Hepatocellular Disease Research Articles

Natural Course of Pediatric Portal Hypertension

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free‐standing children’s hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%; P < 0.01). Surgical interventions differed based on etiology (P < 0.01), with IH more likely resulting in a transplant only (65%) and EH more likely to result in a shunt only (43%); 30% of patients with IH and 47% of patients with EH did not undergo an intervention for pHTN. Kaplan‐Meier analysis revealed a significant increase in mortality in the group that received no intervention compared to shunt, transplant, or both and lower mortality in patients with prehepatic pHTN compared to other etiologies (P < 0.01 each). Multivariate analysis revealed increased odds of mortality in patients with refractory ascites (odds ratio [OR], 4.34; 95% confidence interval [CI], 1.00, 18.88; P = 0.05) and growth failure (OR, 13.49; 95% CI, 3.07, 58.99; P < 0.01). Conclusion: In this single institution study, patients with prehepatic pHTN had better survival and those who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention to improve outcomes.

Phase II study of nivolumab (anti-PD1), tadalafil, and oral vancomycin in patients with refractory primary hepatocellular carcinoma or liver dominant metastatic cancer from colorectal or pancreatic cancers.

TPS4656 Background: Treatment options for advanced hepatocellular carcinoma (HCC) and liver dominant metastatic disease from colorectal or pancreatic cancers are limited with poor overall survival. Tadalafil has shown to increase anti-tumor immunity by decreasing myeloid derived suppressor cells (MDSC) and impair tumor growth in preclinical HCC models. Oral vancomycin affects bile acid metabolizing gut commensal bacteria leading to increased CXCL16 expression in the liver resulting in NKT mediated liver-selective anti-tumor effects. This study combines immune checkpoint inhibition (ICI) treatment with nivolumab in combination with tadalafil and oral vancomycin. We aim to evaluate the synergy of the antitumor effect induced by the change in gut microbiome with oral vancomycin and the immunomodulatory effect of PDE5 inhibition combined with ICI with nivolumab in advanced liver cancer or liver metastasis. Correlative Studies: Paired liver tumor biopsies are analyzed for genomic analysis (WES, RNA-seq), immune cell infiltration, proteomics and metabolomic studies (bile acids) and chemokine expression. Stool samples are analyzed for microbiota. Blood samples are analyzed for immune monitoring, cytokine profiles and pharmacokinetics of study drugs. Serum bile acid levels are determined in blood in the 2 hour period after test meal ingestion. Methods: This is a single-arm study of nivolumab, oral vancomycin and tadalafil. Treatment is delivered in 4-week cycles (C) and continues until off treatment. Imaging is done every 8 weeks. Biopsies are done at baseline and during week 3 of C2. Nivolumab is administered on day (D)1 of each C at a dose of 480 mg IV. Tadalafil is administered orally (PO); 10 mg daily starting on D1 of C1 and continues daily until off study. Vancomycin administration starts on D1 of C1 at 125 mg PO every 6 hours for a total daily dose of 500 mg. Patients will be on vancomycin 3 weeks on, 1 week off per regimen. The study is currently enrolling without DLT. Clinical trial information: NCT03785210 .

To biopsy or to not biopsy, that is the question: A single-center retrospective analysis of outcomes of liver biopsy with hepatocellular carcinoma and other liver diseases.

e16606 Background: Unlike other malignancies, hepatocellular carcinoma (HCC) is most often diagnosed radiologically, based on previous studies suggesting complication rates of 1.4%-3.4% (e.g., bleeding) and concerns regarding “tumor seeding.” Lack of tissue for analysis has led to a lag in understanding the molecular biology of HCC. Molecular characterization of biopsies may allow HCC subtyping in order to personalize medicine, thus the potential of liver biopsy’s safety and utility needs to be reassessed. Methods: We performed a retrospective review of patients who underwent biopsy for suspected HCC or other liver diseases between Jan 1, 2010 and Jan 1, 2020. Demographics and clinical data including comorbidities, renal function, ascites, hepatic encephalopathy, varices, and labs including hemoglobin, WBC, platelets, sodium, creatinine, liver function test and coagulation studies were collected. Child Pugh (CP) and MELD-Na scores were calculated. Adherent medications at the time of biopsy and type of biopsy with any complications were included. Results: A total of 427 patients underwent liver biopsy. Patient characteristics are given in the table. Most patients (97%) underwent core needle biopsy. Biopsy complication rate was 1.23% (n = 5); these included bleeding (80%, n = 4), hospitalization (60%, n = 3), infection (20%, n = 1), and death (20%, n = 1). In the 5 patients, increased creatinine was associated with bleeding complications; however, one patient was on dialysis (Cr = 11.20), and this should be interpreted with caution. Existing comorbidities, concurrent medication use (including anticoagulants), CP and MELD-NA score, and lab findings were not associated with biopsy complications. Conclusions: To our knowledge, this review is first to demonstrate a low complication rate of 1.23% in suspected HCC patients who underwent liver biopsy in the current era of improved radiological techniques. This is consistent with historical data in liver disease patients. Comorbidities, being on anticoagulants, CP and MELD scores do not predict for biopsy complications. Higher creatinine was associated with more complications, but this needs to be examined in a larger study. Biopsy should be considered a valuable tool in understanding the molecular profiles of HCC, which could lead to more novel treatment. [Table: see text]

Impact of the Centers for Disease Control and Prevention Recommendation and State Law on Birth Cohort Hepatitis C Screening of New York City Medicaid Recipients

The Centers for Disease Control and Prevention estimated that, during 1999-2008, people born in 1945-1965 (the baby boomer generation) represented approximately 75% of people infected with hepatitis C virus and 73% of hepatitis C virus-associated deaths and are at greatest risk for hepatocellular carcinoma and liver disease. In 2012, the Centers for Disease Control and Prevention recommended one-time hepatitis C virus screening for people born during 1945-1965. In addition, New York State enacted a Hepatitis C Virus Testing Law in 2014. This analysis assesses the impacts of the 2012 recommendation and 2014 New York State Testing Law on hepatitis C virus screening rates among New York City Medicaid-enrolled recipients born during 1945-1965. The eligible population was determined quarterly as the number of Medicaid recipients continuously enrolled for 12 months with neither a prior hepatitis C virus diagnosis nor antibody test since 2005. Quarterly screening rates during 2010-2017 were examined using interrupted time series analysis. Data were analyzed in 2018-2019. In 2010-2017, the highest screening rate occurred in the quarter immediately after the law (33.64 per 1,000 Medicaid recipients). There was no change in screening rates after the Centers for Disease Control and Prevention recommendation and a significant increase after the New York State Law, which was not sustained. Hepatitis C virus screening rates increased in the quarter after the 2014 New York State Hepatitis C Virus Testing Law became effective. Additional efforts are needed to screen baby boomers and people who were recently infected with hepatitis C virus related to opioid use.

Analysis Of The Natural Course Of Pediatric Portal Hypertension

Presenter: Al-Faraaz Kassam MD | Cincinnati Children's Hospital Medical Center Background: The etiology of portal hypertension (pHTN) in children varies from that of adults and requires understanding of the differences in management strategies. We set out to assess the epidemiology and natural history of pediatric pHTN. Methods: 154 patients with pHTN from 2008-2018 were identified at a free-standing children’s hospital. Etiology, disease course, and interventions were assessed. Patients were then stratified by etiology of pHTN. The primary outcome was overall survival, with a secondary outcome of understanding the interventions and management required. Survival was calculated using Kaplan-Meier survival analysis. Statistical significance was set at p<0.05. Results: The distribution of etiology included 105 (68%) patients with cholestatic disease (CD), 16 (10%) with fibrotic or hepatocellular disease (HFD), four (3%) with hepatic vein obstruction (HVO), and 29 (19%) with pre-hepatic pHTN (PRE) caused by portal vein obstruction or portal vein sclerosis. Median follow-up for the cohort was 4.63 (IQR 2.02-7.25) years. Median age at diagnosis (years) varied between etiologies (0.34, IQR 0.06-0.9 CD vs 0.51, 0.06-3.33 HFD vs 5.85, 1.26-9.52 HVO vs 2.51, 0.85-5.09 PRE; p<0.01). There were no differences in sex, comorbidities, or years of follow up. Patients with PRE were more likely to require an EGD (79.3% vs 40% CD, 50% HFD, 50% HVO, p<0.01) and patients with PRE (2.0±0.4) and HVO (1.8±1.0) required more endoscopic interventions than CD (1.1±0.2) or HFD (1.4±0.5) (p<0.01). However, there were no differences regarding gastrointestinal bleeding or need for banding or sclerotherapy (p=0.31 and p=0.94 respectively). Interventions differed based on etiology (p<0.01) with CD more likely undergoing a transplant only (71.4%) and PRE more likely to undergo a shunt only (44.8%). 24.8% of CD, 62.5% of HFD, 100% of HVO, and 41.4% of PRE patients did not undergo an intervention. Kaplan-Meier analysis revealed no difference in survival based on etiology, however, analysis by type of intervention revealed a significant increase in mortality in the group who received no intervention compared to shunt, transplant, or both (p<0.01) (Figure 1). Of the 18 patients who died without intervention, 7 patients died while listed for transplant, five patients were not candidates due to progression of disease, and six patients had clinical deterioration before workup was completed. Of the 36 patients who are alive and have not undergone intervention, 27 have stable pHTN, six are waitlisted for organs, and three are not candidates for intervention due to severity of disease. Conclusion: The sequelae of pHTN in children is distinct from the adult process and a better understanding of this disease is necessary. In this single institution study, we found that most patients presented with CD as the cause of pHTN followed by PVO. While no difference in overall survival was noted between groups, patients who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention which may improve outcomes. Further work is needed to understand the predictors of mortality in patients with pHTN.

Quality of care provided to outpatients with hepatic cirrhosis in a teaching hospital.

a set of indicators to measure the quality of care of cirrhotic patients has been established and previously published studies report an adherence rate to clinical guide indications of 40-80 %. to assess the adherence to quality indicators in a tertiary teaching hospital. a retrospective observational study was performed of all cirrhotic outpatients seen during one semester in 2017. The charts were studied of 324 patients and quality indicators related to five domains were collected. An overall adherence to 14 quality indicators was recorded and analyzed based on the attending physician's experience. the results were excellent (more than 90 % adherence) for quality indicators related to prophylaxis of variceal bleeding and documentation of cirrhosis etiology, acceptable (60-90 % adherence) for hepatocellular carcinoma screening and disease severity assessment, and poor (less than 50 %) for vaccinations. Residents had significantly better results than experienced physicians in etiology, disease severity assessment and two indicators of prophylaxis of bleeding. Experienced physicians only presented a better adherence to hepatocellular carcinoma screening. despite excellent results for some quality indicators, most required improvement, especially vaccinations. The quality of care achieved by residents is equal to and even better than that of experienced physicians. Measuring quality of care is essential to analyze and improve the health care of cirrhotic outpatients and may be a useful tool for supervising specialists in training.

Correlates of hepatocellular and gastric diseases in cows slaughtered in selected abattoirs in Ogun State, Nigeria

Correlates of hepatocellular and gastric diseases in cows slaughtered in selected abattoirs in Ogun State, Nigeria

Training of Deep Convolutional Neural Networks to Identify Critical Liver Alterations in Histopathology Image Samples

Nonalcoholic fatty liver disease (NAFLD) is responsible for a wide range of pathological disorders. It is characterized by the prevalence of steatosis, which results in excessive accumulation of triglyceride in the liver tissue. At high rates, it can lead to a partial or total occlusion of the organ. In contrast, nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD, with the inclusion of hepatocellular injury and inflammation histological diseases. Since there is no approved pharmacotherapeutic solution for both conditions, physicians and engineers are constantly in search for fast and accurate diagnostic methods. The proposed work introduces a fully automated classification approach, taking into consideration the high discrimination capability of four histological tissue alterations. The proposed work utilizes a deep supervised learning method, with a convolutional neural network (CNN) architecture achieving a classification accuracy of 95%. The classification capability of the new CNN model is compared with a pre-trained AlexNet model, a visual geometry group (VGG)-16 deep architecture and a conventional multilayer perceptron (MLP) artificial neural network. The results show that the constructed model can achieve better classification accuracy than VGG-16 (94%) and MLP (90.3%), while AlexNet emerges as the most efficient classifier (97%).

Persistent Severe Bradycardia During Liver Transplantation

Abstract Background Cardiac electrophysiological disturbances are common in end-stage liver disease (ESLD) patients. It is challenging for anesthesiologists to detect and manage cardiac abnormalities during orthotopic liver transplantation (OLT). Case report A 58-year-old male patient, diagnosed with hepatitis B cirrhosis with hepatocellular carcinoma (MELD score 24) and chronic kidney disease stage V (no hemodialysis requirement), was scheduled for combined OLT with kidney transplantation. He had mild anemia, thrombocytopenia, normal electrolytes, and INR 1.47. CXR showed cardiomegaly with blunting of the bilateral costophrenic angle. ECG presented sinus bradycardia (rate, 45/min) with prolonged QT interval. Echocardiography revealed dilatation of all cardiac chambers with ejection fraction of 65%, good RV function, and mild pulmonary hypertension (mPAP, 29 mmHg) without significant valvular abnormality. After uneventful induction and intubation, noninvasive cardiac output monitoring and central venous catheter were applied. During surgery, his heart rate was 35–40 bpm with no response to high-dose inotropic agents. External cardiac pacing pads were attached. ABG showed mild acidosis without electrolyte abnormality. Reperfusion went successfully despite persistent severe bradycardia. He remained intubated and was transferred to the ICU. Twelve-lead ECG was performed. A cardiologist diagnosed cirrhotic cardiomyopathy with high vagal tone. Transvenous pacing was inserted at a rate of 80/min for 48 hours; his heart rate subsequently rose to 50–60 bpm without treatment. Extubation was 36 hours after surgery, and discharge on postoperative day 10 Conclusions Cardiac abnormalities in ESLD patients present in various forms. Proper preoperative assessment, adequate monitoring, and good team communication result in good patient outcomes

2217 Silent Propafenone-Induced Liver Injury: Case Report

INTRODUCTION: Propafenone is a class Ic antiarrhythmic. It is metabolized primarily by hepatic cytochrome P-450 2D6 and rarely associated with liver toxicity. We report a case of silent propafenone-induced liver injury. CASE DESCRIPTION/METHODS: An 82-year-old man with DM, HTN, COPD, moderate mitral valve regurgitation, CABG, and aortic valve replacement, presented with progressive SOB and orthopnea of 2-week duration. Two weeks prior, he had atrial fibrillation treated with ablation, apixaban, and propafenone. Other medications were losartan, amlodipine, and furosemide. He denied alcohol/illicit drug use. He was alert, oriented, in moderate respiratory distress, and non-icteric. Temperature was 37.4 C, BP 155/67, HR 112, and RR 18. He had shallow breath sounds with bilateral diffuse crackles, bilateral lower extremity pitting edema, and unremarkable abdominal exam. EKG showed atrial fibrillation. He was treated with IV diltiazem and furosemide with improvement of SOB. However, on routine investigations, AST was 2182 IU/L, ALT 1805 IU/L, alkaline phosphatase 210 IU/L, total/direct bilirubin 4.6/1.0 mg/dL, and INR 3.4. Urine and serum toxicology, IgM hepatitis A virus, IgM hepatitis B core, hepatitis B surface antigen, hepatitis C virus Ab, Epstein-Barr virus, and cytomegalovirus were negative. ANA, smooth muscle Ab, LKM Ab, celiac serology, ceruloplasmin, alpha 1 antitrypsin, iron studies, and acetaminophen levels were all normal. Ultrasounography showed normal common bile duct and no intrahepatic biliary dilatation and was consistent with hepatocellular disease. Hepatic vessels doppler was unremarkable. Propafenone was discontinued and 5 days later, AST was 148, ALT 581, alkaline phosphatase 132, total/direct bilirubin 1.1/0.5; all tests normalized within 2 weeks. DISCUSSION: Hepatotoxicity secondary to propafenone is rare; only 9 cases have been previously reported. Our patient developed hepatotoxicity 2 weeks after starting propafenone, had immediate improvement after its withdrawal, and work up was otherwise negative, strongly suggesting propafenone as the cause. Similar to previous cases, hepatotoxicity had a cholestatic pattern and was completely reversible. Unlike previous cases where jaundice, pruritis, and abdominal pain were presenting symptoms; hepatotoxicity was incidentally discovered in our patient. Although very rare, clinicians should be aware of propafenone-associated hepatotoxicity and routine monitoring of hepatic function may be warranted.

2463 Infliximab Drug-Induced Autoimmune Hepatitis in Patient With Crohn's Ileocolitis

INTRODUCTION: Infliximab is an anti-tumor necrosis factor alpha inhibitor commonly used in the treatment of Crohn's disease. It is known to produce mild elevations in liver enzymes, however, severe damage and marked elevations in transaminases related to drug-induced autoimmune hepatitis (AIH) are rare. We present a case of a patient with Crohn's disease who recently began infliximab and presented with severe infliximab-induced autoimmune hepatitis. CASE DESCRIPTION/METHODS: A 37-year-old man with Crohn's ileocolitis, diagnosed at age 28 and recently inducted with infliximab, presented with fatigue, weakness, and epigastric pain. He had previously been on 6-mercaptopurine, adalimumab, and ustekinumab, but had most recently been on azathioprine (AZT) and began infliximab two months prior to presentation. Approximately one month prior to presentation, he developed elevated transaminases with aspartate transaminase (AST) and alanine transaminase (ALT) in the 300s, so AZT was discontinued as this was thought to be the cause. Despite discontinuation of AZT, his liver function tests (LFTs) rose dramatically, prompting hospitalization. Labs on admission revealed a hepatocellular pattern with total bilirubin 7.1, AST 2153, ALT 2931, alkaline phosphatase 156, and international normalized ratio 1.25. Notably, antinuclear antibody was positive 1:1280, smooth muscle antibody was weakly positive, and cytomegalovirus (CMV) IgM was elevated. Hepatobiliary scan and magnetic resonance cholangiopancreatography were consistent with hepatocellular disease. Core liver biopsy revealed active hepatitis with moderate activity (interface moderate), cholestasis, and an infiltrate of eosinophils and plasma cells. CMV staining was negative. Overall, the testing was consistent with drug-induced AIH. Infliximab was stopped and steroids were begun, resulting in normalization of LFTs. DISCUSSION: Infliximab has been implicated in mild cases of hepatotoxicity, and therefore, it is recommended to check LFTs before and after beginning the medication. There are very few reports of severe AIH that have been linked specifically to infliximab, as cases of hepatotoxicity are often secondary to reactivation of viral hepatitis or CMV infections, or related to other biologic therapies. This is a rare case of infliximab-induced AIH, and it is an important consideration in patients with elevated LFTs after starting this drug. Treatment involves cessation of infliximab and treatment with steroids, which usually leads to resolution of the hepatitis.

2215 An Interesting Case of Intrahepatic Porto-Hepatic Shunt as a Cause of Unexplained Encephalopathy

INTRODUCTION: Congenital portosystemic shunts or Abernethy malformations are rare anatomical abnormalities shunting blood from the portal venous system to the systemic venous system, thereby bypassing passage through the hepatic acinus. The presentation may range from incidental finding on imaging to hepatic encephalopathy and liver failure depending on the degree and type of shunt. Here, we describe an interesting case of unexplained encephalopathy in a patient without liver cirrhosis found to have congenital intrahepatic Type II Abernethy malformation. CASE DESCRIPTION/METHODS: A 73-year-old female with a past medical history of Rheumatoid arthritis and Gilbert syndrome was admitted to hospital with clinical evidence of encephalopathy. Vitals were stable and physical examination was unremarkable except for encephalopathy. Laboratory investigations were unremarkable except for elevated ammonia levels (165 µmol/L). Computed tomography (CT) of the brain was unremarkable. Abdominal ultrasonography revealed the normal size and echotexture of the liver. Abdominal CT angiography showed the presence of dilated portal vein measuring up to 1.8 cm at the porta-hepatis along with dilated superior mesenteric and splenic veins. Multiple dilated vascular channels were seen within the right hepatic lobe. An intrahepatic portosystemic shunt between an enlarged middle hepatic vein and 2 separate branches of the right portal vein was visualized. Pressure gradients were measured and were normal. She received conservative management with lactulose and rifaximin and discharged on day 6 after the resolution of encephalopathy. DISCUSSION: Encephalopathy associated with portal-systemic bypass and no intrinsic hepatocellular disease is often referred to as Type B hepatic encephalopathy as was in our patient. Ammonia which is the culprit for the neuropsychiatric manifestation is usually metabolized by the liver in normal conditions, however in cases of portosystemic shunting, whether congenital or not, ammonia bypasses the liver and enters the systemic circulation and directly reaches the brain. The degree of symptomatology associated with these venous shunts depends on the shunt ratio and patient age. Treatment options include medical management including use of lactulose and non-absorbable antibiotics or endovascular shunt closure. Our patient was managed medically with the plan to refer her for shunt closure if she continues to have recurrent episodes.

The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease

Introduction and objectivesHepatocellular liver injury is characterized by elevations in serum alanine (ALT) and aspartate (AST) aminotransferases while cholestasis is associated with elevated serum alkaline phosphatase (ALP) levels. When both sets of enzymes are elevated, distinguishing between the two patterns of liver disease can be difficult. The aim of this study was to document the predicted ranges of serum ALP values in patients with hepatocellular liver injury and ALT or AST values in patients with cholestasis. Materials and methodsLiver enzyme levels were documented in adult patients with various types and degrees of hepatocellular (non-alcoholic fatty liver disease, hepatitis B and C, alcohol and autoimmune hepatitis) and cholestatic (primary biliary cholangitis and primary sclerosing cholangitis) disease. ResultsIn 5167 hepatocellular disease patients with ALT (or AST) values that were normal, 1–5×, 5–10× or >10× elevated, median (95% CI) serum ALP levels were 0.64 (0.62–0.66), 0.72 (0.71–0.73), 0.80 (0.77–0.82) and 1.15 (1.0–1.22) fold elevated respectively. In 252 cholestatic patients with ALP values that were normal, 1–5× or >5× elevated, serum ALT (or AST) values were 1.13 (0.93–1.63), 2.47 (2.13–2.70) and 4.57 (3.27–5.63) fold elevated respectively. In 56 patients with concurrent diseases, ALP levels were beyond predicted values for their hepatitis in 38 (68%) and ALT (or AST) values beyond predicted values for their cholestatic disorder in 24 (43%). ConclusionsThese data provide health care providers with predicted ranges of liver enzymes in patients with hepatocellular or cholestatic liver disease and may thereby help to identify patients with concurrent forms of liver disease.

Safety of Transarterial Y90 Radioembolization in Management for Unresectable-Intermediate and Locally Advanced-HCC

AbstractBackground: Egypt has the highest prevalence of HCV worldwide and has rising rates of hepatocellular carcinoma (HCC). Many have adopted the Barcelona Clinic Liver Cancer (BCLC) staging classification, which links the stage of the disease to a specific treatment strategy. More controversial than the prognostic scoring system is the treatment algorithm that is a part of the BCLC. TACE is usually recommended as the standard treatment of BCLC-B patients, yet it is a relatively contraindicated in BCLC-C1 patients. Radioembolization with yttrium-90 (Y90) is a recently introduced liver-directed therapy, it is a is a sort of internal brachytherapy by arterially injected yttrium-90 (Y90) microspheres for the treatment of HCC. Growing data suggest that (Y90) radioembolization has a potent anticancer effect with negligible adverse events if appropriate pretreatment evaluations. It can be used in BCLC-B and BCLC-C1 in an manner. In contrast toTACE, the rate of adverse effects after such unselective application, as performed over a lobar branch of the hepaticartery, is not significantly increased as compared to segmental or even subsegmental microsphere application, although the tumor response rate may vary.Aim of Study: This study aims to present and discuss the efficacy and clinical outcome of Y90 radioembolization using Y90 microsphere for management of patients with intermediate and locally advanced (BCLC-B and BCLC-C1) Hepato-Cellular Carcinoma (HCC).Patients and Methods: This is a prospective study carried out between June 2014 and May 2016 for patients with hepatocellular carcinoma and liver restricted disease. All patients underwent treatment by Y90 microsphere radioem-bolization (SIR-Tex). A total number of 20 patients with intermediate and locally hepatocellular carcinoma and liver restricted disease, not eligible for curative treatment.Results: Assessment was done according to RECIST and mRECIST guidelines. We found good therapeutic response in patients treated with Y90 radioembolization. The complete response, partial response, stable disease and disease progres-sion rates for the study sample after 3 months using the conventional RECIST criteria was 0%, 55%, 30% and 10%, while after 6 months it became 0, 50%, 20% and 25% respec-tively.Conclusion: Y90 microspheres radioembolization for patients with intermediate and advanced HCC is an effective treatment which can be utilized even in patients with compro-mised liver function.

Liver transplantation in Japan: Registry by the Japanese Liver Transplantation Society.

As of 31 December 2017, a total of 9242 liver transplants have been carried out in 67 institutions in Japan. There were 447 deceased donor transplants (444 from heart-beating donors and 3 from non-heart-beating donors) and 8795 living-donor transplants. The annual total of liver transplants in 2017 was 416 (69 deceased donor transplants and 347 living-donor transplants). The most frequent indication was cholestatic disease, followed by neoplastic disease and hepatocellular disease. In terms of hepatocellular disease in 2017, cirrhosis due to hepatitis C and B decreased (13 and 8, respectively), whereas alcoholic cirrhosis markedly increased (32). Patient survival following transplantation from heart-beating donor (444 transplants: 1year, 89.1%; 3years, 85.2%; 5years, 82.9%; 10years, 75.4%; 15years, 70.7%) was similar to that from living-donor (8794 transplants: 1year, 85.0%; 3years, 80.9%; 5years, 78.5%; 10years, 73.2%; 15years, 68.5%; 20years, 65.7%; 25years, 64.6%). Graft survival was very much the same as patient survival (heart-beating donor: 1year, 88.4%; 3years, 84.5%; 5years, 82.2%; 10years, 74.7%; 15years, 70.1%; livingdonor: 1year, 84.3%; 3years, 79.9%; 5years, 77.3%; 10years, 71.4%; 15years, 66.3%; 20years, 63.3%; 25years, 61.9%). Survival data are reported according to age and sex of recipient, indication, age and sex of donor, ABO compatibility, and other factors.

High-Intensity Statins Are Associated With Increased Incidence of Hypoglycemia During Hospitalization of Individuals Not Critically Ill

BackgroundSerum cholesterol is inversely associated with incident hypoglycemia among patients admitted to internal medicine wards. We examined the association between statin use and incidence of hypoglycemia among patients who were not critically ill. MethodsIn this retrospective study, we included all patients discharged between January 1, 2010, to December 31, 2013 from internal medicine units at the Wolfson Medical Center. Excluded were patients with hepatocellular or cholestatic liver disease upon admission. Patients were allocated to 4 groups, according to diabetes mellitus status (yes or no) and serum albumin <3.5 g/dL (yes or no) on admission. Regression analysis was used to examine the association of incident hypoglycemia during hospitalization and statin treatment (yes or no), and later, statin intensity. ResultsIncluded in this analysis were 31,094 patients (mean age 68.9±17.5 years, 48.4% males, 21.7% with diabetes mellitus). Logistic regression models showed that among patients with low admission serum albumin, administration of high-intensity statins was associated with increased incidence of hypoglycemic events compared to patients not treated with statins (odds ratio [OR] 1.303, 95% confidence interval [CI] 1.016-1.671, P = 0.037), whereas treatment with low-intensity statins was associated with less hypoglycemic events (odds ratio 0.590, 95% confidence interval 0.396-0.879, P = 0.010). Among patients with normal serum albumin, no association was found between incident hypoglycemia and statin intensity. These findings were significant regardless of diabetes mellitus status. ConclusionStatin treatment in general is associated with reduced incidence of hypoglycemia. However, among patients with low serum albumin upon admission, use of high-intensity statins is associated with an increased risk of hypoglycemic events regardless of diabetes mellitus status.

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. The choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples were used to evaluate the hepatobiliary junctional role of the invasive form of DR. Choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.

MON-413 First Reported Case of Combined High-Dose Mifepristone Therapy and Oral Contraceptive in Inducing Reversible Cholestatic Hepatitis in a Patient with Cushing Disease

Background: Cushing syndrome is predisposed to hepatocellular disease due to increased visceral fat resulting in NAFLD, and direct effects of medical therapy, notably ketoconazole. Mifepristone (MIFE) (a competitive glucocorticoid receptor antagonist) is a CYP3A4 inhibitor, whereas loestrin (an oral contraceptive) is a CYP3A4 substrate. Recently, MIFE has been shown to improve liver enzymes in a patient with NAFLD and cortisol-secreting adrenal adenoma (Ragucci E, et al. Case Rep Endocrinol. 2017). Herein, we present a case of high-dose MIFE with loestrin in inducing cholestatic hepatitis that resolved spontaneously upon drug discontinuation. Case: A 35 year-old woman with Cushing disease (CD) underwent transsphenoidal surgery (TSS) twice (April 2014 and November 2017). Upon re-testing in January 2018, persistent hypercortisolemia was confirmed with 24-hr UFCs x 2 and late-night salivary cortisols x 2 that were > 2 ULN, and nonsuppressed AM cortisol after a 1 mg overnight dexamethasone suppression test. The patient declined pasireotide and ketoconazole due concerns of hyperglycemia and potential liver toxicity, respectively. After her first TSS, she developed secondary hypothyroidism, secondary hypogonadism and DI, and was placed on levothyroxine, loestrin and DDAVP. She agreed to consider MIFE therapy in February 2018. Baseline serum potassium and LFTs were normal, and she was initiated on MIFE 300 mg/d. Her dose was escalated to 600 mg/d in March 2018, 900 mg/d in May 2018, and alternating 900 mg/d and 1200 mg/d in June 2018. Fourteen days after being on alternating high-dose MIFE therapy, the patient presented to the ER with abdominal pains, nausea, vomiting, pruritus, jaundice and dark urine, and abnormal LFTs (hyperbilirubinemia, and mild increases in AST and ALP). She was hospitalized, and ultrasound of her abdomen revealed normal liver architecture, whereas liver biopsy confirmed diffuse canalicular and cytoplasmic bile stasis without zonal predilection consistent with acute drug-induced cholestasis. She had not taken any new medications or supplements after MIFE was initiated. Other causes of liver dysfunction were excluded including normal anti-ANA, anti-Sm and anti-mitochondrial antibodies, and normal viral hepatitis screen. She was treated symptomatically for her pruritus, MIFE and loestrin were discontinued, and she was discharged from hospital after 3 days. Her pruritus resolved and LFTs normalized 5 and 11 weeks, respectively, post-discharge. Conclusion: We report the first case of high-dose MIFE with loestrin in inducing reversible cholestatic hepatitis in CD, which contrasts to the direct hepatocellular toxicity induced by ketoconazole. Our case highlights the importance of knowledge of drugs that behave as CYP3A4 substrates or inhibitors, and close monitoring of LFTs, especially when MIFE dosing is escalated in combination with oral contraceptives.

FRI-462-A multicenter international study of sorafenib treatment in patients with hepatocellular carcinoma and chronic kidney disease undergoing hemodialysis

FRI-462-A multicenter international study of sorafenib treatment in patients with hepatocellular carcinoma and chronic kidney disease undergoing hemodialysis

The associations between Toll-like receptor 4 gene polymorphisms and hepatitis C virus infection: a systematic review and meta-analysis.

Background and objective: The hepatitis C virus (HCV) is able to cause a life-threatening disease relating to lethal hepatocellular carcinoma. Previous, Toll-like receptor polymorphisms were proposed as promising biomarker for HCV-related hepatocellular carcinoma and disease progression. This study aimed to summarize the association of TLR4 polymorphisms and HCV infection through meta-analysis.Methods: We applied a systematic review and meta-analysis performed by using PubMed, EMBASE and Web of Science searches. The Modified Newcastle-Ottawa scale was used for quality assessment. The odd-ratio (OR) and 95% confidence interval (CI) were calculated to assess the association. In silico analysis was applied for proposing the function as microRNA (miRNA) of non-coding polymorphism. Finally, the miRNA target was predicted and annotated to suggest the possible relationship between polymorphism and HCV infection.Results: Our meta-analysis incorporated seven studies involving rs4986791, rs4986790 and rs2149356. No association exists between rs4986791 and HCV infection. However, the heterozygous model (AG vs GG) of rs4986790 significantly associates with HCV infection (OR = 0.33, 95% CI = 0.21–0.49, P<0.0001). Moreover, the rs2149356 TG genotype also associates with HCV infection in the over-dominant model (TG vs TT+TG: OR = 0.54, 95% CI = 0.40–0.75). In silico analysis of rs2149356G allele showed that this mutation is siRNA, which targets the set of genes, especially in the autophagy pathway.Conclusion: We demonstrated that rs4986790 and rs2149356 are associated with HCV infection.