Liver Explants Research Articles

Incidental Finding of Multiple Synchronous Neoplasms in Explanted Liver After Transplantation: A Case Report

Liver transplantation is the only potentially curative treatment for patients with end-stage liver disease. After the procedure, histopathologic analysis of the liver explant may reveal neoplasms that were not previously diagnosed in preoperative imaging examinations. This incidental finding of primary liver neoplasms in the explant is not an uncommon situation in liver transplant, and hepatocarcinomas and cholangiocarcinomas are the types of tumors most frequently encountered in this scenario. These are the most common primary neoplasms of the liver, and liver transplantation is often a curative treatment for these types of tumors when they are in their earlier stages. In contrast, liver plasmacytoma is a rare type of plasma cell neoplasm, consisting of a single mass of monoclonal plasma cells, which is treated primarily by radiotherapy and is seldom encountered in the setting of liver transplant. We report the case of a patient who underwent liver transplantation for the treatment of cryptogenic cirrhosis, with no preoperative diagnosis of liver tumors. Analysis of the liver explant revealed the presence of three synchronous neoplasms with different histologic origins: a 27-mm hepatocellular carcinoma, a 17-mm intrahepatic cholangiocarcinoma, and a 25-mm solitary hepatic plasmacytoma. The patient received no further adjuvant treatment and remained well and with no signs of disease recurrence over an observation period of 44 months. We found no previous report in the literature of the synchronous presence of these three types of liver neoplasms.

Epigenetic Age Acceleration as a Risk Predictor of Hepatocellular Carcinoma

IntroductionMortality rates from hepatocellular carcinoma (HCC) have been steadily increasing in the US over the past 15 years. Most patients are diagnosed at advanced stages when the mortality rate is as high as 89%. Early diagnostic indicators are not currently available, and unfortunately, invasive liver core biopsies or resections are the standard of care to confirm HCC diagnosis. While no mutations have have proven to be tumor drivers, novel genome wide methylation studies show clear, cancer‐specific patterns of methylation and identified deregulation of epigenetic signatures. Epigenetic clocks have been shown to be a versatile tool for the prediction of a variety of patient phenotypes. Most commonly used for the prediction of age and mortality risk, these have also been used as indicators of alcohol consumption, smoking, and proxies for various blood‐based biomarkers. Acceleration in a number of clocks has been correlated to increased all‐cause mortality, as well as cancer risk. While much focus in HCC has been on clocks trained to precisely predict chronological age, confidence in the characterization of the notable epigenetic landscape and target region identification will be improved through the use of clocks trained to instead predict biological age with low signal to noise ratio. The goal of this study is to use epigenetic age acceleration to develop early cancer risk detection, improve treatment options, and to understand the relationship between accelerated liver tissue aging and tumorigenesis. Epigenetic aging events are potentially reversible adjuvant. Methylated DNA is also far more stable in serum and tissue than un‐methylated nucleic acids. These factors make epigenetic events attractive candidates for serum and biopsy biomarkers.MethodsGenomic DNA was extracted from IRB‐ approved, post‐operative or snap frozen, clinical patient liver resections or explants. DNA methylation (DNAm) was collected using Illumina BeadChip arrays. DNAm was used to calculate epigenetic age according to PCPhenoAge in over 600 liver samples, 8 tumor infiltrated NK‐cell isolates and 50 cell culture samples. PCPhenoAge is an improved version of the original biological aging clock with increased reliability and reduced susceptibility to technical noise. Multiple regression was used to residualize PCPhenoAge with respect to age and multiple phenotypes, such as alcohol consumption, known to affect epigenetic age. These residuals capture the epigenetic age acceleration independent of known behavioral risk factors for HCC.ResultsPreliminary analysis of 27 of our matched HCC patient tissues‐‐14 Alcohol and 13 Hepatitis C virus (HCV) associated HCC patients‐‐show higher PCPhenoAge in tumor versus non‐tumor tissues. Further, alcohol‐related HCC tumor tissue has significantly higher PCPhenoAge than HCV‐related HCC tumor tissue.

Performance of LI-RADS Version 2018 on CT for Determining Eligibility for Liver Transplant According to Milan Criteria in Patients at High Risk for Hepatocellular Carcinoma.

BACKGROUND. LI-RADS has been investigated primarily in terms of detection of hepatocellular carcinoma (HCC), with less attention given to its performance, particularly on CT, in determining eligibility for liver transplant (LT). OBJECTIVE. The purpose of our study was to assess the performance of LI-RADS version 2018 (v2018) on CT for the diagnosis of HCC and determination of LT eligibility according to the Milan criteria (MC). METHODS. This retrospective study included 136 patients (110 men, 26 women; mean age, 53.9 ± 8.1 [SD] years) at high-risk for HCC who underwent liver protocol CT within 3 months before LT between January 2010 and December 2018. Two radiologists independently reviewed CT examinations using LI-RADS v2018; Organ Procurement and Transplantation Network (OPTN) classes were constructed from the LI-RADS interpretations. Histopathologic analysis of liver explants served as the reference standard for determining the presence of HCC and LT eligibility based on MC. Diagnostic performance was evaluated. Overall survival (OS) was assessed based on medical record review. RESULTS. Based on histopathologic evaluation of liver explants in the 136 patients, 27 patients had no malignancy, 77 were eligible for LT due to HCC within MC, and 32 were unsuitable for LT (i.e., HCC beyond MC in 16 patients, HCC with macrovascular invasion in 12, non-HCC malignancy in four). LR-5 exhibited per-lesion sensitivity and PPV for HCC of 55.9% and 92.8%, respectively, for reader 1 and 39.8% and 86.5% for reader 2. When considering LR-5 observations to represent HCC in assessing MC, LI-RADS had accuracy for determining LT eligibility of 92.7% for reader 1 and 85.3% for reader 2; OPTN criteria had accuracy for determining LT eligibility of 89.0% for reader 1 and 84.4% for reader 2. Five-year OS for patients within MC versus 5-year OS for patients unsuitable for LT was 92.2 months versus 56.0 months for LI-RADS, 92.6 months versus 47.6 months for OPTN criteria, and 93.3 months versus 55.1 months for histopathologic assessment of liver explants. CONCLUSION. LI-RADS v2018, as evaluated on CT in high-risk patients, shows high PPV for HCC detection and high accuracy for determining LT eligibility based on MC. LT eligibility based on preoperative LI-RADS evaluation is associated with post-LT survival. CLINICAL IMPACT. These findings support the use of LI-RADS on CT in assessing eligibility in patients who are candidates for LT.

Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis

Alcohol-associated liver disease is a global health care burden, with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) being two clinical manifestations with poor prognosis. The limited efficacy of standard of care for AC and AH highlights a need for therapeutic targets and strategies. The current study aimed to address this need through the identification of hepatic proteome and phosphoproteome signatures of AC and AH. Proteomic and phosphoproteomic analyses were conducted on explant liver tissue (test cohort) and liver biopsies (validation cohort) from patients with AH. Changes in protein expression across AH severity and similarities and differences in AH and AC hepatic proteome were analyzed. Significant alterations in multiple proteins involved in various biological processes were observed in both AC and AH, including elevated expression of transcription factors involved in fibrogenesis (eg, Yes1-associated transcriptional regulator). Another finding was elevated levels of hepatic albumin (ALBU) concomitant with diminished ALBU phosphorylation, which may prevent ALBU release, leading to hypoalbuminemia. Furthermore, altered expression of proteins related to neutrophil function and chemotaxis, including elevated myeloperoxidase, cathelicidin antimicrobial peptide, complement C3, and complement C5 were observed in early AH, which declined at later stages. Finally, a loss in expression of mitochondria proteins, including enzymes responsible for the synthesis of cardiolipin was observed. The current study identified hepatic protein signatures of AC and AH as well as AH severity, which may facilitate the development of therapeutic strategies.

Recurrent Liver Allograft Injury in Patients With Donor-Derived Malignancy Treated With Immunosuppression Cessation and Retransplantation.

Donor-derived malignancy of the liver allograft is a rare but serious condition in the setting of necessary immunosuppression. Retransplantation after abrupt immunosuppression cessation has been performed with durable cancer-free survival. We present 2 cases of patients with donor-derived malignancy who were treated with complete immunosuppression cessation, which induced rapidly progressive liver allograft rejection and failure, with a need for subsequent retransplantation. We reviewed all serial liver biopsies and explants from both patients and performed C4d immunostaining. Initial explants of both patients showed severe allograft rejection, with unusual features of sinusoidal obstruction syndrome and C4d positivity. Malignant tumors in the explants were necrotic, related to rejection of donor-derived cancer cells and tissue. Follow-up of both patients has shown long-term cancer-free survival but issues with recurrent allograft failure requiring a third transplant. The reasons for retransplantation in both cases were related to allograft failure from antibody-mediated rejection. Clinicians should be aware of a potentially increased risk of rejection and recurrent allograft failure when strategizing treatment of donor-derived malignancy with immunosuppression cessation and retransplantation.

Repeated loco-regional therapies for hepatocellular carcinoma is associated with inferior outcome after living donor liver transplantation in cirrhotic patients.

Liver transplantation is the definitive treatment for defined stage hepatocellular carcinoma (HCC) in cirrhotic patients. Loco-regional therapy (LRT) may be considered before transplantation to prevent the disease progression and the patient from dropping out of the waiting list. This study aims to evaluate the impact of repeated pretransplant LRTs on the long-term outcomes in HCC liver transplant recipients. Between 2004 and 2019, living donor liver transplantation (LDLT) recipients with viable HCC on the explant livers were enrolled. Uni- and multivariate analysis was performed with the Cox regression model to stratify the risk factors associated with HCC recurrence and patent survival after LDLT. A total of 124 patients were enrolled, in which 65.3% (n = 81) were Barcelona Clinic Liver Cancer classification stage B or D and 89% (n = 110) had advanced fibrosis or cirrhosis on the explanted livers. After a median follow-up of 41 months (IQR: 24-86.5), there were 18 cases (13.7%) of HCC recurrence. Univariate analysis showed that the model of end-stage liver disease and Child-Turcotte-Pugh score, pretransplant alpha-fetoprotein value (>500 ng/ml), repeated pretransplant LRTs (N > 4), increased tumor numbers and maximal size, presence of microvascular invasion, and the histological grading of the tumors are risk factors of inferior outcomes. In multivariate analysis, only repeated pretransplant LRTs (N > 4) had a significant impact on both the overall- and recurrence-free survival. The impact of pretransplant LRT was consistently significant among subgroups based on their LRT episodes (N = 0, 1-4, >4 respectively). Repeated LRT for HCC can be associated with the risk of tumor recurrence and inferior patient survival after LDLT in cirrhotic patients. Early referral of those eligible for transplantation may improve the treatment outcomes in these patients.

Proteomic analysis of alcohol-associated hepatitis reveals glycoprotein NMB (GPNMB) as a novel hepatic and serum biomarker.

Alcohol consumption remains a leading cause of liver disease worldwide, resulting in a complex array of hepatic pathologies, including steatosis, steatohepatitis, and cirrhosis. Individuals who progress to a rarer form of alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), require immediate life-saving intervention in the form of liver transplantation. Rapid onset of AH is poorly understood and the metabolic mechanisms contributing to the progression to liver failure remain undetermined. While multiple mechanisms have been identified that contribute to ALD, no cures exist and mortality from AH remains high. To identify novel pathways associated with AH, our group utilized proteomics to investigate AH-specific biomarkers in liver explant tissues. The goal of the present study was to determine changes in the proteome as well as epigenetic changes occurring in AH. Protein abundance and acetylomic analyses were performed utilizing nHPLC-MS/MS, revealing significant changes to proteins associated with metabolic and inflammatory fibrosis pathways. Here, we describe a novel hepatic and serum biomarker of AH, glycoprotein NMB (GPNMB). The anti-inflammatory protein GPNMB was significantly increased in AH explant liver and serum compared to healthy donors by 50-fold and 6.5-fold, respectively. Further, bioinformatics analyses identified an AH-dependent decrease in protein abundance across fatty acid degradation, biosynthesis of amino acids, and carbon metabolism. The greatest increases in protein abundance were observed in pathways for focal adhesion, lysosome, phagosome, and actin cytoskeleton. In contrast with the hyperacetylation observed in murine models of ALD, protein acetylation was decreased in AH compared to normal liver across fatty acid degradation, biosynthesis of amino acids, and carbon metabolism. Interestingly, immunoblot analysis found epigenetic marks were significantly increased in AH explants, including Histone H3K9 and H2BK5 acetylation. The increased acetylation of histones likely plays a role in the altered proteomic profile observed, including increases in GPNMB. Indeed, our results reveal that the AH proteome is dramatically impacted through unanticipated and unknown mechanisms. Understanding the origin and consequences of these changes will yield new mechanistic insight for ALD as well as identify novel hepatic and serum biomarkers, such as GPNMB.

A Retransplant Case for Hepatopulmonary Syndrome Without Liver Cirrhosis or Portosystemic Shunt After Living-Donor Liver Transplantation: A Case Report

Hepatopulmonary syndrome (HPS) is a disease of gas exchange caused by intrapulmonary shunting secondary to liver disease-associated intrapulmonary vascular dilation. HPS is characterized by the triad of cirrhosis, chronic liver disease, or portosystemic shunting (PSS); arterial hypoxemia; and intrapulmonary arteriovenous shunting in the absence of a primary cardiopulmonary anomaly. We encountered a rare case of HPS without liver disease or PSS. The patient was an 8-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 11 months of her age. Eight years after LDLT, hypoxemia and shortness of breath developed. The shunt ratio on 99mTc-macroaggregated albumin (MAA) lung perfusion scintigraphy (99mTc-MAA lung scan) was 32%. The patient had no cardiopulmonary disease, so we diagnosed her illness as HPS. We did not find cirrhosis, chronic liver disease, or PSS as a cause of HPS. We thought the graft was the cause of HPS. A second transplantation was planned. One year after the diagnosis of HPS, the shunt ratio on 99mTc-MAA lung scan worsened to 42%, digital clubbing appeared, and hypoxemia was worsening. Thus, we performed a second LDLT. After LDLT the shunt ratio on 99mTc-MAA lung scan normalized (6%) and cyanosis resolved. We determined that the graft was the cause of HPS; the typical causes of HPS were not clearly revealed in the histologic examination of the second liver explant. Acute rejection occurred twice after LDLT, so we speculated that HPS occurred because the graft became stressed over the long term.

Adult Langerhans Cell Histiocytosis Presenting as Sclerosing Cholangitis in a Liver Explant

Adult Langerhans Cell Histiocytosis Presenting as Sclerosing Cholangitis in a Liver Explant

Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in...

Cortisol and Dexamethasone Mediate Glucocorticoid Actions in the Lesser Spotted Catshark (Scyliorhinus canicula).

Simple SummaryFor the first time, glucocorticoid actions of corticosteroids are evidenced in vivo and ex vivo in sharks, highlighting the importance of carbohydrate metabolism in situations of high-energy expenditure in this taxonomical group. Long-term (7 days) in vivo administration of dexamethasone (DEX, a synthetic glucocorticoid) decreased 1α-hydroxycorticosterone (1α-OHB, the main corticosteroid hormone in sharks), while also modified carbohydrates metabolism in liver and white muscle. Short-term (1 to 5 h) ex vivo incubation of liver and muscle explants with cortisol (corticosteroid not present in sharks) and DEX revealed glucose secretion mediated by glucocorticoid receptors (GR), as seen by the employment of mifepristone (a GR inhibitor).Corticosteroids are hormones produced in vertebrates exerting gluco- and mineralocorticoid actions (GC and MC) mediated by specific receptors (GR and MR, respectively). In elasmobranchs, the major circulating corticosteroid is the 1α-hydroxycorticosterone (1α-OHB). This hormone acts as a MC, but to date its role as a GC has not been established. As there is no 1α-OHB standard available, here we employed a set of in vivo and ex vivo approaches to test GC actions of other corticosteroids in the lesser spotted catshark (Scyliorhinus canicula). Dexamethasone (DEX, a synthetic corticosteroid) slow-release implants decreased plasma 1α-OHB levels after 7 days, and modified carbohydrates metabolism in liver and white muscle (energy stores and metabolic enzymes). In addition, ex vivo culture of liver and white muscle explants confirmed GC actions of corticosteroids not naturally present in sharks (cortisol and DEX) by increasing glucose secretion from these tissues. Dose–response curves induced by cortisol and DEX, altogether with the use of specific GR inhibitor mifepristone, confirmed the involvement of GR mediating glucose secretion. This study highlights the influence of corticosteroids in the glucose balance of S. canicula, though the role of 1α-OHB as a GC hormone in sharks should be further confirmed.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

Background and AimsLipoprotein Z (LP‐Z) is an abnormal free cholesterol (FC)–enriched LDL‐like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP‐Z in alcohol‐associated hepatitis (AH) and interrogate the biology behind its formation.Approach and ResultsWe measured serum levels of LP‐Z using nuclear magnetic resonance spectroscopy, a well‐established clinical assay. Serum levels of LP‐Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z‐index, calculated by the ratio of LP‐Z to total apolipoprotein B–containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z‐index was associated with 90‐day mortality independent from the Model for End‐Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z‐index ≤ 0.6 and a decline of Z‐index by ≥0.1 in 2 weeks predicted 90‐day survival. RNA‐sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP‐Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP‐Z particles caused direct toxicity to human hepatocytes in a concentration‐dependent manner, supporting a pathogenic role of FC in LP‐Z.ConclusionsImpaired lipoprotein metabolism in AH leads to the accumulation of LP‐Z in the circulation, which is hepatotoxic from excessive FC. A Z‐index ≤ 0.6 predicts 90‐day survival independent from conventional biomarkers for disease prognostication.

Inositol 1,4,5-trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma.

The expression of the inositol 1,4,5-trisphosphate receptor type 3 (ITRP3) in hepatocytes is a common event in the pathogenesis of hepatocellular carcinoma (HCC), regardless of the type of underlying liver disease. However, it is not known whether ITPR3 expression in hepatocytes is involved in tumor maintenance. The aim of the present study was to determine whether there is an association between ITPR3 expression and clinical and morphological parameters using HCC samples obtained from liver explants from patients (n=53) with different etiologies of underlying chronic liver disease (CLD). ITPR3 expression, mitosis and apoptosis were analyzed in human liver samples by immunohistochemistry. Clinical and event-free survival data were combined to assess the relationship between ITPR3 and liver cancer growth in patients. RNA sequencing analysis was performed to identify apoptotic genes altered by ITPR3 expression in a liver tumor cell line. ITPR3 was highly expressed in HCC tumor cells relative to adjacent CLD tissue and healthy livers. There was an inverse correlation between ITPR3 expression and mitotic and apoptotic indices in HCC, suggesting that ITPR3 contributed to the maintenance of HCC by promoting resistance to apoptosis. This was confirmed by the upregulation of CTSB, CHOP and GADD45, genes involved in the apoptotic pathway in HCC. The expression of ITPR3 in the liver may be a promising prognostic marker of HCC

Editorial Comment: Recurrence of Hepatocellular Carcinoma in Liver Transplants—Microvascular Invasion and Pathologic Staging of the Explant Liver

This Editorial Comment discusses the following AJR article: Hepatocellular Carcinoma Staging: Differences Between Radiologic and Pathologic Systems and Relevance to Patient Selection and Outcomes in Liver Transplantation.

Hepatocellular Carcinoma Staging: Differences Between Radiologic and Pathologic Systems and Relevance to Patient Selection and Outcomes in Liver Transplantation.

Liver transplant is indicated with curative intent for patients with early-stage hepatocellular carcinoma (HCC). The radiologic T category is used to determine candidacy and priority of patients on the waiting list. After transplant, the explant liver pathologic TNM stage is used as a predictor of postoperative outcomes and overall prognosis. Although the comparison of radiologic and pathologic T categories for concordance is often considered to be straightforward, the staging conventions significantly differ. Not accounting for these differences is in part the reason for the high rates of radiologic-pathologic discordance reported in the literature, with inconsistent terminology being an additional source of confusion when evaluating concordance. These factors may affect the understanding of important radiopathologic phenotypes of disease and the adequate investigation of their prognostic capabilities. The aims of this article are to provide an overview of the pathologic and radiologic TNM staging systems for HCC while describing staging procedures, emphasize the differences between these staging systems to highlight the limitations of radiologic-pathologic stage correlation, present a review of the literature on the prognostic value of individual features used for HCC staging; and signal significant aspects of preoperative risk stratification that could be improved to positively impact posttransplant outcomes.

Can the Limits of Liver Transplantation Be Expanded in Perihilar Cholangiocarcinoma?

The most common location of cholangiocarcinomas is the perihilar region with a frequency of 50-70%. Current standard treatment for perihilar cholangiocarcinomas (pCCA) is surgical resection. In cases where resection treatment is possible, the 5-year survival rate is 8-40%. However, usinga very strict patient selection, neoadjuvant radiochemotherapy (NRCT), staging laparotomy, and liver transplantation (LT), called "the Mayo protocol," 5-year survivals of up to 70% in pCCAwere reported. This treatment protocol clearly requires an intensive workforce and a harmonious multidisciplinary approach. Reoperation and retransplantation rates are high, which is a reflection of the NRCT. Multicenter studies, systemic reviews, and meta-analysis results, comparing both resection and LT in pCCA treatment and evaluating only LT results, pointed to LT with strict patient selection and full compliance with the treatment. The results of centers experienced in LT are better in treatingpCCA. According to Mayo clinical data, histopathological diagnosis could not be obtained in half of the patients with pCCA before NRCT was given. This situation can be explained by the necrosis of the tumor due tothe effect of NRCT and the fact that the tumor cannot be detected in the explant liver. This situation raises the following questions: did all patients actually have pCCA? Were these good results due to some patients not having pCCA? The 5-year survival rate was worse in patients with a pathological diagnosis than those without a pathological diagnosis. However, interestingly, recurrence rates were statistically similar in both groups. There was no difference in survival between LT and resection in the R0N0 subgroup in de novo pCCA. There are still many issues that need to be addressed and corrected in pCCA, which is one of the most problematic indications forLT. Significant success has been achieved with NRCT, staging laparotomy, and LT in selected patients with pCCA developing on the basis of PSC or early-stage unresectable de novo pCCA. It can be expected that new NRCT modalities will provide better survival by expanding the indications for LT in pCCA.

Examining the Hepatic Immune System in Children With Liver Disease With Fine Needle Aspiration.

Liver biopsy is the standard in diagnosing liver diseases. Yet, it provides little space to perform comprehensive immune profiling of the liver. Hence, we explored whether fine needle aspirates (FNAs) could be used to elucidate the hepatic immunity in children. We enrolled 74 children undergoing diagnostic (n = 17) or protocol biopsy (n = 57) following liver transplantation (LT). Matched blood and FNAs were obtained. Additionally, explant liver tissue was collected from children (n = 14) undergoing LT. Immune cells were isolated from peripheral blood, FNAs and explanted livers. Immune-phenotypical profiling was done by flow cytometry. Biopsied patients (58% female) were at a median age of 46 months (interquartile range [IQR]: 12-118) and LT patients (71% female) were 48 months (IQR: 21-134, P = 0.78) old. CD69+, a hallmark of tissue-resident immune cells was expressed in 1.3% of CD3+ T cells from blood being higher in FNA (20%) and tissue (49%, P < 0.001). CD4+ T-cell frequencies in tissue (13%) and FNAs (20%) were lower compared to blood (35%, P < 0.001) whereas CD8+ T cells in tissue (33.5%) and FNA (32%) were higher than in blood (25%, P < 0.01). Mucosal associated invariant T cells were enriched in liver tissue (8.8%) and in the FNA (4.4%) compared to blood (1.7%, P < 0.001). Whereas the percentage of total Tregs (CD4+CD25+FOXP3+CD127low/-) decreased, the proportion of activated Tregs (CD4+CD45RA-FOXP3high) increased in FNA and explant. Breg (CD19+CD20+CD24highCD38high) frequencies were similar in all groups. FNA is a practical method to sample the liver immune system collecting even small cell subsets such as regulatory T/B cells.

S2886 Exertional Heat Stroke-Induced Acute Liver Failure and Liver Transplantation: A Case Report

Introduction: Exertional heat stroke (EHS) is characterized by excessive heat production and inadequate heat dissipation usually following heavy exertion in hot and humid climates. This is a medical emergency associated with hyperthermia and multiorgan dysfunction, including acute liver failure (ALF). Currently, there are no clear guidelines regarding the timing of liver transplantation (LT) in this patient population. Case Description/Methods: A 44-year old marathon runner with no past medical history presented to an outside hospital after being found unconscious following a 5-mile run in summer weather. Vitals were 39.4°C, HR 103, and MAP 50s. He was intubated, fluid resuscitated, started on vasopressors and broad-spectrum antibiotics, and admitted to a local intensive care unit where he underwent external cooling. Labs were notable for acute liver and kidney injury and rhabdomyolysis (peak ALT 10,850 IU/L, AST 870 IU/L, Cr 5.6 mg/dL and CK 16K U/L), and he required renal replacement therapy (Figure 1). He then developed disseminated intravascular coagulopathy (peak INR 7.9), which persisted despite multiple transfusions. Hepatitis panel was negative. He received N-acetylcysteine. On day 3, he was transferred to our hospital for consideration of LT. He was alert and interactive even while intubated. He was extubated, but after 48 hours became progressively encephalopathic. Therefore, he was listed for transplant as Status 1 and underwent successful cadaveric LT on day 7. Liver explant showed massive hepatocyte necrosis (>80%) in zones 2 and 3 and portions of zone 1. The patient was discharged on day 32 with recovery of renal function and at baseline mental status. His hospitalization was complicated by the development of an intra-abdominal hematoma and deep venous thrombosis. Two years post-LT, he continues to exhibit good graft function. Discussion: The overall mortality in EHS-related liver injury or failure has been shown to be 4-5%, and the liver transplantation rate ranges from 12.5-33.3%, with median time to liver transplantation of 3 days. A high index of suspicion and careful monitoring of mental status and coagulopathy are warranted given the high mortality rate in this patient population. In this patient, the decision to perform liver transplant was made after the development of hepatic encephalopathy and continued coagulopathy despite maximal medical therapy. This case illustrates the importance of early liver transplantation referral in patients with EHS-induced ALF.Figure 1.: Trend of patient's AST, ALT and total bilirubin during hospitalization.

Quantification of Viral RNA in Multiple Pieces of Explant Liver Tissue Shows Distinct Focal Differences in Hepatitis B Infection.

Hepatitis B virus (HBV) DNA and RNA were quantified by digital PCR assays in 20–30 tissue pieces from each of 4 liver explants with cirrhosis caused by HBV. The within-patient variability of HBV RNA levels between pieces was up to a 1000-fold. Core RNA and S RNA levels were similar and correlated strongly when replication was high, supporting that transcription was from covalently closed circular DNA (cccDNA). By contrast, enhanced expression of S RNA relative to cccDNA and core RNA in patients with medium-high or low replication supports that HBV surface antigen (HBsAg) can be expressed mainly from integrated HBV DNA in such patients.

HISTOPATHOLOGICAL, CLINICAL AND EPIDEMIOLOGICAL FEATURES OF HEPATOPORTAL SCLEROSIS IN A REFERRAL CENTER FOR LIVER DISEASE IN NORTHEASTERN BRAZIL.

Hepatoportal sclerosis HPS or obliterative portal venopathy (OPV), one of the differential diagnoses for non-cirrohtic portal hypertension, is characterized by the disappearance of the portal branches, portal and septal fibrosis, perisinusoidal fibrosis and regenerative nodular hyperplasia (RNH). It is a spectral disease that may progress to severe portal hypertension. Its etiopathogenesis is still little understood, especially in Brazil, it has been probably misdiagnosed due to its histopatological similarities with the hepatosplenic form of schistosomiasis. To analyze the profile of patients with HPS in Northeastern Brazil and to demonstrate the pathological characteristics of HPS. We retrospectively analyzed cases of OPV in liver biopsies and explants from a referral center for liver in Bahia - Brazil. The qualitative and quantitative analysis of the portal tracts and liver parenchyma was made so that comparisons could be done among the HPS findings of our population and the findings described by other authors. From the 62 patients identified with HPS, 42% were male, while 58% were female. The average age at diagnosis was 48.3 years. From this group, we analyzed the liver biopsy of 10 patients whose diagnosis of schistosomiasis could be ruled out. From these 100% (10/10) presented dense portal fibrosis and portal venous obliteration. Liver parenchymal atrophy was present in 60% (6/10) of the patients, sinusoidal dilation was present in 30% (3/10), the presence of portal septa occurred in 50% (5/10) and dense portal fibrosis in all patients analyzed. Nodular regenerative hyperplasia was found in 30% (3/10) of the patients. HPS seems to be neglected and misdiagnosed in Brazil, due to its similarities with schistossomiasis. In our study dense portal fibrosis, obliteration of the portal vein branches, parenchymal atrophy, sinusoidal dilatation and parenchymal nodular hyperplasia were the main histopathological findings and were similar to that described in other countries.