for virtual screening of drug-like chemicals from the ZINC15 database (~11 million compounds). The 20 best-performing compounds were then experimentally tested for preS1-peptide binding inhibition in NTCP-HEK293 cells. Among them, four compounds were active and revealed experimental IC50 values for preS1-peptide binding inhibition of 9, 19, 20, and 35 µM, which were comparable to the QSAR-based predictions. All these compounds also significantly inhibited in vitro HDV infection of NTCP-HepG2 cells, without showing any cytotoxicity. The best-performing compound in all assays was ZINC000253533654. In conclusion, the present study demonstrates that virtual compound screening based on NTCP-specific pharmacophore and QSAR models can predict novel active hit compounds for the development of HBV/HDV entry inhibitors.

Long-term cold storage preservation does not affect fatty livers from rats fed with a methionine and choline deficient diet

BackgroundWaiting lists that continue to grow and the lack of organs available for transplantation necessitate the use of marginal livers, such as fatty livers. Since steatotic livers are more susceptible to damage from ischemia and reperfusion, it was investigated whether fatty livers with different lipidomic profiles show a different outcome when subjected to long-term cold storage preservation.MethodsEight-week-old male Wistar rats fed for 2 weeks by a methionine-choline-deficient (MCD) diet or control diet were employed in this study. Livers were preserved in a University of Wisconsin (UW) solution at 4 °C for 6, 12 or 24 h and, after washout, reperfused for 2 h with a Krebs-Henseleit buffer at 37 °C. Hepatic enzyme release, bile production, O2-uptake, and portal venous pressure (PVP) were evaluated. The liver fatty acid profile was evaluated by a gas chromatography-mass spectrometry (GC/MS).ResultsMCD rats showed higher LDH and AST levels with respect to the control group. When comparing MCD livers preserved for 6, 12 or 24 h, no differences in enzyme release were found during both the washout or the reperfusion period. The same trend occurred for O2-uptake, PVP, and bile flow. A general decrease in SFA and MUFA, except for oleic acid, and a decrease in PUFA, except for arachidonic, eicosadienoic, and docosahexanaeoic acids, were found in MCD rats when compared with control rats. Moreover, the ratio between SFA and the various types of unsaturated fatty acids (UFA) was significantly lower in MCD rats.ConclusionsAlthough prolonged cold ischemia negatively affects the graft outcome, our data suggest that the quality of lipid constituents could influence liver injury during cold storage: the lack of an increased hepatic injury in MCD may be justified by low SFA, which likely reduces the deleterious tendency toward lipid crystallization occurring under cold ischemia.

Biomagnification of Copper Along the Aquatic Food Chain (Artemia franciscana, Danio rerio, and Astronotus ocellatus).

Nowadays, pollution of aquatic ecosystems with heavy metals is one of the most important environmental challenges due to toxicity, stability, and bioaccumulation in the environment. Heavy metals accumulate in aquatics and plant tissues and can eventually threaten human health by transmission into the food chain. For this reason, in the present study, the effect of copper sulfate (CuSO4) and its transmission in the food chain of Artemia franciscana, Danio rerio (Zebra), and Astronotus ocellatus (Oscar) were investigated. Initially, lethal concentration of Cu on Artemia was obtained in 24h. In the first step, Zebra fishes fed with Artemia (under copper sulfate exposure (LC50)) and water (clean and 10% of CuSO4) treatments. In the second step, Oscar fishes fed with Zebra (under copper sulfate exposure (LC50)) and water (clean and 10% of CuSO4) treatments. In the last step, the concentration of Cu was measured in liver tissues of Zebra and Oscar fishes. Also, the variation of glucose and enzymes including Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and Autologous Conditioned Plasma (ACP) was measured. The results of this study showed that Cu causes histopathological changes liver tissues including hyperemia, necrosis, hepatic portal vein, hepatocyte destruction, nucleolysis, bile stasis, and biliary edema. Also, a strong positive and significant correlation was observed between Cu and increasing glucose and ALT, AST, and ACP.

Modeling alcohol-associated liver disease in a human Liver-Chip.

SUMMARYAlcohol-associated liver disease (ALD) is a global health issue and leads to progressive liver injury, comorbidities, and increased mortality. Human-relevant preclinical models of ALD are urgently needed. Here, we leverage a triculture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi to model ALD employing human-relevant blood alcohol concentrations (BACs) and multimodal profiling of clinically relevant endpoints. Our Liver-Chip recapitulates established ALD markers in response to 48 h of exposure to ethanol, including lipid accumulation and oxidative stress, in a concentration-dependent manner and supports the study of secondary insults, such as high blood endotoxin levels. We show that remodeling of the bile canalicular network can provide an in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a powerful platform for modeling alcohol-induced liver injury with the potential for direct translation to clinical research and evaluation of patient-specific responses.

Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin

BackgroundLeptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway—leptin signaling—leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice.ResultsSix-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes.ConclusionTaken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition.DUGQcxDcUnuc9Bgg7Th-A2Video abstract.

Clinicopathological study of hepatic mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver: a single center study from Iran

BackgroundUndifferentiated embryonal sarcoma of liver (UESL) and hepatic mesenchymal hamartoma (HMH) are two rare entities which mainly affect the pediatric population. The aim of this investigation was to provide a comprehensive overview of the clinicopathologic characteristics of the patients diagnosed with these two conditions in a tertiary referral center in Iran.MethodsIn this retrospective study patients diagnosed with UESL or HMH between 2012 and 2020 were studied. A comprehensive histopathologic evaluation of the cases along with immunohistochemistry evaluation using a panel of antibodies was conducted. Furthermore, clinical, paraclinical, and treatment data and follow up information was collected.ResultsA total of 16 patients (8 UESL, 8 HMH) were studied in this investigation. Patients with UESL had a significantly (p = 0.002) higher age at diagnosis compared with those with HMH. Histologically, UESL cases were characterized by anaplastic cells with eosinophilic cytoplasm and bizarre nuclei and frequent atypical mitosis and spindling in a myxoid stroma while disordered arrangement of hepatic parenchyma, bile ducts, and primitive mesenchyme was seen in HMH. Furthermore, small round cells and extramedullary hematopoiesis were seen in 2 UESL and 3 HMH cases, respectively. Concurrent HMH was also seen in two UESL cases. Immunohistochemistry panel showed positive staining for Vimentin, Glypican-3, Desmin, CD56, CD10, and BCL2 in UESL cases and immunoreactivity for Vimentin, HepPar 1, Glypican-3, SMA, CD56, BCL2, and CD34 in various components of HMH.ConclusionsIn this study, the clinicopathologic features of UESL and HMH cases are presented. We also evaluated the utility of an immunohistochemistry panel in the diagnosis of these two rare entities and suggested novel markers. Our study corroborated the findings of previous investigations and expanded the clinicopathologic features of these two rare entities with diagnostic and potential therapeutic implications.

Magnetic compression anastomosis via EUS-guided hepaticogastrostomy for recanalization of complete common hepatic bile duct transection.

Video 1Magnetic compression anastomosis via EUS-guided hepaticogastrostomy for recanalization of complete common hepatic bile duct transection.

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology.

Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium–dependent bile acid transporter (gene SLC10A2) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B). The Na+‐taurocholate cotransporting polypeptide (gene SLC10A1) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na+‐taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium–dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion: We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.

The crystal structure of mouse SULT2A8 reveals the mechanism of 7α-hydroxyl, bile acid sulfation

Bile acids play essential roles in facilitating the intestinal absorption of lipophilic nutrients as well as regulation of glucose, lipid, and energy homeostasis via activation of some receptors. Bile acids are cytotoxic, and consequently their concentrations are tightly controlled. A critical pathway for bile acid elimination and detoxification is sulfation. The pattern of bile acid sulfation differs by species. Sulfation preferentially occurs at the 3α-OH of bile acids in humans, but at the 7α-OH in mice. A recent study identified mouse cytosolic sulfotransferase 2A8 (mSULT2A8) as the major hepatic 7α-hydroxyl bile acid-sulfating enzyme. To elucidate the 7α-OH specific sulfation mechanism of mSULT2A8, instead of 3α-OH specific sulfation in humans, we determined a crystal structure of mSULT2A8 in complex with cholic acid, a major bile acid, and 3′-phosphoadenosine-5′-phosphate, the sulfate donor product. Our study shows that bile acid-binding mode of mSULT2A8 and how the enzyme holds the 7α-OH group of bile acids at the catalytic center, revealing that the mechanism underlying 7α-OH specific sulfation. The structure shows the substrate binds to mSULT2A8 in an orientation perpendicular to that of human 3α-hydroxyl bile acid-sulfotransferase (hSULT2A1). The structure of the complex provides new insight into species different bile acid metabolism.

A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL). The piglets received BDL and TXR for 2wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA). We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7α-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL. TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.

Substrate Specificities and Inhibition Pattern of the Solute Carrier Family 10 Members NTCP, ASBT and SOAT.

Three carriers of the solute carrier family SLC10 have been functionally characterized so far. Na+/taurocholate cotransporting polypeptide NTCP is a hepatic bile acid transporter and the cellular entry receptor for the hepatitis B and D viruses. Its intestinal counterpart, apical sodium-dependent bile acid transporter ASBT, is responsible for the reabsorption of bile acids from the intestinal lumen. In addition, sodium-dependent organic anion transporter SOAT specifically transports sulfated steroid hormones, but not bile acids. All three carriers show high sequence homology, but significant differences in substrate recognition that makes a systematic structure-activity comparison attractive in order to define the protein domains involved in substrate binding and transport. By using stably transfected NTCP-, ASBT-, and SOAT-HEK293 cells, systematic comparative transport and inhibition experiments were performed with more than 20 bile acid and steroid substrates as well as different inhibitors. Taurolithocholic acid (TLC) was identified as the first common substrate of NTCP, ASBT and SOAT with K m values of 18.4, 5.9, and 19.3 µM, respectively. In contrast, lithocholic acid was the only bile acid that was not transported by any of these carriers. Troglitazone, BSP and erythrosine B were identified as pan-SLC10 inhibitors, whereas cyclosporine A, irbesartan, ginkgolic acid 17:1, and betulinic acid only inhibited NTCP and SOAT, but not ASBT. The HBV/HDV-derived myr-preS1 peptide showed equipotent inhibition of the NTCP-mediated substrate transport of taurocholic acid (TC), dehydroepiandrosterone sulfate (DHEAS), and TLC with IC50 values of 182 nM, 167 nM, and 316 nM, respectively. In contrast, TLC was more potent to inhibit myr-preS1 peptide binding to NTCP with IC50 of 4.3 µM compared to TC (IC50 = 70.4 µM) and DHEAS (IC50 = 52.0 µM). Based on the data of the present study, we propose several overlapping, but differently active binding sites for substrates and inhibitors in the carriers NTCP, ASBT, SOAT.

Microscopic study of potential toxic effects of monosodium glutamate on liver of chicken embryos aged 16 days

BackgroundThis experimental study aimed to determine the changes caused by monosodium glutamate (MSG) on morphology and histology of liver of chicken embryos aged 16 days of incubation. In this research, 50 fertilized eggs were used. They were divided into two equal groups, one group was used as control with normal liver structure, while the other group (MSG) was treated with MSG in 0 day of incubation (0.1ml/egg).ResultsThe results showed many harmful effects on hepatic cells, blood sinusoids, and bile ducts in MSG group. These changes included alterations in nuclei conformation and nuclear envelope. Chromatin distribution was associated with increased electronic intensity. Also, there were rupture in smooth endoplasm systems and malfunction of mitochondria and Golgi apparatus, with increased lysosomes and lipid droplets.ConclusionsThis study concluded that MSG had severe toxic effects on liver structure if it was given in pre-conception period as this period is considered critical for liver growth (organogenesis).

Intrahepatic cholestasis induced by α-naphthylisothiocyanate can cause gut-liver axis disorders

Clinical studies have shown that Intrahepatic cholestasis is closely related to intestinal injury. The gut-liver axis theory suggests that the intestine and liver are closely related, and that bile acids are important mediators linking the intestine and liver. We compared two cholestasis models: a single injection model that received a single subcutaneous ANIT injection (75 mg/kg), and a multiple subcutaneous injection model that received an injection of ANIT (50 mg/kg) every other day for 2 weeks. We used Transmetil (ademetionine 1,4-butanedisulfonate) to relieve intrahepatic cholestasis in the multiple injection group. In the multiple injection group, we found increased hepatic bile duct hyperplasia, increased fibrosis of the liver, increased small intestine inflammation and oxidative damage, increased harmful bile acids, decreased bile acids transporter levels. After treatment with Transmetil, the liver and gut injuries were relieved. These results suggest that intrahepatic cholestasis can cause disorders of the gut-liver axis.

Psychological Burden and Psycho-Oncological Interventions for Patients With Hepatobiliary Cancers-A Systematic Review.

BackgroundWorldwide, hepatobiliary cancers are frequent diseases and often accompanied by a poor prognosis. These cancers, with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CHC) being the most frequent, are often associated with a considerable amount of psychological burden such as anxiety, depressiveness, and reduced health-related quality of life (HRQOL) which may lead to psychiatric comorbidities. This systematic review gives an overview on psychological burden and on the effectiveness of psycho-oncological interventions for patients with HCC and CHC.MethodsThe databases PubMed, PubPsych, and PsycINFO were used and searched using the following combination of terms: (Neoplasm OR Cancer OR Tumor OR Carcinoma) AND (Psycho-Oncology OR Psychotherapy OR Psychiatr∗) AND (Liver OR Hepatic OR Hepatocellular OR Gallbladder OR Bile∗). Studies were eligible for inclusion if investigating patients affected with tumors of the liver (HCC/CHC) and using diagnostic instruments to assess mental health symptoms and research concerning specific psycho-oncological interventions. In total, 1027 studies were screened by one author with regard to title and abstracts. Afterward, the two authors of the paper discussed inclusion of possible articles.ResultsTwelve studies focusing on distress, anxiety, and depression symptoms as well as quality of life among patients with HCC/CHC and three studies on psycho-oncological interventions were included. Patients suffering from hepatobiliary cancers often experience considerable psychological burden. A quarter of patients suffer from depressive symptoms; anxiety is even more common among these patients with almost 40%. The HRQOL of those affected is reduced in almost all areas, suicide rates increased and the level of distress is considerably increased in one third of patients even in comparison to those with other kinds of cancer. By psycho-oncological intervention the prevalence of depressive symptoms and anxiety can be reduced, while the quality of life and also the survival rate of patients with hepatobiliary cancer can be increased.Discussion and ConclusionPsychological burden is high in patients with hepatobiliary cancers as reflected in high levels of depressiveness and anxiety as well as reduced quality of life. The use of psycho-oncological interventions can reduce psychological burden and increase quality of life compared to patients receiving standard support only.Systematic Review Registration(prospero), identifier (CRD42021243192).

Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration.

The involvement of bile salt–fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt–FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous‐arterial differences (ΔVA), and determined hepatic transcript levels on two intra‐operative time points: before (< 1 hour) and immediately after (> 2‐3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)–liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra‐operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt–homeostatic regulator farnesoid X receptor (FXR) was markedly up‐regulated following surgery (P < 0.001). Cell‐cycle re‐entry priming factors (interleukin 6 [IL‐6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up‐regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.

Patient-specific fluid–structure interaction model of bile flow: comparison between 1-way and 2-way algorithms

Gallbladder disease is one of the most spread pathologies in the world. Despite the number of operations dealing with biliary surgery increases, the number of postoperative complications is also high. The aim of this study is to show the influence of the biliary system pathology on bile flow character and to numerically assess the effect of surgical operation (cholecystectomy) on the fluid dynamics in the extrahepatic biliary tree, and also to reveal the difference between 1-way and 2-way FSI algorithms on the results. Moreover, the bile viscosity and biliary tree geometry influence on the choledynamics were evaluated. Bile velocity, pressure, wall shear stress (WSS), displacements and von Mises stress distributions in the extrahepatic biliary tree are presented, and comparison is made between a healthy and a lithogenic bile. The patient-specific biliary tree model is created using magnetic resonance imaging (MRI) and imported in a commercial finite element analysis software. It is found that in the case of lithogenic bile, velocities have lower magnitude while pressures are higher. Furthermore, stress analysis of the bile ducts shows that the WSS distribution is found mostly prevailing in the common hepatic duct and common bile duct areas. It is shown that when it is necessary to evaluate the bile flow dynamics in urgent medical situations, 1-way analysis is acceptable. Nevertheless, 2-way FSI provides more accurate data, if necessary to evaluate the stress–strain state of bile ducts. The proposed model can be applied to medical practice to reduce the number of post-operative complications.