Subsequent Liver Research Articles

S1062 Predictors and Outcomes of Palliative Care Consultations for Cirrhotics: Results of a Cohort Study of 75 Million Medical Records

INTRODUCTION: Approximately 600,000 adults in the United States (US) have liver cirrhosis. The total annual cost of hospitalizations due to cirrhosis is estimated to be about $7 billion. Liver transplantation is the only effective cure for decompensated cirrhosis, however, annually only about 8,000 liver transplants are performed in the US. Palliative care consultation can decrease health care utilizations and improve quality of life for patients and their caregivers. We aim to study the utilization of palliative care consultations and their impact on patient care across the US by conducting a large population-based cohort study. METHODS: The Explorys database (IBM, New York) is a source of de-identified data collected from electronic medical records from over 26 health systems in the United States amounting to over 75 million unique electronic medical records (EMR). All data including demographics, observations, diagnosis and procedures are coded by the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) criteria. We queried the database for a diagnosis of ‘cirrhosis’ followed by ‘palliative care consultation’ in a temporal manner and collected demographic and clinical data from 1999-2020. Odds ratio (OR) with 95% confidence intervals (CI) were calculated, with P < 0.05 considered significant. RESULTS: The Explorys database contained over 75 million patients at the time of our search. We identified 316,970 patients with cirrhosis and 0.76% (n = 2,400) patients with subsequent orthotopic liver transplant. Palliative care was consulted for 10.9% (n = 34,600) of patients. Patients who underwent a liver transplant were less likely to receive palliative care [OR 0.05 (0.05–0.067), P < 0.0001]. Patients aged >65 [OR 1.33 (1.30–1.36), P < 0.0001], male gender [OR 1.13 (1.11–1.16), P < 0.0001], a diagnosis of hepatocellular carcinoma (HCC) [OR 2.53 (2.45–2.60), P < 0.0001] and Medicare insurance [OR 4.2 (4.1–4.3), P < 0.0001] were more likely to receive a palliative care consultation. Patients for whom palliative care were consulted were less likely to undergo endoscopic [OR 0.32 (0.31–0.33)] and surgical procedures [OR 0.49 (0.47–0.50)]. CONCLUSION: Only about 1 in 10 cirrhotics received a palliative care consultation. Older patients, males, and patients with a diagnosis of HCC are more likely to receive palliative care. There is a need to address the under-utilization of palliative care consultations in cirrhotics to improve quality of life and decrease hospital resource utilization.Table 1.: Comparison of characteristics of cirrhotics with and without palliative care consultationsFigure 1.: Distribution of palliative care consultations amongst cirrhotics based on liver transplantation status.

S2557 A Case of Immune-Mediated Liver Injury Secondary to Olaparib

INTRODUCTION: Immune mediated drug-induced liver injury (IM-DILI) presents with a hepatocellular or mixed pattern of liver injury that, for some patients, persists after drug withdrawal. Olaparib is an oral inhibitor of poly-ADP-ribose polymerase and is approved for treatment of relapsed metastatic ovarian cancer with BRCA 1/2 mutations. Mild alterations in liver tests have been reported in < 5% of treated patients. CASE DESCRIPTION/METHODS: A 56-year-old female with BRCA1 mutation and relapsed metastatic ovarian cancer was admitted to the hospital in August 2019 due to a severe acute hepatocellular liver injury with jaundice, elevated INR, and concern for impending fulminant liver failure (Table 1). Her liver tests had previously been normal prior to and until three months after she had started olaparib in May 2019. She had no alcohol history or use of herbal supplements. Physical examination was notable for jaundice, mild right upper quadrant tenderness, and no hepatic encephalopathy. Computed tomography showed mild hepatomegaly with periportal edema. Laboratory work-up for infectious, metabolic, and autoimmune etiologies of liver injury was negative. Liver biopsy revealed areas of submassive necrosis with lobular collapse, moderate to severe portal and lobular inflammation with predominantly lymphocytes, cholestasis with focal hepatocyte rosette formation, acute cholangitis with bile duct injury and ductular proliferation, and ceroid-laden histiocytes, consistent with IM-DILI. No portal fibrosis was seen. Olaparib was promptly withdrawn and prednisone (60 mg/day) was initiated. Liver tests had significantly improved within 4 weeks (Table 1 and Figure 1) and prednisone was tapered while liver enzymes normalized. DISCUSSION: We report the first case of IM-DILI secondary to olaparib use in the United States. Olaparib is largely metabolized by the liver through cytochrome P450 and it is hypothesized that reactive metabolites can bind cellular proteins, leading to the creation of neo-antigens and subsequent liver injury. This case report highlights the need for close monitoring of liver tests while on olaparib and that the diagnosis of IM-DILI and prompt initiation of corticosteroids should be considered if an acute liver injury develops.Table 1.: Liver tests and INR values after olaparib withdrawalFigure 1.: A graphical illustration of livers tests and INR after olaparib was withdrawn and prednisone was started.Figure 2.: liver biopsy shows areas of submassive necrosis with lobular collapse. Note that no viable hepatocytes are identified in this microscopic area.

S2429 Primary Splenic Angiosarcoma With Liver Metastasis: A Rare Cause of Portal Hypertension

INTRODUCTION: Primary splenic angiosarcoma (PSA) is an extremely rare neoplasm that commonly metastasizes to the liver. We present a patient with abdominal pain and abnormal splenic imaging, found to have PSA with hepatic metastasis causing portal hypertension. CASE DESCRIPTION/METHODS: A 34-year-old female with no significant history presented with a 1-month history of progressively worsening left-sided upper abdominal pain. CT showed a heterogeneous area of low-attenuation in the spleen measuring 7.5 × 9.5 cm concerning for a large splenic infarct and cirrhotic liver morphology. Abdominal ultrasound with elastography revealed F4 fibrosis compatible with hepatic cirrhosis with patent hepatic vasculature. MRI/MRA for further evaluation of liver and splenic vasculature showed a hemorrhagic mass within the spleen, with no evidence of hepatic steatosis or fibrosis. Subsequent liver biopsy with portal pressures revealed nodular regenerative hyperplasia and portal hypertension. Free hepatic vein pressure was 20 mmHg, wedged hepatic vein pressure was 36 mmHg, and hepatic venous pressure gradient was 16 mmHg. Given concern for lymphoma, she underwent a PET/CT scan which showed a hypermetabolic 8.6 cm mass in the spleen with central necrosis, highly concerning for neoplasm and diffusely increased hypermetabolism in the liver. She subsequently underwent splenectomy and repeat liver biopsy. Pathology was consistent with high-grade angiosarcoma in the spleen and the liver. The patient was diagnosed with PSA with metastasis to the liver complicated by portal hypertension. DISCUSSION: Primary splenic angiosarcoma (PSA) is an extremely rare neoplasm with a reported incidence of 0.15–0.26 cases per million. The majority of patients present with distant metastases, most commonly in the liver with an incidence of 70%. Pathogenesis remains unclear. Possible causes include ionizing radiation, arsenic, vinyl chloride, and chemotherapy for lymphoma, versus originating from previously existing benign tumors, such as hemangioma or hemangioendothelioma. Upper abdominal pain is the most common clinical manifestation. There has only been 1 reported case of primary splenic hemangiosarcoma associated with portal hypertension in the literature. There are no guidelines for diagnosis of PSA, and our patient was diagnosed after splenectomy, which is the primary treatment for PSA without metastasis. In metastatic PSA, the role of adjuvant therapy is unclear with no treatment consensus, and prognosis is poor.Figure 1.: PET/CT with large, hypermetabolic region in the medial spleen measuring approximately 7.6 × 8.6 cm. No discrete lesions are seen in the liver; however, there is abnormally increased background activity.Figure 2.: Immunohistochemical stain for CD31 highlights abnormal vascular proliferation in liver.Figure 3.: Spleen with proliferation of abnormal vessels and abnormal endothelial cells.

S2656 New Diagnosis of Autoimmune Hepatitis in a Patient With Remote History of SVR From DAA-Based Hepatitis C Treatment

INTRODUCTION: Autoimmune hepatitis (AIH) is characterized by increased aminotransferases, often in the presence of autoantibodies, and biopsy evidence of interface hepatitis. The cause of AIH is not known but it is likely due to a “triggering event” which leads to a T-cell mediated response directed against liver autoantigens. Hepatitis C virus (HCV) and its treatment with direct antiviral agents (DAA) have both has been suspected as risk factors for the development of AIH. We describe a patient with remote history of DAA-cured HCV who later developed decompensated cirrhosis secondary to AIH requiring liver transplantation. This case raises the question as to whether immunologic changes associated with HCV viral clearance are the cause of AIH in some cases. CASE DESCRIPTION/METHODS: A 67-year-old male was referred to our clinic for abnormal liver function tests. He was diagnosed with HCV cirrhosis, treated with 12 weeks of sofosbuvir/ledipasvir and achieved sustained virologic response (SVR). He was well for nearly five years until he developed new-onset ascites and worsening MELD-Na. Acute viral hepatitis serologies for hepatitis A/B/E were negative and HCV RNA levels were undetectable. CT imaging was negative for HCC or thrombus and he denied alcohol use. Smooth muscle IgG antibody was strongly positive and IgG was elevated at 3g/dL; ANA and LKM antibodies were negative. He was on not on any medications traditionally associated with AIH. His liver disease rapidly progressed and he was transplanted without receiving steroids. He is now well post-transplant. Explant biopsy demonstrated interface activity and lobular hepatitis with lymphoplasmacytic inflammation and plasma cells cluster (Figures 1 and 2). DISCUSSION: HCV has been linked to the development of AIH, likely through a process of molecular mimicry whereby the immune system reacts to hepatic autoantigens. While rare, this association has only been documented during active HCV infection or during treatment with DAAs. Our patient had successfully completed treatment for HCV with DAA therapy five years before onset of AIH. We present this case not only to highlight an atypical timeline for development of HCV-induced AIH but to emphasize that providers need to maintain a high index of suspicion for AIH in patients with prior history of HCV treated with DAAs who experience subsequent liver injury.Figure 1.: Low magnification (10x) view of liver section obtained from liver explant, demonstrating interface activity and lobular hepatitis with lymphoplasmacytic inflammation.Figure 2.: Higher magnification (40x) view of the liver section demonstrating plasma cells cluster.

S2193 Splenic Artery Collaterals Masquerading as Gastric Varices: An Uncommon Cause of Massive Upper GI Bleed

INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is most commonly due to peptic ulcer disease (PUD). However in patients with splenic artery thrombosis, collateral arterial vessels can develop. If these abnormal vessels erode into the stomach mucosa, massive UGIB can occur. Here we present a case of UGIB from submucosal splenic collateral arteries. CASE DESCRIPTION/METHODS: A 56 year old male with history of Factor 5 Leiden and antiphospholipid antibody syndrome (APLS) presented with melena and hematemesis. Esophagogastroduodenoscopy (EGD) showed possible gastric varices in the fundus with an area of ulceration (Figure 1). The patient’s prior history of heavy alcohol use and the presence of a nodular liver on CT scan suggested underlying cirrhosis and portal hypertension as the etiology for the gastric varices. However the patient was found to have a low hepatic venous pressure gradient (2 mmHg) and a subsequent liver biopsy did not reveal cirrhosis. The splenic vein was also noted to be patent on CT scan. Several days after admission, the patient experienced another episode of hematemesis with associated hypotension and tachycardia. CT angiogram at the time did not reveal any active bleeding, but did show a splenic artery thrombosis with several collateral vessels. Subsequent angiogram demonstrated large arterial collaterals in the gastric fundus with outflow to the spleen, bypassing the occluded splenic artery (Figure 2). These collateral vessels were embolized successfully and he had no further bleeding. DISCUSSION: This case highlights the importance of multidisciplinary patient care and careful assessment of a patient’s medical history and anatomy to accurately diagnose and treat underlying pathology. While our patient was thought to have varices on EGD, he did not have cirrhosis, splenic vein thrombosis or portal hypertension which made the diagnosis of gastric varices unlikely. However, he did have a splenic artery thrombosis due to underlying APLS which led to the formation of submucosal gastric arterial collateral vessels and UGIB. Submucosal arterial collateral vessels are a rare cause of UGIB and there are only a few cases described in the literature. They can form as a result of splenic artery thrombosis due to underlying coagulopathy, pancreatitis, abdominal trauma or congenital absence of the splenic artery. If these abnormal collateral vessels erode through the stomach mucosa, they can lead to UGIB. Treatment involves surgery (partial gastrectomy and splenectomy) or embolization.Figure 1.: Possible gastric varix in the stomach fundus with an area of ulceration seen on EGD.Figure 2.: Angiogram demonstrating large arterial collaterals in the gastric fundus with outflow to the spleen, bypassing an occluded splenic artery.

S2637 Whey Protein-Associated Liver Injury

INTRODUCTION: Drug-induced liver injury (DILI) is a common cause of liver injury and failure. Injury from dietary supplements is increasing, with an estimated rise from 8% to 20% over a ten year period from 2004 to 2014. While potential toxicity of some supplements is well documented, the potentially damaging effects of whey protein are not. Here we document a case of severe DILI caused by ingestion of whey protein. CASE DESCRIPTION/METHODS: A 44-year-old incarcerated male with no medical history presented to an outside hospital after two weeks of worsening fatigue and jaundice. He had nausea, vomiting and forty-pound weight loss over the previous month. Imaging indicated a bile duct stricture prompting transfer to our institution. On admission, ALT and AST were mildly elevated to 53U/L and 64U/L, respectively. Alkaline phosphatase was 312IU/L and total bilirubin was 26.86mg/dL with a direct bilirubin of 19.01mg/dL. Endoscopic retrograde cholangiopancreatography revealed no stricture, obstruction or mass. Viral, autoimmune and other causes of liver injury were ruled out. Although he had a strong family history of lymphoma and was subsequently found to have a mass behind his right eye, no source of malignancy could be found, as imaging was unremarkable and orbital mass was determined to be a hematoma secondary to a burst vessel. Subsequent liver biopsy suggested a drug-induced origin. He denied any medication use but admitted to taking whey protein daily for several months. A month prior to symptom onset, he increased his usage, consuming a minimum of five scoops at once, up to three times a day, well above the recommended dosage. Supportive care was provided. Over the next two weeks, he improved and was discharged. DISCUSSION: DILI is the most common cause of acute liver failure in the western world. Incidence secondary to dietary supplements is on the rise. Supplement-induced injury can lead to more severe and prolonged cases of liver injury and is also more often in a cholestatic pattern, as seen here. While no active ingredients of his supplementation are on the National Institute of Health liver toxicology list, with no other discernable cause of liver injury, whey protein was determined to be the most likely culprit. Liver injury from whey protein is poorly described with only two reported cases. Determining the causative reason for liver injury can be convoluted. When faced with DILI from an unknown source, all avenues should be explored and protein supplementation, including whey, should be considered.Figure 1.: Canalicular and hepatic perivenular cholestasis with minimal lobular and portal inflammation.Figure 2Figure 3

Sphingolipid metabolism as a marker of hepatotoxicity in drug-induced liver injury

Drug-induced liver injury (DILI) has a substantial impact on human health and is a major monetary burden on the drug development process. Presently, there is a lack of robust and analytically validated markers for predicting and early diagnosis of DILI. Sphingolipid metabolism and subsequent disruption of sphingolipid homeostasis has been documented to play a key role contributing to hepatocellular death and subsequent liver injury. A more comprehensive understanding of sphingolipid metabolism in response to liver toxicity has great potential to gain mechanistic insight into hepatotoxicity and define molecular markers that are responsible for hepatocyte dysfunction. Here, we present an analytical platform that provides multidimensional mass spectrometry-based datasets for comprehensive structure characterization of sphingolipids extracted from human primary hepatocytes (HPH) exposed to toxic levels of acetaminophen (APAP). Sphingolipid metabolism as measured by characterization of individual sphingolipid structure was sensitive to APAP toxicity displaying a concentration-dependent response. A number of sphingolipid structures were differentially expressed across varying APAP exposures highlighting the unique role sphingolipid metabolism has in response to hepatotoxicity and its potential use as a molecular marker in DILI.

Liver transplantation using grafts from donors after circulatory death - the first Czech Republic experience.

Liver transplantation is established as alifesaving procedure for patients with acute and chronic liver failure, as well as certain selected malignancies. Due to acontinuing organ shortage and ever-growing patient waiting lists, donation after cardiac death (DCD) is becoming more frequently utilized in order to close the gap between &#8220;supply and demand&#8221;. Aretrospective analysis of DCD and subsequent liver transplantations was performed. From May 2016 to September 2019, atotal of 9 DCD liver transplantations were performed in our institution. All cases except one were primary liver transplantations. The recipients comprised 5 (56%) males and 4 (44%) females. The mean DCD donor age was 41±12 (22-57) years, with ventilation duration of 7±1 days and warm ischemia time 19±3 minutes. The average recipient age was 51±22 (4-73) years, with an average cold ischemia 3h:59m±27m and manipulation time of 23±5 minutes. Periprocedural mortality was 1 (11%). Hepatitis C recurrence was documented in 1 (11%) patient. The mean follow-up time was 19±13 (7-37) months. Until now, we have not observed any signs of ischemic cholangiopathy. DCD liver transplantation allows us to enlarge the pool of potential liver grafts, thus decreasing the time spent on the liver recipient waiting list. This paper documents the first series of DCD liver transplantations in the Czech Republic.

Plasma metabolomic profiles in liver cancer patients following stereotactic body radiotherapy.

BackgroundStereotactic body radiotherapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). This study sought to identify differentially expressed plasma metabolites in HCC patients at baseline and early during SBRT, and to explore if changes in these metabolites early during SBRT may serve as biomarkers for radiation-induced liver injury and/or tumour response.MethodsForty-seven HCC patients were treated with SBRT on previously published prospective trials. Plasma samples were collected at baseline and after one to two fractions of SBRT, and analysed by GC/MS and LC/MS for untargeted and targeted metabolomics profiling, respectively.FindingsSixty-nine metabolites at baseline and 62 metabolites after one to two fractions of SBRT were differentially expressed, and strongly separated the Child Pugh (CP) B from the CP A HCC patients. These metabolites are associated with oxidative stress and alterations in hepatic cellular metabolism. Differential upregulation of serine, alanine, taurine, and lipid metabolites early during SBRT from baseline was noted in the HCC patients who demonstrated the greatest increase in CP scores at three months post SBRT, suggesting that high protein and lipid turnover early during SBRT may portend increased clinical liver toxicity. Twenty annotated metabolites including fatty acids, glycerophospholipids, and acylcarnitines were differentially upregulated early during SBRT from baseline and separated patients with complete/partial response from those with stable disease at three months post SBRT.InterpretationDysregulation of amino acid and lipid metabolism detected early during SBRT are associated with subsequent clinical liver injury and tumour response in HCC.

THE USE OF ORGAN DONOR BLOOD IN LIVER TRANSPLANTATION

BACKGROUND Blood removed from organs during deceased organ procurement is routinely discarded but is a potential resource for donor-specific transfusion (DST) in subsequent liver transplantation (LT). This study retrospectively analyses the impact of DST on intraoperative bank product usage, long-term graft, and patient survival, as well as frequency of rejection post-LT. METHODS A total of 992 adult LT performed from 1993 to 2018 in a single quaternary center were included. Intraoperative product usage, patient, and graft survival, as well as acute and chronic rejection were assessed in patients who received retrieved from the organ donor, the donor blood (DB) group (n = 437) and patients who did not, the blood (NDB) group (n = 555). RESULTS Processing of DB ensured safe levels of potassium, magnesium, and insulin. There were fewer units of bank red cells transfusion required in the DB group compared to NDB group (2 vs. 4 units, P = .01). Graft survival was significantly superior in the DB group (10-year survival 75% vs. 69%, respectively, P = .04) but DST was not an independent predictor of graft survival. There was no significant difference in patient survival or rejection between the groups. There was no difference in treated, biopsy-proven rejection between the two groups. CONCLUSIONS This is the first large-cohort study assessing long-term outcomes of intraoperative DST in LT. The collection of organ and subsequent use in LT recipients appeared feasible with appropriate quality checks ensuring safety. DST resulted in a reduction in the use of packed red cells. There was no difference in the rate of rejection or graft or patient survival.

Overlap of concurrent extrahepatic autoimmune diseases is associated with milder disease severity of newly diagnosed autoimmune hepatitis

BackgroundConcurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. MethodsThis study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009–2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. ResultsAmong the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45–75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51–0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66–1.10) and subgroup B (median 1.10, IQR 0.89–1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5–3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2–2.8; P = 0.380) whereas the ongoing inflammation was comparable. ConclusionsAST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When fenofibrate was added to Ursodiol therapy there was a significant reduction and in some cases normalization of serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase abnormalities, as well as pro-inflammatory cytokines. Combination fenofibrate treatment also reduced 7α-hydroxy-4-cholesten-3-one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In addition, principal components analysis and heatmap analysis show that bile acid metabolites trended closer to that of healthy control subjects. These favorable effects of fenofibrate on bile acid metabolism may contribute to its beneficial clinical effects in patients with PBC and PSC experiencing a subtherapeutic response to Ursodiol monotherapy.

The novel usage of dead biomass of green algae of Schizomeris leibleinii for biosorption of copper(II) from aqueous solutions: Equilibrium, kinetics and thermodynamics

Copper ion Cu(II) as a toxic and carcinogenic component can be deposited in liver resulting in subsequent abdominal pain, respiratory problems, liver and kidney failure. According to US Environmental Protection Agency, the maximum Cu(II) should be below 1.3 mg/L in industrial effluents. Cu(II) must be removed from wastewaters before disposal. Dead green algae Schizomeris leibleinii, an abundant solid waste, was applied as a novel sorbent for Cu(II) removal from aqueous solutions. Experimental factors including initial pH, contact time, adsorbent dosage, initial copper concentration and temperature were studied. FTIR and FE-SEM/EDS analyses were performed before and after adsorption. The maximum adsorption capacity was 55.06 mg/g obtained at 700 mg/L in optimal condition of initial pH = 6, contact time = 60 min, 0.4 g adsorbent in 50 ml copper(II) solution and T = 25 °C. The maximum adsorption was obtained 96.71 % at initial concentration of 100 mg/L in a 3.5 h contact time. Three kinetic models of Morris-Weber, pseudo first-order and pseudo second-order were used and the pseudo second-order was the best fit with correlation coefficient of 1 compared to Morris-Weber and pseudo first-order models with correlation coefficients of 0.977 and 0.843, respectively. Freundlich and Langmuir isotherms were more precise for experimental data to describe the equilibrium of the adsorption. This proves the process is both physisorption and chemisorption. The thermodynamic analysis revealed the process of Cu(II) sorption on S. leibleinii was feasible, spontaneous and exothermic. Comparing the adsorption capacity of S. leibleinii to other adsorbents for Cu(II) removal shows this biosorption has potential for industrial applications.

IJU this issue

In this issue, a Guideline with Editorial Comment, a Review Article with Editorial Comment, five Original Articles with three Editorial Comments and a Urological Note were published in the International Journal of Urology. Interstitial cystitis/bladder pain syndrome (BPS) bothers both patients and urologists. Homma et al. (Tokyo, Japan) revised the previous guidelines completing articles identified by the PubMed database published from 2016 to 2019. In this article, the authors clearly defined Hunner-type interstitial cystitis (HIC) associated with Hunner’s ulceration and non-Hunner-type BPS featuring glomerulations or bladder bleeding after distension are different entities of disorder in terms of pathophysiology. Interestingly, HIC shows immunological inflammatory reaction accompanied by B-cell clonal expansion, which demonstrates HIC is genetically different from BPS. Urologists should keep in mind that patients should be treated differently based on the diagnosis of HIC or BPS, which requires cystoscopy to determine the presence or absence of Hunner lesions. Malignant ureteral obstruction, defined as either intrinsic or extrinsic compression caused by metastasis, lymphadenopathy or direct extension of the tumors, is an unfortunate finding that most urologists encounter in the daily practice. Tabib et al. (New York, USA) reviewed many types of ureteral stents, including tandem stents or metallic stents that aim for the resolution of malignant ureteral obstruction, and attempted to provide considerations regarding the treatment and management of malignant ureteral obstruction. Ochi et al. (Chiba, Japan) examined the anatomical relationship between the urinary system and perirenal fat using computed tomography images from 50 men, as well as macroscopic imaging in nine cadavers. They found that perirenal fat belongs to the connective tissue of the gonad and the adrenal gland. The urinary system is separated from perirenal fat, and is located on the dorsal side inside the renal fascia. The authors concluded that this anatomical finding might help aid in the isolation of periureteric fat from perinephric fat in retroperitoneoscopic donor nephrectomy. A substantial number of non-classic angiomyolipomas (AML), including fat-poor or epithelioid AML, are encountered in daily practice, and are occasionally difficult to discriminate from renal cell carcinoma. Kaneko et al. (Tokyo, Japan) retrospectively evaluated the incidence of epithelioid AML (17.9%) out of 39 renal tumors diagnosed as non-classical AML. They found that magnetic resonance imaging findings (apparent diffusion coefficient value) are potentially useful to differentiate between epithelioid and fat-poor AML. A recent trend for the treatment of metastatic castration-sensitive prostate cancer (CSPC) is upfront intensification therapy including androgen deprivation therapy (ADT) plus docetaxel, ADT plus abiraterone acetate, ADT plus enzalutamide and ADT plus apalutamide. However, indication is limited in high-risk (LATITUDE criteria) or high-volume (CHARRTED criteria) patients. Hatakeyama et al. (Hirosaki, Japan) retrospectively evaluated 679 patients with metastatic castration-sensitive prostate cancer. They found that the overall survival from the initiation of castration-resistant prostate cancer in patients with low-volume disease and those with high-volume disease was not significantly different, and concluded that upfront intensification therapy might be beneficial to patients with low-volume disease, because approximately half of patients with low-volume disease experienced metastatic castration-resistant prostate cancer progression in real-world practice. The Editorial Comment by Kato (Nagoya, Japan) is worthwhile to correctly evaluate this article. As most of the metastatic spread is reported to be in a hematogenous fashion in renal cell carcinoma, the impact of regional lymph node metastases on subsequent distant metastasis remains unknown. Yang et al. (Rochester, USA) retrospectively evaluated 1049 patients (135 pN1, 914 pN0/x) who were surgically treated at the Mayo Clinic. They found that pN1 nodal status in M0 patients treated with nephrectomy for renal cell carcinoma is associated with more frequent early metastasis to sites conferring poor prognosis when compared with pN0/x in the lung, bone and non-regional lymph nodes. Interestingly, pN1 status did not affect subsequent liver metastasis, one of the most hematogenous metastatic organs. Although this article involves several limitations, their finding might stimulate discussion of the predictive/therapeutic role of regional lymph node dissection during renal cancer surgery. None declared.

Changing delta hepatitis patient profile: A single center experience in Valencia region, Spain.

BACKGROUNDDelta hepatitis is a rare infection with an aggressive disease course. For almost three decades, however, there have been no epidemiological studies in our traditionally endemic area.AIMTo investigate the prevalence of delta hepatitis in a sample of patients with chronic hepatitis B virus (HBV) infection followed at a Hepatology Unit in Valencia, Spain.METHODSRetrospective evaluation of anti-hepatitis D virus-immunoglobulin G seroprevalence among patients with chronic HBV infection (n = 605) followed at a reference Hepatology Unit in Spain.RESULTSThe prevalence of anti-hepatitis D virus-immunoglobulin G among HBV-infected patients was 11.5%: Male (63%) and median age of 52 years. The majority were born in Spain (67%) and primarily infected through intravenous drug use. However, a significant percent (24.5%), particularly those diagnosed in more recent years, were migrants presumably nosocomially infected. Comorbidities such as diabetes (8.5%), obesity/overweight (55%), and alcohol consumption (34%) were frequent. A high proportion of patients developed liver complications such as cirrhosis (77%), liver decompensation (81%), hepatocellular carcinoma (HCC) (16.5%), or required liver transplantation (LT) (59.5%). Diabetes was associated with progression to cirrhosis, LT, and death. Male sex, increasing age, and alcohol were associated with LT and HCC. Compared to HBV mono-infected patients, delta individuals developed cirrhosis and liver decompensation more frequently, with no differences in HCC rates.CONCLUSIONPatients infected in the 1980’s were mostly locals infected through intravenous drug use, whereas those diagnosed recently are frequently non-Spanish natives from endemic areas. Regardless of their origin, patients are predominantly male with significant comorbidities, which potentially play a major role in disease progression. We confirm a high rate of subsequent liver complications.

A Systematic Review of the Current Hepatitis B Viral Infection and Hepatocellular Carcinoma Situation in Mediterranean Countries.

Viral hepatitis B is a global public health problem affecting nearly two billion subjects; 3.3% of whom are from the WHO (World Health Organization) Eastern Mediterranean Region (EMRO). It induces both acute and chronic hepatic disorders with subsequent liver cirrhosis and hepatocellular carcinoma (HCC) in a considerable percentage of patients based on the age of exposure. In this review, hepatitis B virus (HBV) and HCC prevalence, distribution and prevalence of different genotypes, and male/female infection frequencies in relation to the vaccination status in the Mediterranean countries were reported. Study Design. This systematic review describes the prevalence of hepatitis B infection, genotype distribution of hepatitis B virus, and prevalence and incidence of hepatocellular carcinoma in Mediterranean countries belonging to three different continents: Southern Europe (Spain, France, Italy, Croatia, and Greece), North Africa (Morocco, Algeria, Tunisia, Libya, and Egypt), and the Near East region (Syria, Lebanon, Turkey, Israel, and Palestine). We tried to collect new data from electronic databases: PubMed, ScienceDirect, ResearchGate, Google Scholar, and public health reports between 1980 and 2019. For each publication, we recorded reference, publication year, study characteristics (date, locations, sample size, and study population), and participant characteristics (population group, year, age, and sex). No language limitation was imposed, and articles or reports from non-peer-reviewed sources were not considered for this analysis. The main keywords were HBV prevalence, hepatitis B infection, HBV genotype, and HCC. Inclusion and Exclusion Criteria. Healthy population-based studies included the following sample populations: (i) voluntary blood donors, (ii) pregnant women, (iii) community studies, (iv) hemodialysis patients, (v) hospitalized patients, (vi) healthcare workers, (vii) sex workers, (viii) drug abusers, and (ix) prisoners. We excluded studies from the following special groups who were assumed to be at a special high risk: patients from sexually transmitted disease clinics and thalassemia clinics and professional or paid blood donors.

Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.

1925-P: Beneficial Effects of a Novel Long-Acting Glucagon Analog, HM15136, on Obesity and Obesity-Related Metabolic Disorders in Animal Models

Obesity is a major risk factor for a number of metabolic disorders such as hyperlipidemia, glucose intolerance, and T2DM. Recent researches indicated a stimulatory effect of glucagon (GCG) on energy expenditure and appetite inhibition, suggesting the utilization of GCG as a pharmacological therapy for obesity and related metabolic disorders. In line with this, we previously observed that chronic treatment of HM15136, a novel long-acting glucagon analog, conferred efficient body weight loss (BWL) in DIO mice. Here, we further investigated the potential benefits of HM15136 in obesity-related metabolic disorders. In DIO mice, time-course change in fat mass, liver triglyceride (TG), and fasting blood glucose (FBG) was determined. Chronic treatment of HM15136 was associated with progressive BWL (-37.5% vs. vehicle (Veh) at day17) and fat mass reduction with little effect on lean mass, confirming its potent anti-obesity effect. Interestingly, despite marginal BWL at initial drug treatment period, significant reduction in blood TG (-56.5% vs. Veh at day2) and subsequent liver TG (-41.5% vs. Veh at day7) was achieved, and maintained thereafter. Moreover, the TG lowering both in blood and liver was followed by sustainable FBG lowering, suggesting that rapid depletion of lipid, the main sources for gluconeogenesis, might contribute to FBG control by HM15136. To evaluate the potential effect on post-prandial glucose control, oral glucose tolerance test (oGTT) was performed, and reduced BG level during oGTT was observed as BWL occurred. Time-dependent reduction in HOMA-IR evidenced the insulin sensitivity improvement. To our knowledge, this is the first study demonstrating the potential benefits of chronic GCG engagement in the management of BW, blood lipid, and even BG. Based on these results, HM15136 may be a novel option for the management of obesity and related metabolic disorders. Human study is ongoing for the clinical relevance of these findings. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Spouse/Partner; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.

Cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis.

Introduction: Early-stage liver fibrosis is potentially reversible, but difficult to diagnose. Clinical management would be enhanced by the development of a non-invasive imaging technique able to identify hepatic injury early, before end-stage fibrosis ensues. The analog of the amino acid proline, cis-4-[18F]fluoro-L-proline ([18F]fluoro-proline), which targets collagenogenesis in hepatic stellate cells (HSC), was used to detect fibrosis.Methods: Acute steatohepatitis was induced in experimental animals by liquid ethanol diet for 8 weeks, intra-gastric binge feedings every 10th day along with lipopolysaccharide (LPS) injection. The control animals received control diet for 8 weeks and an equivalent volume of saline on the same schedule as the acute steatohepatitis model. First, in vitro cellular experiments were carried out to assess [3H]proline uptake by HSC, hepatocytes and Kupffer cells derived from rats with acute steatohepatitis (n = 14) and controls (n = 14). Next, ex vivo liver experiments were done to investigate unlabeled proline-mediated collagen synthesis and its associated proline transporter expression in acute steatohepatitis (n = 5) and controls (n = 5). Last, in vivo dynamic and static [18F]fluoro-proline micro-PET/CT imaging was performed in animal models of acute steatohepatitis (n = 7) and control (n = 7) mice.Results: [3H]proline uptake was 5-fold higher in the HSCs of steatohepatitis rats than controls after incubation of up to 60 min. There was an excellent correlation between [3H]proline uptake and liver collagen expression (r-value > 0.90, p < 0.05). Subsequent liver tissue studies demonstrated 2–3-fold higher proline transporter expression in acute steatohepatitis animals than in controls, and proline-related collagen synthesis was blocked by this transporter inhibitor. In vivo micro-PET/CT studies with [18F]fluoro-proline showed 2–3-fold higher uptake in the livers of acute steatohepatitis mice than in controls. There was an excellent correlation between [18F]fluoro-proline uptake and liver collagen expression in the livers of acute steatohepatitis mice (r-value = 0.97, p < 0.001).Conclusion: [18F]fluoro-proline localizes in the liver and correlates with collagenogenesis in acute steatohepatitis with a signal intensity that is sufficiently high to allow imaging with micro-PET/CT. Thus, [18F]fluoro-proline could serve as a PET imaging biomarker for detecting early-stage liver fibrosis.

Herbal formulation MIT ameliorates high-fat diet-induced non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and is caused by obesity, diabetes, high blood pressure, and insulin resistance. Many studies have explored novel candidates to treat NAFLD using herbal medicines owing to their fewer side effects. In this study, we examined the effect of MIT, an herbal formula comprising Ephedra sinica, Panax ginseng, and Alisma orientale, on the murine model of NAFLD. MethodsTo evaluate the effect of MIT on NAFLD, we used the high-fat diet (HFD)-induced NAFLD mice model. The mice were divided into four groups: control, HFD, HFD with metformin administration, and HFD with MIT administration. Freeze-dried MIT was dissolved in phosphate buffered saline and orally administered for 8 weeks to MIT-treated mice (60 mg/kg) after feeding them with HFD for 16 weeks. ResultsMIT treatment significantly attenuated fat accumulation, serum glucose levels, and excessive cholesterol. It also reduced the activation of NF-κB, JNK, ERK, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ in the HFD-induced NAFLD mice. The expression level of enzymes involved in the synthesis and oxidation of fatty acids, acetyl-coA carboxylase and CYP2E1, were clearly reduced by MIT treatment. Reactive oxygen species (ROS) production and subsequent liver damage were effectively reduced by MIT treatment. ConclusionWe suggest that MIT is a potent herbal formula that can be used for the prevention and treatment of obesity-related NAFLD via regulating the levels of serum glucose and free fatty acids, inflammation, lipid accumulation, and ROS-mediated liver damage.