Subsequent Liver Research Articles

Impact of Machine Perfusion on Biliary Complications after Liver Transplantation.

We describe in this review the different types of injuries caused to the biliary tree after liver transplantation. Furthermore, we explain underlying mechanisms and why oxygenated perfusion concepts could not only protect livers, but also repair high-risk grafts to prevent severe biliary complications and graft loss. Accordingly, we summarize experimental studies and clinical applications of machine liver perfusion with a focus on biliary complications after liver transplantation. Key points: (1) Acute inflammation with subsequent chronic ongoing liver inflammation and injury are the main triggers for cholangiocyte injury and biliary tree transformation, including non-anastomotic strictures; (2) Hypothermic oxygenated perfusion (HOPE) protects livers from initial oxidative injury at normothermic reperfusion after liver transplantation. This is a unique feature of a cold oxygenation approach, which is effective also end-ischemically, e.g., after cold storage, due to mitochondrial repair mechanisms. In contrast, normothermic oxygenated perfusion concepts protect by reducing cold ischemia, and are therefore most beneficial when applied instead of cold storage; (3) Due to less downstream activation of cholangiocytes, hypothermic oxygenated perfusion also significantly reduces the development of biliary strictures after liver transplantation.

Primary tumor location in stage III colon cancer has prognostic impact on subsequent liver metastasis

We aim to investigate whether a difference exists between right-sided and left-sided colon cancer at the same disease stage and subsequent liver metastasis and identify whether tumor location can independently influence survival. Right-sided colon cancer was defined as malignancy arising from the cecum to the transverse colon; left-sided colon cancer was defined as malignancy arising from the splenic flexure to the sigmoid colon. Clinicopathological features and survival data were collected for analysis. Overall, 1442 patients were included for analysis. The median follow-up time was 58.2 months. Patients with left-sided colon cancer had better 5-year overall survival (75.2% vs 61.7%, P = 0.005), 5-year cancer-specific survival (81.6% vs 73.4%, P = 0.001), and 5-year recurrence-free survival (70.9% vs 66.5%, P = 0.033) compared with patients having right-sided colon cancer. After the presentation of subsequent liver metastasis, patients with primary left-sided colon cancer had better 3-year cancer-specific survival ( P < 0.001). In the multivariate analysis, cancer location was an independent prognostic factor for cancer-specific survival (right vs left, HR: 1.276, 95% CI: 1.002-1.625). The primary tumor location can serve as a prognostic factor for treatment outcomes either in primary stage III colon cancer or subsequent liver metastasis.

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment.

Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4 ). Aggravated liver damage was shown in CCl4 -administrated MBL-/- mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl4 -induced liver injury was validated by administration of an MBL-expressing liver-specific adeno-associated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL-/- mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency.

Preliminary Findings on Overall Survival from a Recent Single-Center Cohort of Patients Treated with Yttrium-90 Resin Microspheres for Unresectable HCC

Median overall survival (OS) after selective internal radiation therapy with Y-90 resin microspheres (Y-90 SIRT) for unresectable hepatocellular carcinoma (HCC) has ranged from 4 to 41 months in prospective and retrospective studies. In a previous study of patients treated at our center from 2004 to 2013, OS was 13.1 months (Mantry et al. 2017). We are retrospectively examining a more recent cohort of patients to determine whether outcomes have improved from those we reported earlier and to further examine factors that predict response. Demographics, disease etiology and presentation, Y-90 treatment parameters, response, and OS were abstracted from the charts of patients with unresectable HCC treated with Y-90 SIRT at our facility from April 2013 through March 2017 (n = 150). OS (from the first Y-90 SIRT treatment to death or last follow-up) was assessed with the Kaplan-Meier method. To date, we have analyzed data from 63 patients with HCC who underwent 89 SIRT procedures. Most were male (78%) and white (71%). Hepatitis C was the most common etiology (49%). Mean MELD score was 6.6 (SD 4.9). Most patients (41/63, 65%) had a single Y-90 SIRT treatment, 19 (30%) had 2 treatments, and 3 (5%) had >2 treatments. Best RECIST response was available for 45 patients and was complete response in 10 (22%), partial in 16 (36%), stable disease in 12 (27%), and progression in 7 (16%). Median OS was 19.3 months (95% CI 12.4, 26.1). The presence of ascites was associated with shorter OS (9.6 vs. 26.1 months, P < .001), and white race was associated with shorter OS (16.3 months) than nonwhite race (median not reached, P = .007). Median OS was also not reached for patients (n = 6) with subsequent liver transplant. Survival in this analyzed subset of patients (19.3 months) was longer than in our previously reported cohort (13.1 months), possibly due to improved technique (especially the use of single-lobe and segmental SIRT) and patient selection over time. Future analyses will investigate OS in the full cohort and compare factors predicting survival between our current and previous cohorts and in the 2 cohorts combined.

Predictors of Successful Kasai Portoenterostomy and Survival with Native Liver at 2 Years in Infants with Biliary Atresia

Kasai portoenterostomy (KPE) is the primary treatment for biliary atresia (BA) with subsequent liver transplantation in failed cases. The aim of this work was to study the outcome of KPE in children with BA and identify the factors predicting a successful KPE. Children diagnosed with BA and undergoing KPE between January 2010 and January 2018 were included in the study. A successful KPE was defined as decrease in bilirubin to less than 2mg/dL at 6 months after KPE. Factors affecting the outcome (successful KPE and survival with native liver [SNL] at 2 years) were evaluated by logistic regression. A total of 79 children with post-KPE BA were included. Successful KPE was achieved in 29 (36.7%) of 79 children undergoing KPE. The data for survival with native liver at 2 years were available for 61 children as 9 were lost to follow up before 2 years and another 9 were aged less than 2yearsat the time of analysis. Twenty-seven (44.3%) of these 61 survived with their native liver at 2 years. On logistic regression analysis, lower age at KPE, use of postoperative steroids and absence of cholangitis were significant predictors of a successful KPE. A successful KPE at 6 months was the lone independent predictor of SNL at 2 years in these children. Early age at KPE, use of postoperative steroid and prevention of cholangitis can result in successful KPE. Those with successful KPE are likely to survive with their native liver at 2 years.

Successful Treatment for End—Stage Hepatic Alveolar Echinococcosis With ex vivo Liver Resection and Autologous Liver Transplantation: A Case Report

3045_A.tif Figure 1: Preoperative 3D imaging analysis system revealed the retro—hepatic IVC was involved (arrow)3045_B.tif Figure 2: The irregular outflow of right/short hepatic vein reconstruction (A: great saphenous veins; B—C: right/short hepatic vein reconstruction using the great saphenous veins wall)Objective To explore the surgical process of ex—vivo liver resection and autologous liver transplantation (ERAT) for end—stage hepatic alveolar echinococcosis (HAE) and evaluate the therapeutic effect and surgical benefit. Methods The clinical data of one end—stage HAE patient treated with ERAT combined complicated hepatic vein reconstructionwas analyzed retrospectively. Preoperative examination and intraoperative exploration revealed the second hepatic portal was involved. We successfully initiated an operation through ex—vivoliver resection, hepatic vein reconstruction with the autogenous saphenous vein, and subsequent piggyback autologous liver transplantation by wide—mouth hepatic vein—artificial inferior vena cava anastomosis (end to side). Results This patient discharged uneventfully 14 days after the operation. The injection of low—molecular—weight heparin sodium and consequent oral warfarin sodium tablets were administered for anticoagulant therapy. Regular autograft ultrasound examination revealed no tarombokinesis in autologous liver and inferior vena cava. Conclusion ERAT is an ideal surgical method for end—stage HAE. Wide—mouth hepatic vein reconstruction using an autogenous saphenous vein is the key procedure. Postoperative anticoagulant therapy is significant for the improvement of transplanted liver function.3045_C.tif Figure 3: Piggyback autologous liver transplantation (A—C)

Biliary-Enteric Drainage vs Primary Liver Transplant as Initial Treatment for Children With Biliary Atresia

Some infants with biliary atresia are treated with primary liver transplant (pLT), but most are initially treated with biliary-enteric drainage (BED) with a subsequent salvage liver transplant. Given the improvements in liver transplant outcomes, it is important to determine whether BED treatment remains the optimal surgical algorithm for patients with biliary atresia. To compare the survival of patients with biliary atresia initially treated with BED with patients who underwent pLT. This cohort study used deidentified records from the California Office of Statewide Health Planning and Development database to identify patients with biliary atresia (n = 1252) between January 1, 1990, through December 31, 2015. Patients were categorized into 1 of 2 cohorts: those who received BED treatment and those who underwent pLT. Excluded from the study were those born before January 1, 1995, and those without any documented operative intervention by age 5 years. Data analysis was performed from January 1, 1990, to December 31, 2015. Overall survival was compared between the BED and pLT cohorts using the Kaplan-Meier method. The treatment's association with treatment era was examined by comparing survival before 2002 and on or after January 1, 2002. In total, 1252 patients with biliary atresia were identified. After exclusions, 626 remained; of these patients, 351 (56.1%) were female and 275 (43.9%) were male with a median (interquartile range) age at intervention for initial BED treatment of 65 (48-81) days. Among the 626 patients studied, initial BED treatment was performed in 313 patients (50.0%), and pLT was performed in 313 patients (50.0%). Although patients who underwent pLT had a higher mortality rate within the first 3 months after the procedure, they had a reduced risk of long-term mortality compared with patients initially managed with BED treatment (hazard ratio [HR] ≥6 months after the initial procedure, 0.19; 95% CI, 0.08-0.42; P = .01). Patients requiring salvage liver transplant had a substantially higher risk of mortality than patients who received pLT (HR, 0.43; 95% CI 0.25-0.76; P = .003). Those who underwent pLT had superior survival compared with BED treatment recipients on or after 2002 (HR, 0.16; 95% CI, 0.05-0.54; P < .001), and that persisted when censoring patients who underwent salvage liver transplant (HR, 0.23; 95% CI, 0.07-0.82; P = .01). Patients who underwent pLT experienced superior long-term survival compared with patients who underwent BED treatment. Multi-institutional trials are needed to determine which initial treatment is most advantageous to patients with biliary atresia.

Radio-frequency assisted liver partition with portal vein embolization in staged liver resection (RALPPS) in patients with hilar and intrahepatic cholangiocarcinoma

Objective: Estimation of the short-term results of Radio-frequency Assisted Liver Partition with Portal vein embolization in Staged liver resection (RALPPS) compared with Portal Vein Embolization (PVE) and subsequent major liver resection in patients with hilar (h-CCA) and intrahepatic (i-CCA) cholangiocarcinoma. Summary background data: Unsatisfactory immediate outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in surgery of cholangiocarcinoma suggested that patients with biliary cancer should not be treated by ALPPS. Short-term results of ALPPS variants with reduced surgical trauma on the first stage in patients with cholangiocarcinoma were not yet estimated. Methods: RALPPS and PVE were applied in 10 and 18 patients respectively. Future liver remnant (FLR) was estimated by CT. The propensity score matching method was used in compared groups. Results: The mean rate of FLR hypertrophy after RALPPS/PVE before and after matching was 42%/32% and 49%/31%, respectively. The mean duration of hypertrophy after RALPPS/PVE before and after matching was 16/20 days and 14/17 days, respectively. Major morbidity rate (IIIa grade, Clavien-Dindo) after the stage 1 was significantly larger for RALPPS before matching. There were no differences in morbidity of stage 1 after matching as well as for stage 2 before and after matching. Conclusions: According to preliminary short-term results estimation RALPPS may be considered as an effective and safe minimally invasive variant of ALPPS for rapid FLR hypertrophy in patients with h-CCA and i-CCA.

Fast-track two-stage hepatectomy using hybrid radiology/operating room suite as alternative option to ALPPS procedure

Background: Colorectal liver metastasis (CLM) with bilateral distribution can be managed by two-stage hepatectomy (TSH), however the timeline between the two stages can be concerning for potential drop-out and failure to complete TSH. We present the concept of fast-track TSH (FT-TSH) with first-stage hepatectomy and portal vein embolization (PVE) simultaneously performed in a hybrid interventional radiology/operating room suite (hybrid IR/OR). Methods: Following preoperative chemotherapy, a 38 year-old female patient with bilobar CLM underwent first-stage resection of four left-sided liver lesions immediately followed by a right-sided percutaneous PVE, in collaboration with interventional radiology, using a hybrid IR/OR. Results: First-stage hepatecomy and right PVE were performed without any complications with a total combined operating time of 3.5 hours. Subsequent future liver remnant (FLR) volumetry 28 days after combined first-stage hepatectomy + right PVE procedures demonstrated adequate hypertrophy with a post-PVE FLR of 46.5% of the total estimated total liver volume (kinetic growth rate: 3.2% per week). Patient underwent completion TSH with a right hepatectomy 33 days following the first-stage procedure. There was no perioperative morbidity. Conclusion: Fast-track two-stage hepatectomy is an efficient strategy to reduce time between stages, number of hospital encounters, and allows early return to intended oncologic treatment. It provides an alternative to ALPPS procedure in patients with advanced bilateral liver metastases.

Insuficiência hepática fulminante após transplante simultâneo de rim‐pâncreas: um relato de caso

We describe an unusual case of hyperacute hepatic failure following general anesthesia in a patient receiving a simultaneous kidney-pancreas transplant. Despite an aggressive evaluation of structural, immunological, viral, and toxicological causes, a definitive cause could not be elucidated. The patient required a liver transplant and suffered a protracted hospital course. We discuss the potential causes of fulminant hepatic failure and the perioperative anesthesia management of her subsequent liver transplantation.

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and helperadicate S. aureus. However, at later time points,AT causes aberrant and damaging thrombosisthroughout the liver. Treatment with an AT neutralizing antibody (MEDI4893∗) prevents platelet aggregationand subsequent liver damage, without affecting theinitial and beneficial platelet recruitment. Thus,AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction.

Human skin commensals augment Staphylococcus aureus pathogenesis.

All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that virulence of the human pathogen, Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as “proinfectious agents”. The outcome is pathogen proliferation but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan (PGN), reducing the S. aureus infectious dose by over 1000-fold. This phenomenon occurs using a range of S. aureus strains, infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver resident macrophages (Kupffer cells, KC), that capture and internalise both pathogen and ‘proinfectious agent’, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in initiation of disease by an invading pathogen. As human microflora is ubiquitous2 its role in increasing susceptibility to infection S. aureus highlights potential strategies for disease prevention.

Engaging new refugee in Australian communities at risk for chronic hepatitis B infection into care: A peer-educator intervention.

Chronic Hepatitis B (CHB) infection and subsequent liver complications are rising in prevalence in Australia due to increased migration from endemic regions. Nearly 50% of all those living with CHB in Australia are undiagnosed, leading to missed opportunities for liver cancer and cirrhosis prevention. Health literacy around CHB among refugee communities such as Afghan, Rohingyan, and Sudanese populations (all with a high prevalence of CHB) is low, partly due to a paucity of targeted health promotion programmes; despite the release of the Victorian Hepatitis B Strategy (2016-2020). We developed a peer-education intervention in these three communities to deliver CHB focused radio programmes and community forums in their own language, following a needs assessment consisting of semistructured interviews and surveys. Effectiveness of this intervention was measured through paired comparison of disease-knowledge assessment pre and post forum. Community forums were held between 2015 and 2016, with 25 attendees at the Rohingyan forum (68% male), 10 attendees at the Afghan forum (90% male) and 0 attendees at the Sudanese forum. Participants demonstrated a significant improvement in CHB knowledge between pre- and post-forum surveys (p-value<0.05). A peer-educator approach was a cost-effective health promotion strategy in building CHB knowledge and dispelling misconceptions within the Afghan and Rohingya communities. There were significant barriers in the engagement of the South Sudanese community, which will inform future strategies for health promotion.

Hepatocyte Transplant and Bridge to Subsequent Liver Transplant in an Infant with Carbamoyl Phosphate Synthetase Deficiency

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an autosomal recessive disorder of the urea cycle that causes hyperammonemia. Two forms of CPS1D are recognized: a lethal neonatal type and a less severe, delayed-onset type. Neonatal CPS1D cases often present their symptoms within the first days of life. Severe hyperammonemia in the neonatal period leads to serious brain damage, coma, and death if not treated promptly. We report a case of successful hepatocyte transplant and subsequent deceased donor liver transplant in an infant diagnosed with neonatal CPS1D. Hepatocytes were isolated from liver and deceased donors. At the first transplant, approximately 2.4 x 10^9 cells (7.4% of the estimated recipient's total hepatocytes) were infused over 3 sessions spanning 8 days. Hepatocytes were infused into the portal vein via an indwelling catheter inserted through the umbilical vein. After the first hepatocyte transplant, the patient showed stabilization of ammonia levels after several days and ammonia levels remained stable despite increased protein intake and discontinuation of ammonia scavengers. After 5 months, graft function seemed to deteriorate with elevated ammonia levels at times. A second hepatocyte transplant was done and was also successful in sustaining stable ammonia levels for another 5 months. The infant received deceased donor liver transplant at 13 months of age. This was the first successful hepatocyte transplant and subsequent bridge to liver transplant in a CPS1D baby in Korea. Hepatocyte transplant allowed ammonia stabilization despite protein intake, which allowed for normal growth and development in this infant.

Prospective Association between Gestational Diabetes and Subsequent Abnormal Liver Function Scores 9 to 16 Years after Pregnancy

Chronic hyperglycemia is a risk factor for liver dysfunction. Women with gestational diabetes mellitus (GDM), glucose intolerance first recognized in pregnancy, may identify a population of individuals at an increased risk for liver complications. However, large prospective studies examining liver function following a GDM pregnancy are lacking. The Diabetes &amp; Women’s Health (DWH) Study (2012-2014) followed women with and without GDM in the Danish National Birth Cohort (DNBC). DNBC was a population-based cohort study of pregnant Danish women (1996-2002). At 9-16 years postpartum, the DWH Study conducted a clinical exam and collected bio-specimens on 607 of 1,274 women with GDM and 619 of a random sample of 1,457 women without GDM during the index DNBC pregnancy. Markers of liver function measured at follow-up included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT). Liver function scoring indices were used to assess liver capacity including: nonalcoholic fatty liver disease liver fat score (NAFLD-LFS), fatty liver index (FLI), hepatic steatosis index (HSI), and liver fat percentage. The mean (standard deviation) age (years) at follow-up for women without and with prior GDM was 43.4 (4.5) and 43.8 (4.6), respectively. Women with prior GDM had an increased risk at follow-up of elevated NAFLD-LFS (Adjusted Relative risk [RR], 2.34; 95% CI, 1.68-3.27), FLI (RR, 1.59; 95% CI, 1.27-1.99), and HSI (RR, 1.44; 95% CI, 1.21-1.71) adjusted for pre-pregnancy BMI and other relevant risk factors compared to women without prior GDM. Women with prior GDM also had a significantly higher fatty liver percentage (Adjusted difference (%), 1.93; 95% CI, 1.10-2.77). Women with GDM during pregnancy were at an increased risk for subsequent abnormal liver function 9-16 years postpartum. GDM may serve as another risk indicator for the early identification and prevention of liver dysfunction. Disclosure S. Donnelly: None. S. Hinkle: None. S. Rawal: None. L. Grunnet: None. J.E. Chavarro: None. A.A. Vaag: Employee; Self; AstraZeneca. J. Wu: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. M. Li: None. A.A. Bjerregaard: None. A. Thuesen: None. R.E. Gore-Langton: None. E.C. Francis: None. F. Hu: None. M.Y. Tsai: None. S.F. Olsen: None. C. Zhang: None.

Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages.

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases; however, the mechanisms underlying interactions between microbial products and immune responses in the liver remain unknown. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury, and the severity of colitis directly affected susceptibility to such injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota play a substantial role in this process. Altered gut microbiota and their metabolites, along with a disrupted intestinal barrier, directly gave rise to immunological permissiveness in the inflamed liver. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages. Consistently, expression of nicotinamide N-methyltransferase, which converts nicotinamide to 1-MNA, was upregulated in the liver of DSS-Con A mice, and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation.

These results suggest that lipotoxic activation of TBK1 and subsequent p62 phosphorylation are critical steps in the NASH pathology of protein inclusion accumulation in hepatocytes. This mechanism can provide an explanation for how hypernutrition and obesity promote the development of severe liver pathologies, such as steatohepatitis and liver cancer, by facilitating the formation of p62 inclusions. (Hepatology 2018).

Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury

Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an invitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. We performed a prospective study of patients referred to the University Hospital in Munich,Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory testand imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanateto cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT02353455.

Radiation Segmentectomy: Potential Curative Therapy for Early Hepatocellular Carcinoma.

Purpose To report long-term outcomes of radiation segmentectomy (RS) for early hepatocellular carcinoma (HCC). The authors hypothesized that outcomes are comparable to curative treatments for patients with solitary HCC less than or equal to 5 cm and preserved liver function. Materials and Methods This retrospective study included 70 patients (median age, 71 years; range, 22-96 years) with solitary HCC less than or equal to 5 cm not amenable to percutaneous ablation who underwent RS (dose of >190 Gy) between 2003 and 2016. Patients who underwent subsequent curative liver transplantation were excluded to eliminate this confounding variable affecting survival. Radiologic response of time to progression and median overall survival were estimated by using the Kaplan-Meier method per the guidelines of the European Association for the Study of the Liver (EASL) and the World Health Organization (WHO). Results Seventy patients were treated with RS over 14 years. Sixty-three patients (90%) showed response by using EASL criteria, of which 41 (59%) showed complete response. Fifty patients (71%) achieved response by using WHO criteria, of which 11 (16%) achieved complete response. Response rates at 6 months were 86% and 49% by using EASL and WHO criteria, respectively. Median time to progression was 2.4 years (95% confidence interval: 2.1, 5.7), with 72% of patients having no target lesion progression at 5 years. Median overall survival was 6.7 years (95% confidence interval: 3.1, 6.7); survival probability at 1, 3, and 5 years was 98%, 66%, and 57%, respectively. Overall survival probability at 1, 3, and 5 years was 100%, 82%, and 75%, respectively, in patients with baseline tumor size less than or equal to 3 cm (n = 45) and was significantly longer than in patients with tumors greater than 3 cm (P = .026). Conclusion RS provides response rates, tumor control, and survival outcomes comparable to curative-intent treatments for selected patients with early-stage HCC who have preserved liver function. © RSNA, 2018 Online supplemental material is available for this article.

Liver Disease in Men Undergoing Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy is associated with the development of diabetes and metabolic syndrome. To our knowledge its effect on the development of nonalcoholic fatty liver disease, a condition which frequently co-occurs with metabolic syndrome and other subsequent liver conditions such as liver cirrhosis, hepatic necrosis or any liver disease, has not been investigated. We identified 82,938 men 66 years old or older who were diagnosed with localized prostate cancer in the SEER (Surveillance, Epidemiology and End Results)-Medicare database from 1992 to 2009. Men with preexisting nonalcoholic fatty liver disease, liver disease, diabetes or metabolic syndrome were excluded from study. Propensity score adjusted, competing risk regression models were created to compare the risk of nonalcoholic fatty liver disease in men who were vs were not treated with androgen deprivation. We also explored the influence of cumulative exposure to androgen deprivation therapy, calculated as monthly equivalent doses of gonadotropin-releasing hormone agonists/antagonists (fewer than 7, 7 to 11 or more than 11 doses). Overall 37.5% of men underwent androgen deprivation therapy. They were more likely to be diagnosed with nonalcoholic fatty liver disease (HR 1.54, 95% CI 1.40-1.68), liver cirrhosis (HR 1.35, 95% CI 1.12-1.60), liver necrosis (HR 1.41, 95% CI 1.15-1.72) and any liver disease (HR 1.47, 95% CI 1.35-1.60). A dose-response relationship was observed between the number of androgen deprivation therapy doses, and nonalcoholic fatty liver disease and any liver disease. Androgen deprivation therapy in men with prostate cancer is associated with the diagnosis of nonalcoholic fatty liver disease. The usual limitations of an observational study design apply, including possible inaccuracy in defining outcomes in a population based registry.