Worsening Liver Function Research Articles

Prophylactic Antibiotics in Cirrhosis: Are They Promoting or Preventing Infections?

Prophylactic Antibiotics in Cirrhosis: Are They Promoting or Preventing Infections?

Antioxidant Effects of Oral Ang-(1-7) Restore Insulin Pathway and RAS Components Ameliorating Cardiometabolic Disturbances in Rats.

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPβCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPβCD) or HPβCD/Ang-(1-7) in the last 6 weeks. FAT-HPβCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPβCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPβCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.

Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases.

Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates' clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation.Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration.This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.

Combination of Mac-2 Binding Protein Glycosylation Isomer and Up-To-Seven Criteria as a Useful Predictor for Child-Pugh Grade Deterioration after Transarterial Chemoembolization for Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). In patients who became refractory to TACE, a treatment switch to tyrosine kinase inhibitors (TKIs) needs to be considered. However, TACE could worsen liver function, thereby narrowing the time window for a switch to TKIs because TKIs are recommended for patients with Child-Pugh grade A (CP-A). We investigated the factors associated with CP grade deterioration after TACE. Among patients who underwent TACE, 125 patients with CP-A were enrolled. The cumulative CP grade deterioration rates were 20.3%, 27.1%, and 41.4% at six months, one year, and two years, respectively. Multivariate analysis revealed that factors associated with CP grade deterioration included high Mac-2 binding protein glycosylation isomer (M2BPGi) levels (>2.00 cut-off index) and beyond the up-to-seven criteria. The cumulative CP grade deterioration rates of patients with high M2BPGi and beyond the up-to-seven criteria were 50.6% and 59.2% at six months and one year, respectively, which were significantly higher than for those in any other groups. The combination of M2BPGi and up-to-seven criteria could be a surrogate marker for predicting CP grade deterioration after TACE. In patients with intermediate-stage HCC, elevated M2BPGi levels, and beyond the up-to-seven criteria, an early treatment switch to TKIs should be considered to improve their prognosis.

A study on the relationship between tissue factor expression and liver damage in diabetic patients with hepatitis C virus-related cirrhosis

Objective The aim of this study was to identify a possible role for tissue factor (TF) in the pathogenesis of hepatic damage in patients with hepatitis C virus (HCV)-related cirrhosis with type 2 diabetes mellitus (T2DM). Background HCV infection and T2DM are both prevalent diseases worldwide. The exact mechanism by which type 2 diabetes worsens liver function is needed to be clarified. TF is a key link that connects hemostatic, immune, and inflammatory processes. Materials and methods The study included 80 participants divided into three groups: 30 patients with HCV-related cirrhosis and T2DM, 30 cirrhotic patients, and 20 healthy controls. Flow cytometry analysis was used for measuring TF (CD142) and the costimulatory molecule (CD86) on lipopolysaccharide-activated monocytes (CD14 positive cells) in peripheral blood in different studied groups. Results Our results have shown higher TF and CD86 expression in cirrhotic patients with T2DM compared with those with cirrhosis and healthy controls (34.06 ± 5.99, 24.65 ± 6.76 and 11.90 ± 3.04 for TF and 72.09 ± 12.57, 49.38 ± 15.07 and 9.35 ± 3.07 for CD86, respectively; P Conclusion On the basis of our data, we suggest a possible role for TF in the pathogenesis of liver damage through exaggerating the inflammatory process. This can, at least partially, explain the worsened liver function in HCV-related cirrhosis in patients with T2DM.

A novel role for programmed cell death receptor ligand 2 in sepsis-induced hepatic dysfunction.

The liver is an organ that, when dysfunctional in a septic patient, is strongly associated with morbidity and mortality. Understanding the pathophysiology of liver failure during sepsis may lead to improved diagnostics and potential therapeutic targets. Historically, programmed cell death receptor (PD) ligand 1 (PD-L1) has been considered the primary ligand for its checkpoint molecule counterpart, PD-1, with PD-L2 rarely in the immunopathological spotlight. PD-1 and PD-L1 contribute to liver dysfunction in a murine cecal ligation and puncture (CLP) model of sepsis, but virtually nothing is known about PD-L2's role in sepsis. Therefore, our central hypothesis was that sepsis-induced changes in hepatic PD-L2 expression contributed to worsened liver function and, subsequently, more pronounced morbidity and mortality. We found that although PD-L1 gene deficiency attenuated the hepatic dysfunction seen in wild-type mice after CLP, the loss of PD-L2 appeared to actually worsen indices of liver function along with a trend toward higher liver tissue vascular permeability. Conversely, some protective effects of PD-L2 gene deletion were noted, such as reduced liver/peritoneal bacterial load and reduced IL-6, IL-10, and macrophage inflammatory protein 2 levels following CLP. These diverse actions, as well as the unique expression pattern of PD-L2, may explain why no overt survival advantage could be witnessed in the septic PD-L2-/- mice. Taken together, these data suggest that although PD-L2 has some selective effects on the hepatic response seen in the septic mouse, these factors are not sufficient to alter septic mortality in this adult murine model. NEW & NOTEWORTHY Our study shows not only that ligands of the checkpoint protein PD-1 respond inversely to a stressor such as septic challenge (PD-L2 declines, whereas PD-L1 rises) but also that aspects of liver dysfunction increase in septic mice lacking the PD-L2 gene. Furthermore, these differences in PD-L2 gene-deficient animals culminated in the abrogation of the survival advantage seen in the septic PD-L1-knockout mice, suggesting that PD-L2 may have roles beyond a simple immune tolerogen.

Outcomes following Stereotactic Body Radiation Therapy for Patients with Child-Pugh B or C Hepatocellular Carcinoma

SBRT is a treatment option for patients (pts) with hepatocellular carcinoma (HCC). Due to concern for causing worsening liver function, caution has been recommended when using SBRT in pts with Child-Pugh (CP) B or C disease. Here we report our institutional outcomes. An institutional review board-approved registry was used to identify CP B and C patients with non-metastatic HCC treated with SBRT between 2011 and 2017. Baseline patient and disease factors, laboratory values, and treatment information were recorded. Patients were followed with radiographic imaging as well as clinical and laboratory follow-up. CP score after treatment was calculated at 2 or 3 months as available. Overall survival (OS) was evaluated using the Kaplan-Meier method and logistic regression analysis was used to identify factors predictive for CP change ≥2 and grade III hepatotoxicity. Thirty-seven pts treated with SBRT to 44 lesions met study criteria. About half of pts (54%) had received prior therapies including embolization, radiofrequency ablation, or y90 radioembolization. Twenty pts were treated with definitive intent, 8 as a bridge to transplant, and 9 were treated for downstaging for transplant. At the time of treatment, 27 pts had CP score of B (7-9) and 10 pts had CP score of C (10-12). The median overall survival (OS) was 14.8 months. Thirteen pts proceeded on to liver transplant after SBRT (7 of 8 bridging, 6 of 9 downstaging), and transplantation was associated with a significant improvement in median OS (32.2 months vs 7.3 months, p=0.018). Among non-transplant patients, CP score of B7 predicted for improved OS relative to CP B8-C scores (1 yr OS 56% vs 18.8% p=0.04). The most commonly used regimen was 40 Gy in 5 fractions, median PTV was 103.7 cc, and median liver mean dose was 10.3 Gy. The median radiographic follow up was 8.3 months, during which only one patient experienced local progression. Among the 30 pts undergoing follow-up with laboratory studies, 8 pts (26.7%) had a rise in CP score exceeding 2 points at 2 or 3 month follow-up and only a single patient died of liver toxicity. Among pts treated with definitive intent, only 10% experienced a change in CP score of ≥2. Neither liver mean dose nor PTV size predicted for CP score change ≥2. Following SBRT, 2 pts developed new grade III hypoalbuminemia, 11 pts developed new grade III hyperbilirubinemia, and 6 pts developed new grade III transaminitis. Liver mean dose, PTV size, and prescription dose did not predict for development of new grade III hepatotoxicity. However, in patients who did not have disease progression in the liver, RT dose ≥40 Gy predicted for grade III hepatotoxicity (p=0.003). SBRT can be successfully employed as local therapy for well-selected patients with CP B and C HCC with low rates of clinically significant hepatotoxicity. SBRT is also feasible in such patients as a part of bridging or downstaging prior to liver transplant.

Ciprofloxacin—Induced Cholestatic Jaundice in Setting of Chronic Liver Disease

Ciprofloxacin is a frequently prescribed fluoroquinolone antibiotic for its broad—spectrum coverage. It is commonly used for spontaneous bacterial peritonitis (SBP) prophylaxis in patients with cirrhosis. Severe adverse effects associated with its use include tendon rupture, Stevens—Johnson syndrome, interstitial nephritis, and liver injury. Liver injury associated with ciprofloxacin can cause mild asymptomatic elevation of liver enzymes, although rarely it can cause acute liver injury or cholestatic jaundice. We present a case of a 69 year—old male with a past medical history of alcoholic liver cirrhosis diagnosed in 1995, (has been sober since then with stable liver function) who was admitted for evaluation of hyperbilirubinemia reaching 27.4 mg/dl from 0.9 mg/dl in the time span of 5 weeks. 5 weeks back the patient had presented with small bowel obstruction managed by bowel resection and diverting ileostomy, which was complicated by him developing a pelvic abscess. CT scan showed minimal ascites. The abscess was drained by Interventional Radiology, treated with levofloxacin and metronidazole. The patient was discharged on ciprofloxacin daily for spontaneous bacterial peritonitis prophylaxis. Extensive viral and autoimmune panels were negative. Ceruloplasmin levels, transferrin saturation, and a—1 anti—trypsin level were normal. ERCP was unremarkable. Liver biopsy showed established cirrhosis and hepatocytes showed marked intracellular and intracanalicular cholestasis with proliferation along with scattered eosinophils suggesting drug—induced liver injury (DILI). Ciprofloxacin—induced cholestasis was suspected by exclusion, and ciprofloxacin was discontinued with gradual improvement of the bilirubin to 14 mg/dl over a period of 4 weeks. This case demonstrates the potential for cholestasis from ciprofloxacin use. The gradual resolution of liver function after the withdrawal of ciprofloxacin supports the diagnosis. We aim to highlight the increased risk of cholestasis and worsening liver function in patients with chronic liver disease with ciprofloxacin use. Chronic liver disease patients should be closely monitored when prescribed ciprofloxacin, and should be discontinued promptly at the first signs of liver injury.3044_A.tif Figure 1: No Caption available.3044_B.tif Figure 2: High Power showing eosinophils indicating Drug induced Liver Injury.3044_C.tif Figure 3: No Caption available.

Carnitine Palmitoyltransferase 1A Deficiency: A Rare Cause of Chronic Liver Disease with Rare Presentation

Carnitine Palmitoyltransferase 1A (CPT1A) deficiency is a very rare autosomal recessive disorder of fatty acid oxidation (FAO) which presents in children during concurrent febrile or gastrointestinal illness with hepatic encephalopathy (HE), hepatomegaly and rarely acute liver failure. Chronic liver damage is not reported in CPT1A deficiency. A 27-year-old female with history of CPT1A deficiency diagnosed in early childhood and chronic liver disease (CLD) complicated by thrombocytopenia, splenomegaly with model for end stage liver disease (MELD) score of 12; presented to emergency department with massive hematemesis. Vitals signs were stable. Physical exam was unremarkable except splenomegaly. Labs were significant for hemoglobin 7 g/dL, platelets 45 uL, electrolytes and liver enzymes unremarkable, INR 1.42, prothrombin time 17.2 sec, and total bilirubin 1.6 mg/dL. Computed tomography abdomen revealed prominent para-esophageal and peri-splenic varices, marked splenomegaly and fatty infiltration of liver (Image 1). The patient was started on IV fluids, ceftriaxone and octreotide. EGD revealed four columns of Grade IV esophageal varices (EV) that required 10 variceal bands (Image 2). Hospital course was further complicated by HE, thought to be multifactorial i.e. worsening liver function, poor oral intake and underlying defect in FAO. The patient was treated with lactulose, rifaximin with minimum improvement. Liver function continued to worsen with bilirubin 5.2 mg/dL, INR of 1.8 and MELD score of 24. A diagnosis of ACLF was made as her liver function 3 months prior to this admission was with in normal limits. She was high risk for re-bleeding and not a candidate for TIPS, so emergently transferred to a liver transplant center. CPT1A deficiency is a rare disorder with 60 cases reported so far. Either CLD or presentation as ACLF has not been reported in CPT1A deficiency. Our patient did not have history alcohol use or risk factors for NAFLD and Hepatitis B and C, hemochromatosis, Wilson's disease, autoimmune hepatitis were ruled out.2293_A Figure 1 No Caption available.2293_B Figure 2 No Caption available.

A Rare Case of Obstructive Jaundice After Endoscopic Sphincterotomy

Obstructive jaundice due to formation of a biliary clot is exceedingly rare with less than 8 documented cases reported in literature to date. The pathogenic mechanism underlying these cases are biliary hemorrhaging due to endoscopic manipulation. We present a case of obstructive jaundice after endoscopic sphincterotomy due to biliary hemorrhaging and subsequent clot formation. An 87 year old female with past medical history of atrial fibrillation on Coumadin and past surgical history of cholecystectomy presented to the hospital with nausea, vomiting, fever, and RUQ pain. Labs revealed abnormal liver function and leukocytosis. CT abdomen/pelvis revealed multiple stones in the distal common bile duct, which was dilated at 1.6 cm. ERCP with sphincterotomy was performed and multiple stones were removed via balloon extraction. No post-sphincterotomy bleeding was noted at the time of the procedure. Three days later the patient developed worsening liver function, jaundice, and RUQ pain. Repeat CT abdomen/pelvis showed a small filling defect measuring 5x5 mm in the distal common bile duct. Repeat ERCP was performed and revealed an ulcerated papilla with a large, protruding blood clot. The clot was partially removed with a snare during attempted cannulation. A wire was then passed into the biliary tree through the blood clot and injection of contrast revealed a dilated common bile duct with no filling defects. A 12 mm balloon sweep of the common bile duct was performed and the blood clot was removed.1293.tif Figure 1: Blood clot seen during ERCP at the papillaPatients experiencing post-sphincterotomy hemobilia present with clinical findings indicative of hemorrhage such as fatigue, hypotension, low hemoglobin, and hematochezia. Subsequent clot formation as seen in this case can obscure the diagnosis due to signs of obstructive jaundice mimicking choledocolithiasis. Standardizing treatment for blood clots induced by endoscopic instrumentation in the setting of hemobilia has been difficult due to lack of consensus on diagnostic classification, variability in presentation, and infrequency of incidence. As suggested in literature, most cases arise within the first 10 days following biliary manipulation. Treatment modalities for clot extraction vary but typically include: nasobiliary catheter placement, balloon catheter retrieval, Dormia basket, heparin irrigation. The literature suggests improved outcomes with ERCP and endoscopic catheter retrieval, but further comparative studies of treatment modalities need to be conducted.

Pembrolizumab-Induced Hepatitis and Pancreatitis in a Patient With Stage IV Non-Small Cell Lung Cancer

Immune checkpoint inhibitors are a novel approach to treat cancers. Firstly used for treatment of malignant melanomas with promising results, they were later expanded to treat other cancers including non-small cell lung cancers (NSCLC) expressing PD-L1. We present a case of a 66-year-old male who was admitted to the hospital for generalized gastrointestinal complaints consisting of abdominal pain, nausea, vomiting, and loose stools occurring five times daily. Labs were significant for acute transaminitis with hyperbilirubinemia and elevated lipase. All workup for infectious and noninfectious causes was negative. The patient was started pembrolizumab 15 days before admission and his previous labs had all been normal before the initiation of treatment. He was treated with high dose of steroids with initial improvement and discharged on oral steroids taper. He subsequently presented again with worsening liver function tests (LFTs) results and was restarted on a higher dose but unable to tolerate it due to steroid-induced psychosis and left the hospital against medical advice. Presented the third time with persistent elevation of LFTs and worsening hyperbilirubinemia, this time he was started on different class of steroid with atypical antipsychotic but left again a few days later seeking care at a tertiary care institute. This case highlights one of the severe side effects of the immune checkpoint inhibitors which is acute hepatitis that can sometimes lead to acute liver failure. Prompt treatment with steroids is indicated for these patients; and those who are refractory or intolerant to steroids can be treated with a multimodal approach using topical steroids, N-acetylcysteine (NAC), ursodeoxycholic acid and immune suppressant drugs. J Med Cases. 2018;9(9):320-322 doi: https://doi.org/10.14740/jmc3131w

925 EFFICACY AND SAFETY OF ENDOSCOPIC SUBMUCOSAL DISSECTION FOR GASTRIC NEOPLASMS IN PATIENTS WITH COMPENSATED LIVER CIRRHOSIS: A PROPENSITY SCORE-MATCHED CASE-CONTROL STUDY

The clinical outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms in liver cirrhosis patients are not adequately reported; hence, clinicians perform this procedure with vague fears regarding adverse events, including bleeding and worsening of liver function. We compared the efficacy and safety of ESD between cirrhosis and non-cirrhosis patients. From January 2005 to December 2014, 158 cirrhosis patients underwent ESD for gastric neoplasms at a tertiary medical institution. To compare the clinical outcomes, a propensity score-matched control group (158 patients) was selected from non-cirrhosis patients, using age, sex, histology, tumor location, and lesion size as variables. En bloc resection (96.8%), curative resection (89.9%), and adverse event [bleeding (10.1%) and perforation (1.9%)] rates in the cirrhosis group did not significantly differ from those in the non-cirrhosis group. Median procedure time (25.0 vs. 23.0 min) was also comparable between the groups. In the survival analysis, cirrhosis patients exhibited a significantly higher mortality risk than non-cirrhosis patients [hazard ratio (HR), 3.52; 95% confidence interval (CI), 1.35–9.23, p = 0.01], and those without HCC exhibited a mortality risk similar to the non-cirrhosis group (HR, 2.14; 95% CI, 0.72–6.39; p = 0.171). Three among 153 patients (2%) exhibited worsening of prognosis from Child–Pugh class A to B. ESD for gastric epithelial neoplasms can be performed in compensated cirrhosis patients, especially in those without HCC, with comparable safety and efficacy and without worsening of liver function.Tabled 1Outcomes of endoscopic submucosal dissection in the cirrhosis and non-cirrhosis groups after propensity score-matchingCirrhosis (n = 158)Non-cirrhosis (n = 158)p valueSize of the specimen, mm41.0 (35.0-50.0)44.5 (35.0-54.0)0.143Procedure time, minutes25.0 (16.0-31.2)23.0 (15.3-32.0)0.808En bloc resection153 (96.8)153 (96.8)1.000Curative resection142 (89.9)144 (91.1)0.838Bleeding16 (10.1)12 (7.6)0.571Perforation3 (1.9)0 (0)0.248Hospital duration, days3.0 (3.0-5.0)3.0 (3.0-4.0)<0.001Overall mortality17 (10.8)5 (3.2)0.01Procedure-related mortality0 (0)0 (0)1.000The data represent the number of patients (%) or the median (interquartile range) Open table in a new tab

Transient Exacerbation After Infections in Patients With Autoimmune Hepatitis

Aims Although the pathogenesis of autoimmune hepatitis (AIH) is unknown, many recent studies have demonstrated that infection can act as a trigger for the onset of AIH. The existence of a pathogenetic link between AIH and infections has not been confirmed. If AIH is triggered by infections, it is possible that infections may transitorily worsen liver function in patients with AIH. We investigated the association between the effects of infections and the exacerbation of liver dysfunction in patients with AIH. Methods We determined the changes in liver function before and after infections in 20 patients with definite AIH, 33 with probable AIH, 24 with primary biliary cholangitis (PBC), 30 with chronic hepatitis C (CH(C)), and 23 control subjects. Results During the study period, 19 of the 20 patients (95%) with AIH experienced one or more signs of liver dysfunction after infection. Seventy-three (59%) out of the 124 total occurrences of infectionsin 19 patients met the criteria for transient exacerbation of liver dysfunction. The incidence of liver dysfunction and the serum IgG levels after infection were significantly higher in the patients with definite AIH than in the patients with probable AIH, PBC and CH(C), and in the control subjects. Serum IgG level was a significant independent predictor of liver dysfunction. Conclusion The present study results suggested that infection was one cause of exacerbation of liver dysfunction in patients with AIH, and that serum IgG level was a significant independent predictor of exacerbation of liver dysfunction after infection.

Human intrahepatic ILC2 are IL-13positive amphiregulinpositive and their frequency correlates with model of end stage liver disease score.

IntroductionInnate lymphoid cells (ILC) have been implicated in the initiation of inflammation and fibrosis in mice. However, ILC have not been characterized in inflamed human liver tissue.MethodsHuman intrahepatic lymphocytes were isolated by mechanical digestion and phenotyped by flow cytometry. Conditioned medium from cultures of primary human biliary epithelial cells, stellate cells, fibroblasts and inflamed human liver tissue was used to model the effects of the inflammatory liver environment of ILC phenotype and function.ResultsAll three ILC subsets were present in the human liver, with the ILC1 (CRTH2negCD117neg) subset constituting around 70% of intrahepatic ILCs. Both NCRpos (NKp44+) and NCRneg ILC3 (CRTH2negCD117pos) subsets were also detected. ILC2 (CRTH2pos) frequency correlated with disease severity measured by model of end stage liver disease (MELD) scoring leading us to study this subset in more detail. ILC2 displayed a tissue resident CD69+ CD161++ phenotype and expressed chemokine receptor CCR6 allowing them to respond to CCL20 secreted by cholangiocytes and stellate cells. ILC2 expressed integrins VLA-5 and VLA-6 and the IL-2 and IL-7 cytokine receptors CD25 and CD127 although IL-2 and IL-7 were barely detectable in inflamed liver tissue. Although biliary epithelial cells secrete IL-33, intrahepatic ILC2 had low expression of the ST2 receptor. Intrahepatic ILC2 secreted the immunoregulatory and repair cytokines IL-13 and amphiregulin.ConclusionsIntrahepatic ILC2 express receptors allowing them to be recruited to bile ducts in inflamed portal tracts. Their frequencies increased with worsening liver function. Their secretion of IL-13 and amphiregulin suggests they may be recruited to promote resolution and repair and thereby they may contribute to ongoing fibrogenesis in liver disease.

Acute on Chronic Liver Failure—In-Hospital Predictors of Mortality in ICU

We studied in-hospital predictors of mortality of acute on chronic liver failure (ACLF) in Indian patients. Patients admitted to the intensive care unit of our institute fulfilling the definition of ACLF based on the Asia-Pacific Association for Study of Liver Disease (APASL) consensus were included. Complete history and medical evaluation to assess the etiology of underlying liver cirrhosis and to identify the acute precipitating insult of worsening liver function was done. Data was prospectively recorded and various scoring systems and individual clinical and laboratory parameters were assessed to identify predictors of 28 days mortality. 64 out of 240 patients screened for ACLF were analyszed in the study. Median age was 44 years and 53% were males. Alcohol was the primary cause of cirrhosis in 60.93%. Infections and active alcoholism was the main precipitating acute insult in 43% and 37% patients respectively. 28% patients had history of ingestion of hepato-toxic drugs as the acute insult. More than one acute insult was seen in 37.5% patients and type-II hepatic injury was the most common type. 28 days in hospital mortality was 43.75% and was highest in patients with sepsis (67.8%). Presence of hepato-renal syndrome and need for ventilation was associated with poor outcome. Though multiple variables were significant in predicting mortality on univariate analysis, yet on regression model only APACHE II and shock could significantly predict mortality with odds ratio of 3.18 and 9.14 respectively. Highest mortality was seen with cerebral and lung as organ failure and mortality increased as the number of organ failure worsened. CLIF-SOFA and APACHE-II scores having area under curve>0.8 had higher ability to predict mortality. ACLF carries high short-term mortality and early intervention by liver transplantation should be considered in patients who shows high risk of mortality.

Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma

Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation. We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status. In the competing-risk regression, the sum of tumor number and size and of log10 level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). Our model, based on patients' level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P= .044) to predict which patients will survive for 5 years after liver transplantation. We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov IDNCT02898415.

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.

BackgroundFew data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure.AimTo evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage.MethodsData on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers.ResultsAmong 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5–14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3–12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications.ConclusionsFailure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

Fulminant Liver Failure Secondary to Doxycycline Requiring Rescue Liver Transplantation

Introduction: Doxycycline is a broad-spectrum antibiotic of the tetracycline family that inhibits bacterial protein synthesis by binding the 30S ribosomal subunit. Due to its effectiveness in treating wide range of infections, doxycycline is one of the more commonly prescribed antibiotics in the United States. The hepatotoxicity of tetracyclines has been well characterized; however, only a few cases of fulminant liver failure attributed to doxycycline exist in English literature. We present a rare case of doxycycline induced liver failure requiring rescue liver transplantation. Case Report: A 36-year old female with past medical history only significant for a resected medulloblastoma presented with a two week history of fatigue, malaise, and jaundice. She had been prescribed doxycycline to treat a ureaplasma urealyticum genitourinary infection one week prior to her symptoms starting. On arrival, laboratory investigation revealed total bilirubin 12.8 mg/dL, AST 2620 IU/L, ALT 1990 IU/L, ALP 143 mg/dL. A complete inpatient workup for acute liver failure with laboratory and imaging studies was unrevealing and the patient's liver indices progressively worsened. Transjugular liver biopsy was performed which revealed massive hepatocellular necrosis with pigmented macrophage infiltrate and early fibrosis. The patient progressed to fulminant liver failure and received rescue orthotopic liver transplantation ten days after admission. The Roussel Uclaf Causality Assessment Method (RUCAM) score for this case was 8, indicating probable drug induced liver injury. Discussion: Drug induced liver injury is a commonly encountered clinical entity accounting for up to 10% of cases of acute hepatitis. The diagnosis pertaining to drug induced liver injury can be difficult and is a diagnosis of exclusion. Doxycycline is known to be hepatotoxic and generally produces mild transaminase elevation that is self-limiting. To our knowledge, less than five cases of doxycycline induced liver failure exist in reported literature. We present an unusual case of fulminant liver failure attributed to doxycycline, following extensive negative workup for alternative explanation. When suspecting drug induced liver injury, progressive worsening of liver function despite cessation of the offending drug should prompt evaluation for liver transplant.

Hepatocyte Growth Factor is Associated With Liver Dysfunction and Survival: Biomarker Results of a Phase 2 Study of Proton Beam Therapy in Patients with Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

HGF is the ligand to c-MET, a receptor tyrosine kinase upstream of multiple oncogenic pathways. In a prior study from the University of Michigan, high circulating HGF levels after liver SBRT were correlated with increased risk of worsening of liver function. The purpose of this study is to explore the association of plasma HGF with outcomes of patients treated with H-PBT for HCC and ICC. Using ELISA, we measured plasma HGF at baseline and weekly during H-PBT in pts with localized HCC or ICC enrolled in a phase II study (NCT00976898) at MGH. Pts received 15 fraction PBT to a dose of 67.5 Gy, with dose de-escalation based on mean liver dose. HGF levels at day 1, 8 and 15 were analyzed for correlations with overall survival (OS) and worsening of liver function defined as an increase in Childs-Turcotte-Pugh (CTP) score of 2 or greater at any time point. Forty-one pts were evaluated: 20 pts had HCC, 20 pts had ICC, 1 patient had both (analyzed as ICC). Thirteen (32%) pts were female. Twelve (60%) HCC pts and 4 (19%) ICC pts had history of hepatitis C. Fifteen (75%) HCC pts and 17 (81%) ICC pts were CTP A, and the remainder of patients had CTP B at baseline, except 2 HCC and 1 ICC pts with no cirrhosis. Median tumor size was 6.3 cm (HCC 6.7 cm, ICC 5.4 cm). Median dose was 58.0 Gy for both HCC and ICC pts. The median of mean liver-GTV dose was 19.8 Gy for HCC pts and 15.8 Gy for ICC pts. 2 yr OS and PFS were 49% and 30% for HCC pts and 32% and 17% for ICC pts. A CTP increase ≥2 points occurred in 10/41 patients. No increase in CTP occurred in pts with an HGF level below the median (P = 0.001). The median baseline level of HGF was 2,284 pg/mL, when stratified by the median HGF, pts with HGF above the median had a 2 yr OS of 29%, vs. 86% if HGF was below the median (log rank P = 0.001). The outcomes of H-PBT in both HCC and ICC were associated with baseline HGF. High HGF was associated with worsening liver function and worse OS. HGF will be used as an integral biomarker in NRG GI-003, a randomized trial of protons vs. photons in HCC.

THU-216 - Persistence of hepatitis C virus core antigenemia after sustained virological response is associated with worsening of liver function and increased risk of hepatocellular carcinoma

THU-216 - Persistence of hepatitis C virus core antigenemia after sustained virological response is associated with worsening of liver function and increased risk of hepatocellular carcinoma