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Santiago Mirazo,1 Natalia Ramos,1 Victoria Mainardi,2 Solange Gerona,2 Juan Arbiza1 1Laboratory of Virology, Faculty of Sciences, University of the Republic, Montevideo, Uruguay; 2Hepatic Diseases Unit, Central Hospital of the Armed Forces, Montevideo, Uruguay Abstract: Hepatitis E virus (HEV) infection is an important public health concern in many developing countries, causing waterborne outbreaks as well as sporadic autochthonous hepatitis. HEV is mainly transmitted by the fecal–oral route in endemic areas through drinking of contaminated water. However, zoonotic transmission from animal reservoirs to humans has also been suggested. Three additional routes of HEV transmission have been proposed to occur: blood borne, human to human, and vertical transmission from mother to child. Acute HEV infection is usually diagnosed by detecting specific anti-HEV antibodies. However, the performance of the available assays in different settings is not optimal. Analysis of HEV ribonucleic acid in biologic specimens such as stools, serum, and liver biopsy by using nucleic acid amplification techniques is also employed. Nonetheless, additional consensus regarding the best technologies suitable for serosurveys and diagnosis of acute HEV infection is also needed. This review article summarizes the current status of HEV infection end epidemiology with particular emphasis in transmission, diagnosis, and clinical management. Keywords: HEV, epidemiology, clinical features, routes of infection

Introduction In liver transplant (LT) recipients, surgical site infection (SSI) represents an important cause of morbidity and mortality. Objective This study measures the impact of a multimodal approach to the incidence of surgical site infection in LT recipients. Materials and Methods All of the LT recipients in our department were registered on the national database in solid organ transplant. A study was performed in two analytical-interventional phases. Phase 1 took place between July 14, 2009, and February 20, 2014. Phase 2 took place between February 21, 2014, and July 15, 2015. The multimodal change implemented during phase 1 was that 0.5% alcoholic chlorhexidine and ether were applied to the surgical field; surgical prophylaxis was primarily with ampicillin/sulbactam plus cefazolin. In phase 2, 2% alcoholic chlorhexidine alone was applied to the surgical field. The prior standard prophylaxis was changed to piperacillin tazobactam administered during surgery as a continuous infusion of 13.5 g over 8 hours with a pre-incision loading dose of 4.5 g. The loading dose of piperacillin tazobactam was combined with a single dose of gentamicin of 5 mg/kg. Results One hundred eight patients have received transplants since the start of the program: 82 patients during phase one and 26 patients during phase two. During phase 1, 13 cases of SSI were recorded, representing a rate of 15.85 per 100 transplants. Sixteen micro-organisms were isolated during phase 1, of which 12 corresponded to gram-negative bacilli. With regard to resistance profiles, 13 showed multidrug resistant and extensively drug resistant profiles. During phase 2, no cases of SSI were recorded (relative risk = 0.158 [95% confidence interval 0.0873–0.255], P = .0352]. Conclusion A multimodal approach allowed for the reduction of the incidence of SSI in LTs and offered a protective strategy. [ABSTRACT FROM AUTHOR]

To achieve WHO's goal of eliminating hepatitis C virus (HCV), innovative strategies must be designed to diagnose and treat more patients. Therefore, we aimed to describe an implementation strategy to identify patients with HCV who were lost to follow-up (LTFU) and offer them re-linkage to HCV care. We conducted an implementation study utilizing a strategy to contact patients with HCV who were not under regular follow-up in 13 countries from Latin America. Patients with HCV were identified by the international classification of diseases (ICD-9/10) or equivalent. Medical records were then reviewed to confirm the diagnosis of chronic HCV infection defined by anti-HCV+ and detectable HCV-RNA. Identified patients who were not under follow-up by a liver specialist were contacted by telephone or email, and offered a medical reevaluation. A total of 10,364 patients were classified to have HCV. After reviewing their medical charts, 1349 (13%) had undetectable HCV-RNA or were wrongly coded. Overall, 9015 (86.9%) individuals were identified with chronic HCV infection. A total of 5096 (56.5%) patients were under routine HCV care and 3919 (43.5%) had been LTFU. We were able to contact 1617 (41.3%) of the 3919 patients who were LTFU at the primary medical institution, of which 427 (26.4%) were cured at a different institutions or were dead. Of the remaining patients, 906 (76.1%) were candidates for retrieval. In our cohort, about one out of four patients with chronic HCV who were LTFU were candidates to receive treatment. This strategy has the potential to be effective, accessible and significantly impacts on the HCV care cascade., (© 2022 John Wiley & Sons Ltd.)

Liver transplantation is the last therapeutic option in patients with end-stage liver diseases. The adequate clinical management of transplant-patients impacts their vital prognosis and decisions on many occasions are made from the interaction of multiple variables involved in the process. This work is based on the National Liver Transplantation Program in Uruguay. We performed predictive analysis of cardiometabolic diseases on the transplanted cohort between 2014 and 2019, considering vascular age as a key factor. This aims at classification of the cohort based on the vascular age of the evaluated patients before transplantation for risk-profiling. Predicted high-risk group of the patients showed substantial deterioration of post-transplant health-conditions, including higher mortality rate. In our knowledge, this is the first study in Latin America incorporating vascular age toward predictive analysis of cardiometabolic risk factors in liver transplantations. Predictive risk-modeling using vascular age in a pre-transplantation scenario provides significant opportunity for early prediction of post-transplant risk factors, leading to efficient treatment with anticipation.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide. We report the full-length genome sequence of an HEV-3 strain obtained from a chronically infected patient from Uruguay. This strain shared only 86% nucleotide sequence identity with the most closely related reference strain belonging to subtype 3m.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future., (Copyright © 2020. Published by Elsevier España, S.L.U.)

Background: Cytomegalovirus (CMV) hepatitis constitutes a challenging diagnostic entity in liver transplant (LT) recipients., Aim: To determine the real incidence of CMV hepatitis using more specific diagnostic tools as those currently used before., Methods: Retrospective/prospective study conducted in a hepatic transplant unit from 2009 to 2019. LT recipients with CMV specific or suggestive elements in histopathology of hepatic biopsies were included. Immunohistochemistry (IHQ) was performed in tissue samples of the studied cohort as well as in a control one., Results: 41 patients met the inclusion criteria. IHQ was diagnostic in 6 (14.6%), and was negative in 100% of the control population. The negative predictive value of the histopathology for CMV hepatitis diagnosis was 100% and the positive predictive value was 14.6%. 85% of patients in whom the IHQ was negative had alternative diagnosis Antiviral therapy in the retrospective analysis was indicated in 48% of patients and in 21% of the prospectively analyzed cohort., Conclusions: Histopathology and IHQ combination improves the diagnostic accuracy of CMV hepatitis which translates into a rational us of expensive antiviral therapy and to search for differential diagnosis.

Introduction & Objectives: Liver cirrhosis is a major cause of mortality worldwide. Adequate diagnosis and treatment of decompensating events requires of both medical skills and updated technical resources. The objectives of this study were to search the demographic profile of hospitalized cirrhotic patients in a group of Latin American hospitals and the availability of expertise/facilities for the diagnosis and therapy of decompensation episodes., Methods: A cross sectional, multicenter survey of hospitalized cirrhotic patients., Results: 377 patients, (62% males; 58±11 years) (BMI>25, 57%; diabetes 32%) were hospitalized at 65 centers (63 urbans; 57 academically affiliated) in 13 countries on the survey date. Main admission causes were ascites, gastrointestinal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis/other infections. Most prevalent etiologies were alcohol-related (AR) (40%); non-alcoholic-steatohepatitis (NASH) (23%), hepatitis C virus infection (HCV) (7%) and autoimmune hepatitis (AIH) (6%). The most frequent concurrent etiologies were AR+NASH. Expertise and resources in every analyzed issue were highly available among participating centers, mostly accomplishing valid guidelines. However, availability of these facilities was significantly higher at institutions located in areas with population>500,000 (n=45) and in those having a higher complexity level (Gastrointestinal, Liver and Internal Medicine Departments at the same hospital (n=22)., Conclusions: The epidemiological etiologic profile in hospitalized, decompensated cirrhotic patients in Latin America is similar to main contemporary emergent agents worldwide. Medical and technical resources are highly available, mostly at great population urban areas and high complexity medical centers. Main diagnostic and therapeutic approaches accomplish current guidelines recommendations., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.

Introduction and Aim: Wilson's disease (WD) is an uncommon cause of acute liver failure (ALF). Our aim was to describe clinical features, diagnostic findings, treatments, and outcomes of patients with ALF due to WD., Material and Methods: Retrospective medical record reviews of all patients with ALF due to WD in eight years in Uruguay., Results: WD was the cause of six (15%) of thirty-nine ALF cases. All patients were females, with a mean age of 18 years. Four patients presented with hyperacute liver failure and two with acute failure. Jaundice was the main complaint of all patients. Mean total bilirubin (TB), alkaline phosphatase (AP), AST, and ALT were 27.5 mg/dL, 45.5 lU/l, 156 IU/L, and 51 IU/L, respectively. Ceruloplasmin levels were low in four patients, urinary cooper was high in four, and two had Kayser-Fleischer rings. All patients had Coombs-negative hemolytic anemia, acute kidney injury, histochemical identifiable copper, and advanced fibrosis on liver histology. The average MELD score was 36. All patients were treated with d-penicillamine and listed for urgent liver transplantation (LT). Prometheus® was performed in one patient. Three patients died: two without LT and one after LT. Three patients survived: one without LT (New Wilson Index<11) and two with LT. The referral time to the program and the total time (referral plus waiting list time) were longer for non-survivors than for survivors (14 vs. 3 days and 23 vs. 8 respectively)., Conclusion: All cases had typical clinical, analytical and histopathology characteristics. Early referral was determinant of prognosis., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC)., Methods: The calcineurin pathway activity was explored ex vivo in stimulated and nonstimulated PBMC from 19 patients. The inhibition of NFAT1 translocation to PBMC nuclei, expression of intracellular IL-2, and membrane CD25 in different T-cell subsets were measured by multiparametric flow cytometry before and after exposure to TAC. We also studied the influence on the individual response of polymorphisms in 3 key genes of the calcineurin pathway: PPIA , PPP3CA , and IL2RA ., Results: All pharmacodynamics profiles closely fitted an I/I max sigmoid model. Interindividual variability was higher in nonstimulated than in stimulated conditions, as well as in the presence of TAC. IL-2 + CD8 + cells at TAC I max showed the highest interindividual variability, suggesting its usefulness as a biomarker of individual TAC effects integrating many different sources of regulation and variability. Moreover, in the absence of TAC, patients with end-stage liver disease exhibited lower NFAT1 translocation and T-cell activation than healthy volunteers from a previous study under similar conditions. Multivariate statistical analysis showed strong and significant associations between TAC pharmacodynamic parameters and 2 polymorphisms in the gene-coding cyclophilin A (rs8177826 and rs6850)., Conclusions: We show the feasibility of using nonstimulated PBMCs to explore the calcineurin pathway under more physiologic conditions and point toward potential biomarkers for TAC pharmacodynamic monitoring. ClinicalTrials.gov Identifier: NCT01760356., (© 2017 American Association for Clinical Chemistry.)

Torque Teno Virus (TTV), member of Anelloviridae family, is considered a worldwide distributed emergent virus and is currently classified into seven genogroups. Interestingly, the pathogenicity of TTV remains unclear. However, it has been constantly associated to hepatitis cases of unknown etiology (HUE) as well as extensively studied in concurrent infections with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1). In South America, TTV epidemiological data is scant, involving some studies from Brazil, Venezuela, Colombia and Bolivia. The aim of this work was to investigate for the first time in Uruguay the presence of TTV by a nested-PCR system in 85 human serum samples infected with HBV and/or HCV and/or HIV-1 and in HUE cases. Overall, our results reported a TTV infection rate of 79% (67/85). Furthermore, the molecular characterization of Uruguayan strains revealed that one of them clustered in genogroup 1, while the remaining ones formed separate clusters closely related to genogroup 3, which should be confirmed by complete genome sequencing. Further investigation about TTV circulation in Uruguayan population is needed in order to provide additional information about the genetic variability and TTV epidemiology in South America., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway., Methods: Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1-50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4(+) and CD8(+) T cells and the surface activation marker CD25 in CD3(+) cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays., Results: All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit α isoenzyme, and CD25., Conclusions: This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics., (© 2014 American Association for Clinical Chemistry.)

Background: Multidisciplinary team work and centralization of health care in specialized teams, improves outcomes and quality of assistance in medical practice., Objectives: To describe the evolution of surgical and anesthetic practice and outcomes during a period of improving team work and centralization of liver surgery., Methods: A retrospective descriptive study of the type of surgery, anesthesia practice, outcomes and hospitalization was performed in 68 patients that underwent major hepatic surgery in our service, between Febriary 2004 and December 2007., Results: Fifty-one patients (75%) had hydatid liver disease. Ten surgeries (15%) were categorized as major; 20 (29%) as minor and 38 (56%) as hydatidic cystectomy. The number of surgeries tends to increase by year: 2004 (n = 13); 2005 (n = 14); 2006 (n = 18); 2007 (n = 23). An 87% of the anesthetics techniques were combined: epidural-general (n = 49; 72%) and spinal-general (n = 10O; 15%). The use of thoracic epidural was 0% in 2004 and 59% in 2007. A 62% of the cases bled less than 500 mL and 28% of the patients were transfused. The transfused volume in those patients (1,120 +/- 618mL) was 12% of the mean volume documented in 1998 in the same surgical service. There were no re-interventions or mortality. An 85% of the patients were admitted to the intensive care unit (ICU) for postoperative care in 2004 compared with only 22% in 2007. An 80% of the patients were discharged fom the hospital in the first 8 days after surgery (the majority by the fourth day)., Conclusions: Our multidisciplinary approach and teamwork may have positively influenced quality standards in liver surgery by diminishing transfusions of blood products and utilization of ICU resources.

Systemic and splanchnic hemodynamic parameters were evaluated in 12 patients with cirrhosis before and 3 and 6 months after liver transplantation. Results were compared with those obtained in 8 healthy subjects. Three months after liver transplantation recipients had an increase in mean arterial pressure (98 +/- 7 v 78 +/- 9 mmHg; P < .05), an insignificant decrease in cardiac index (3. 4 +/- 0.6 v 4.0 +/- 1.0 L . min-1 . m-2), and a marked increase in peripheral vascular resistance (1,563 +/- 308 v 800 +/- 205 dyne . s . cm-5; P < .05) compared with pretransplantation values. Portal blood flow was also significantly increased (1,494 +/- 200 v 829 +/- 130 mL/min; P < .05). These hemodynamic changes were more pronounced 6 months after transplantation (mean arterial pressure, 100 +/- 8 mmHg; cardiac index, 3.0 +/- 1.0 L . min-1 . m-2; P < .01; peripheral vascular resistance, 1,680 +/- 405 dyne . s . cm-5; portal blood flow, 1,520 +/- 180 mL/min). Systemic hemodynamics 6 months after liver transplantation were similar to those observed in the healthy control group (mean arterial pressure, 95 +/- 6 mmHg; cardiac index, 2.9 +/- 0.9 L . min-1 . m-2; peripheral vascular resistance, 1,480 +/- 380 dyne . s . cm-5). However, portal blood flow was still significantly higher than in healthy controls at 6 months (1,520 +/- 180 v 910 +/- 140 mL/min; P < .05). This study shows that systemic hemodynamics are normalized after liver transplantation. However, an increase in portal blood flow occurs and persists for at least 6 months after liver transplantation. Further studies are needed to clarify the cause of the abnormally high portal flows., (Copyright 1998 W.B. Saunders Company.)

Renal failure is a common finding in patients undergoing orthotopic liver transplantation. The aim of the present study was to evaluate the incidence, prognostic value of pre, intra and postoperative factors and severity of renal dysfunction in patients who undergo liver transplantation. Therefore, the records of 38 consecutive adult patients were reviewed. Renal failure was defined arbitrarily as an increase in creatinine (> 1.5 mg/dl) and/or blood urea (> 80 mg/dl). Three patients were excluded of the final analysis (1 acute liver failure and 2 with a survival lower than 72 hs.) Twenty one of the 35 patients has renal failure after orthotopic liver transplantation. Six of these episodes developed early, having occurred within the first 6 days. Late renal impairment occurred in 15 patients within the hospitalization (40 +/- 10 days) (Mean +/- SD). In he overall series, liver function, evaluated by Child-Pugh classification, a higher blood-related requirements and cyclosporine levels were observed more in those who experienced renal failure than those who did not (p < 0.05). Early renal failure was related with preoperative (liver function) and intraoperative (blood requirements) factors and several causes (nephrotoxic drugs and graft failure) other than cyclosporine were present in patients who developed late renal impairment. No mortality. No mortality was associated with renal failure. We conclude that renal failure a) is a common finding after liver transplantation, b) the pathogenesis of this complication is multifactorial and, c) in not related with a poor outcome.