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September - October, 2015

Vol. 14 Issue 5

On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Liver-specific case fatality due to chronic hepatitis C virus infection: a systematic review Shelagh M. Szabo, Jennifer C. Samp, David R. Walker, Suzanne Lane, Stephanie K. Cline, Katherine L. Gooch, Ricardo Jiménez-Méndez, Adrian R. Levy Page 618-630

    Despite reports that mortality is increasing, overall case fatality due to hepatitis C virus (HCV) is thought to be low. Given the variability in published rates, we aimed to synthesize estimates of liver-specific case fatality and all-cause mortality in chronic HCV according to follow-up duration, sustained viral response (SVR) to treatment, and liver disease severity. A systematic review was conducted of studies published in English from 2003 to 2013, reporting liver-specific case fatality estimates from HCV-infected samples. Thirty-five eligible articles were identified; 26 also presented estimates of all-cause mortality. Among community-based samples, liver-specific case fatality ranged from 0.3% over 5.7 years to 9.2% over 8.2 years of follow-up; and of all-cause mortality, from 4.0% over 5.7 years, to 23.0% over 8.2 years of follow-up. Estimates were higher among clinic-based samples and those with more severe liver disease. Among treated patients achieving SVR, liver-specific case fatality was low: up to 1.4% over 11.5 years of follow-up among samples with any severity of liver disease. Estimates were higher among those without SVR: up to 14.0% over 10 years of followup among samples with any severity of liver disease, and higher still among samples with more severe liver disease. The proportion of deaths attributable to liver-specific causes ranged from 55 to 85% among those with severe liver disease. Published estimates of fatality are high among certain populations of chronic HCV patients, with liver-specific causes being an important contributor. Understanding current HCV mortality rates is important for quantifying the total burden of HCV disease.

  • Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis Norberto C. Chávez-Tapia, Indira Mendiola-Pastrana, Victoria J. Ornelas-Arroyo, Camilo Noreña-Herrera, Desiree Vidaña-Perez, Guadalupe Delgado-Sanchez, Misael Uribe, Tonatiuh Barrientos-Gutiérrez Page 631-641

    Acute-on-chronic liver failure (ACLF) is associated with increased short and long-term mortality. Animal models of liver failure have demonstrated that granulocyte-colony stimulating factor (G-CSF) accelerates the liver regeneration process and improves survival. However, clinical evidence regarding the use of G-CSF in ACLF remains scarce. The aim of this study was to assess the benefits and harms of G-CSF in patients with acute-on-chronic liver failure. An electronic search was made in The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS up to November 2013. Randomized clinical trials comparing the use of any regimen of G-CSF against placebo or no intervention in patients with ACLF were included. Primary outcomes included overal mortality, mortality due multi-organ failure, and adverse events. Relative risk (RR) and mean difference (MD) were used. Two trials involving 102 patients were included. A significant reduction in short-term overall mortality was observed in patients receiving G-CSF compared to controls (RR 0.56; 95%CI 0.39,0.80). G-CSF failed to reduce mortality secondary to gastrointestinal bleeding (RR 1.45; 95%CI 0.50, 4.27). Adverse effects reported included: fever, rash, herpes zoster, headache and nausea. In conclusion, the use of G-CSF for the treatment of patients with ACLF significantly reduced short-term mortality. While the evidence is still limited, the apparent benefit observed on short-term mortality, mild adverse effects and lack of an alternative therapy make the use of G-CSF in ACLF patients a reasonable alternative when liver transplantation is contraindicated or unavailable.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Increase of drug use and genotype 3 in HCV-infected patients from Central West and Northeast Mexico Linda E. Muñoz-Espinosa, Maria E. Trujillo-Trujillo, Roberto F. Martínez-Macías, Arturo Panduro, Ana M. Rivas-Estilla, Nora A. Fierro, Ana L. Silvera-Linares, Rafael Torres-Valadez, Paula Cordero-Pérez, Karina González-Aldaco, Carlos Y. Chen-López, Alexis José-Abrego, Jaime R. Zuñiga-Noriega, Maria C. Gutiérrez-Ruiz, Sonia Roman Page 642-651

    Background. The evolving pattern of HCV genotypes (GTs) and risk factors (RFs) in HCV-infected patients in Mexico is poorly understood. This study aimed to access the temporal trend of HCV GTs and RFs in HCV patients from two care centers. Material and methods. Chronic HCV patients [177 and 153 patients from the Northeast (NE) and Central West (CW) regions, respectively] were selected. Baseline features were demographics, date of birth (DOB), blood transfusion before 1992 (BTb1992), RFs, sexual promiscuity (SP), dental procedure (DP), injection drug use (IDU), viral load (VL), GTs, cirrhosis status and antiviral therapy (AT). Data were analyzed by Chi-square test for trends, unpaired T-test, and logistic regression. Results. HCV GT distribution was: GT1, 67%; GT2, 16%; GT3, 12% and GT4, 1%. RFs were BTb1992, 56%; surgeries, 56%; tattooing, 18% and IDU, 16%. GT1a mostly prevailed in CW than NE patients. GT1b, surgeries, BTb1992 and cirrhosis were more prevalent in older patients (p < 0.05); GT3, male gender IDU, SP, and tattooing showed an upward trend as younger were the patients in both regions (p < 0.05), contrariwise to the prevalence of GT1b. BTb1992 and surgeries were seen in elder women; BTb1992 was an independent RF for GT1. Age ≥ 50 years old, GT1 and exposure to AT (p < 0.05) were associated with cirrhosis. Conclusion. GT1a prevalence in CW Mexico remained stable, whereas GT3 increased and GT1b decreased in younger patients in both regions, along with associated RFs. Further regional molecular epidemiology and RF analyses are required in order to avoid the dissemination of new cases of HCV infection.

  • Intermediate fibrosis staging in hepatitis C: a problem not overcome by optimal samples or pathologists’ expertise Maria C. Chindamo, Vera L. Nunes-Pannain, João M. Araújo-Neto, Henrique S. Moraes-Coelho, Ronir R. Luiz, Cristiane A. Villela-Nogueira, Renata M. Perez Page 652-657

    Background and aims. The prediction of intermediate stage of fibrosis in chronic hepatitis C represents a prognostic factor for disease progression. Studies evaluating biopsy performance in intermediate stage considering current patterns of liver samples and pathologists’ variability are scarce. We aimed to evaluate the effect of optimal liver specimens (≥ 20 mm and/or ≥ 11 portal tracts) and pathologists’ expertise on agreement for intermediate stage of fibrosis in chronic hepatitis C. Material and methods. Guided biopsies with large TruCut needle were initially scored by four pathologists with different expertise in liver disease and posteriorly reviewed by a reference hepatopathologist to evaluate fibrosis agreement. Results. Of the 255 biopsies initially selected, 240 met the criteria of an optimal fragment (mean length 24 ± 5 mm; 16 ± 6 portal tracts) and were considered for analysis. The overall agreement among all fibrosis stages was 77% (κ = 0.66); intraobserver and interobserver agreement was, respectively, 97% (k = 0.96) and 73% (κ = 0.60). Excluded samples (< 20 mm and < 11 portal tracts) presented a lower agreement (40%; κ = 0.24). Stratifying fibrosis stages, an interobserver agreement of 42% was found in intermediate stage (F2), ranging from 0 to 56% according to pathologists’ expertise, compared to 97% in mild (F0-F1) and 72% in advanced fibrosis (≥ F3) (p < 0.001). Of the 23% misclassified cases, fibrosis understaging occurred in 82% of specimens, predominantly in F2, even when evaluated by a hepatopathologist. Conclusions. Liver biopsy presents intrinsic limitations to assess intermediate stage of fibrosis not overcome by optimal samples and experienced pathologists’ analysis, and should not be considered the gold standard method to evaluate intermediate fibrosis in chronic hepatitis C.

Non alcoholic fatty liver disease (NAFLD)
  • Fatty liver and abdominal fat relationships with high C-reactive protein in adults without coronary heart disease Guillermo C. Cardoso-Saldaña, Aida X. Medina-Urrutia, Carlos Posadas-Romero, Juan G. Juárez-Rojas, Esteban Jorge-Galarza, Gilberto Vargas-Alarcón, Rosalinda Posadas-Sánchez Page 658-665

    Background and rationale. Fatty liver (FL) and abdominal visceral fat (AVF) are strongly associated with systemic inflammation, however, it has not been defined if each one is independently involved, and if the insulin resistance is associated. To investigate if FL, AVF and insulin resistance are independently or additively associated with the high-sensitivity C-reactive protein (hs-CRP) in subjects without coronary artery disease we included 491 men and 553 women. Material and methods. All had anthropometric and plasma biochemical measurements, FL and AVF assessments by computed tomography. Results. The FL prevalence was 35.6% in men and 28.0% in women, p < 0.01. The prevalence of obesity, metabolic syndrome and homeostasis model assessment of insulin resistance (HOMA-IR) was significantly higher in FL compared to non FL subjects. FL and AVF accounted for 21 and 17%, respectively, to hs-CRP plasma levels. FL, AVF ≥ P75 and HOMA-IR ≥ P75 were independently and additively associated with plasma hs-CRP. The risk of hs-CRP ≥ 3 mg/L increased progressively in men from 1.36 (0.5-3.86) through 3.58 (1.32-9.7) in those with 1 or 3 factors respectively. In women from 2.25 (1.2-4.2) to 4.67 (2.3-9.4), respectively. In conclusion, both the FL and hs-CRP ≥ 3 mg/L occur in 1 of every 3 non CAD subjects. In men, FL and AVF ≥ P75 were associated with 3.6 times the risk of hs-CRP ≥ 3 mg/L, while in women, these factors were independently and additively associated with a 4.7 times higher risk of systemic inflammation.

  • SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women Roxana Gutiérrez-Vidal, Joel Vega-Badillo, Laura M. Reyes-Fermín, Hugo A. Hernández-Pérez, Fausto Sánchez-Muñoz, Guadalupe S. López-Álvarez, Elena Larrieta-Carrasco, Itzel Fernández-Silva, Nahum Méndez-Sánchez, Armando R. Tovar, Hugo Villamil-Ramírez, Ana M. Mejía-Domínguez, Teresa Villarreal-Molina, Rogelio Hernández-Pando, Francisco Campos-Pérez, Carlos A. Aguilar-Salinas, Samuel Canizales-Quinteros Page 666-674

    Background and aims. Secreted frizzled-related protein 5 (SFRP5) was recently described as a new adipokine protective for hepatic steatosis and other obesity-related complications in the mouse model. To date, SFRP5 expression in non-alcoholic fatty liver disease (NAFLD) has not been fully assessed in humans. We measured circulating SFRP5 levels and its expression in liver and adipose tissue, and evaluated its association with NAFLD in morbidly obese women. Material and methods. Fifty-four morbidly obese women undergoing bariatric surgery were included in the study. Liver biopsies were used for histology and hepatic triglyceride content quantification. Circulating SFRP5 levels were measured through enzyme-linked immunoabsorbent assay, and SFRP5 expression was performed in hepatic and adipose tissue (subcutaneous and visceral). Results. Although circulating SFRP5 levels showed a tendency to decrease with NAFLD progression, no significant differences were observed among non-alcoholic steatosis, steatohepatitis, and control subjects. Hepatic SFRP5 expression showed a negative correlation with hepatic triglyceride content (r = -0.349, P = 0.016 for mRNA and r = -0.291, P = 0.040 for SRFP5 protein) and ALT serum levels (r = -0.437, P = 0.001 for SRFP5 protein). In addition, hepatic SFRP5 protein levels were significantly lower in NASH than in control subjects (P = 0.006). Conclusion. This is the first study reporting an association of hepatic SFRP5 expression with NAFLD in humans.

Liver transplantation
  • Transient hyperglycemia during liver transplantation does not affect the early graft function Annabel Blasi, Joan Beltran, Nuria Martin, Graciela Martinez-Palli, Juan J. Lozano, Jaume Balust, Abigail Torrents, Pilar Taura Page 675-687

    Background and rationale for the study. Hyperglycemia after graft reperfusion is a consistent finding in liver transplantation (LT) that remains poorly studied. We aim to describe its appearance in LT recipients of different types of grafts and its relation to the graft function. Material & methods. 436 LT recipients of donors after brain death (DBD), donors after cardiac death (DCD), and familial amyloidotic polyneuropathy (FAP) donors were reviewed. Serum glucose was measured at baseline, during the anhepatic phase, after graft reperfusion, and at the end of surgery. Early graft dysfunction (EAD) was assessed by Olthoff criteria. Caspase-3, IFN-γ, IL1β, and IL6 gene expression were measured in liver biopsy. Results. The highest increase in glucose levels after reperfusion was observed in FAP LT recipients and the lowest in DCD LT recipients. Glucose level during the anhepatic phase was the only modifiable predictive variable of hyperglycemia after reperfusion. No relation was found between hyperglycemia after reperfusion and EAD. However, recipients with the highest glucose levels after reperfusion tended to achieve the best glucose control at the end of surgery and those who were unable to control the glucose value after reperfusion showed EAD more frequently. The highest levels of caspase-3 were found in recipients with the lowest glucose values after reperfusion. In conclusion, glucose levels increased after graft reperfusion to a different extent according to the donor type. Contrary to general belief, transient hyperglycemia after reperfusion does not appear to impact negatively on the liver graft function and could even be suggested as a marker of graft quality.

  • Risk factors for acute kidney injury and 30-day mortality after liver transplantation Adller G. C. Barreto, Elizabeth F. Daher, Geraldo B. Silva Junior, José Huygens P. Garcia, Clarissa B. A. Magalhães, José Milton C. Lima, Cyntia F. G. Viana, Eanes D. B. Pereira Page 688-694

    Introduction. The aim of this study is to evaluate the risk factors for acute kidney injury (AKI) and 30-day mortality after liver transplantation. Material and methods. This is a retrospective cohort of consecutive adults undergoing orthotopic liver transplantation (OLT) at a referral hospital in Brazil, from January 2013 to January 2014. Risk factors for AKI and death were investigated. Results. A total 134 patients were included, with median age of 56 years. AKI was found in 46.7% of patients in the first 72 h after OLT. Risk factors for AKI were: viral hepatitis (OR 2.9, 95% CI = 1.2-7), warm ischemia time (OR 1.1, 95% CI = 1.01-1.2) and serum lactate (OR 1.3, 95%CI = 1.02-1.89). The length of intensive care unit (ICU) stay was longer in AKI group: 4 (3-7) days vs. 3 (2-4) days (p = 0.001), as well as overall hospitalization stay: 16 (9-26) days vs. 10 (8-14) days (p = 0.001). The 30-day mortality was 15%. AKI was an independent risk factor for mortality (OR 4.3, 95% CI = 1.3-14.6). MELD-Na ≥ 22 was a predictor for hemodialysis need (OR 8.4, 95%CI = 1.5-46.5). Chronic kidney disease (CKD) was found in 36 patients (56.2% of AKI patients). Conclusions. Viral hepatitis, longer warm ischemia time and high levels of serum lactate are risk factors for AKI after OLT. AKI is a risk factor for death and can lead to CKD in a high percentage of patients after OLT. A high MELD-Na score is a predictor for hemodialysis need.

  • Secondary sclerosing cholangitis following major burn Ziv Ben-Ari, David Levingston, Ella Weitzman, Yael Haviv-Yadid, Oranit Cohen-Ezra, Peretz Weiss, Eli Zuckerman, Yael Inbar, Michal Amitai, Uri Rimon, Maya Goder, Josef Haik Page 695-701

    Background and aims. Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a relatively new previously unrecognized entity which may lead to severe biliary disease with rapid progression to cirrhosis. We present for the first time a case series of patients with rapidly progressive SSC-CIP requiring aggressive intensive care treatment following major burn injury. Results. SSC-CIP was diagnosed in 4 consecutive patients hospitalized due to major burn injuries at our Intensive Care Unit (ICU). SSC-CIP was diagnosed when ERCP (n = 1) or MRCP (n = 3) demonstrated irregular intrahepatic bile ducts with multiple strictures and dilatations and, when a liver biopsy (n = 3) demonstrated severe cholestasis and bile duct damage. All patients were males; none of whom had pre-existing liver disease. Ages: 18-56 y. All patients suffered from severe (grade 2-3) burn injuries with total burn surface area ranging from 35 to 95%. Mean length of ICU hospitalization was 129.2 ± 53.0 days. All patients required mechanical ventilation (with a mean PEEP of 8.4 ± 2.1 cm H2O) and the administration of catecholamines for hemodynamic stabilization. All patients demonstrated severe cholestasis. Blood cultures and cultures from drained liver abscesses grew hospital acquired multiple resistant bacteria. Liver cirrhosis developed within 12 months. One patient underwent orthotopic liver transplantation. Two patients (50%) died. In conclusion, SSC-CIP following major burn injury is a rapidly progressive disease with a poor outcome. Liver cirrhosis developed rapidly. Awareness of this grave complication is needed for prompt diagnosis and considerations of a liver transplantation.

Miscellaneous
  • Gallstone disease and obesity: a population-based study on abdominal fat distribution and gender differences Amir Reza Radmard, Shahin Merat, Soheil Kooraki, Mahya Ashrafi, Abbas Keshtkar, Maryam Sharafkhah, Elham Jafari, Reza Malekzadeh, Hossein Poustchi Page 702-709

    Background. Existing evidence suggests the visceral fat is more metabolically active than subcutaneous fat. We aimed to investigate the value of subcutaneous (SAT) and visceral adipose tissue thickness (VAT) for prediction of gallstone disease (GSD) in general population by focus on gender differences and comparison with body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). Material and methods. In this cross-sectional survey, 1,494 subjects (51.4 % men), aged above 50, randomly selected from Golestan Cohort Study residing in Gonbad City, Iran, underwent anthropometric measurements and abdominal ultrasonography. Results. Prevalence of GSD was 17.8% (95% CI 15.9-19.8). Following adjustment for age and then other potential risk factors, all obesity indices, except for SAT, were associated with GSD in women with the highest odds ratio observed in WHtR (OR 1.52, 95% CI 1.22-1.89). In contrast, WHR was the only associated index in men (OR 1.49, 95% CI 1.08-2.06). The trend of increasing obesity measures across the quartiles with the risk of GSD was significant in subgroups of WHtR and BMI in women and WHR in men. No significant association was found between SAT and GSD in men or women. Conclusions. The best anthropometric indicators of the risk of GSD may differ by gender. In men, WHR might be the only preferred index to estimate risk of GSD. WHtR, WHR, VAT and BMI are associated with GSD risk in women, although WHtR might better explain this risk. SAT is the poor indicator for identifying subjects with GSD in both genders.

  • Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19 Francisco Barrera, Lorena Azócar, Héctor Molina, Kurt A. Schalper, Marcia Ocares, Jessica Liberona, Luis Villarroel, Fernando Pimentel, Rosa M. Pérez-Ayuso, Flavio Nervi, Albert K. Groen, Juan F. Miquel Page 710-721

    Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investigated whether hGBECs secrete FGF19 and the effects of cholecystectomy on serum FGF19 ([FGF19]s) and BA synthesis. Material and methods. FGF19 expression was assessed by qRT-PCRs and immunostaining in hGBECs and terminal ileum, and quantified in bile and serum by ELISA. Basal and BA (chenodexycholic acid, CDCA) induced FGF19 expression and secretion was analyzed in primary cultured hGBECs and GB-d1 cell line. Pre and postprandial serum changes in [FGF19]s, 7α-hydroxy-4-cholestene-3-one (C4, a marker of BA synthesis) and BA were evaluated in plasma of gallstone disease patients at baseline and after cholecystectomy. Results. FGF19 mRNA levels were ~250-fold higher in hGBECs compared to distal ileum. GB bile contained ~23-fold higher FGF19 levels compared to serum (p < 0.0001). CDCA induced dose-dependent expression and secretion of FGF19 in hGBECs and GB-d1 cells. Cholecystectomy increased plasma BA synthesis ≥ 2-fold (p < 0.0001), and altered the diurnal rhythm and significantly reduced [FGF19]s noon peak. BA serum levels, serum cholesterol and triglyceride content remained unchanged. Conclusions. In conclusion human GB cholangiocytes constitutively express and secrete high levels of FGF19 in a process regulated by BA. Resection of this organ doubles BA synthesis concomitantly with changes in [FGF19]s. These findings suggest a potential connection between GB cholangiocytes-derived FGF19 and BA metabolism that could lead to metabolic dysregulation following cholecystectomy.

  • Etiology, outcome and prognostic factors of childhood acute liver failure in a German Single Center Simone Kathemann, Lars P. Bechmann, Jan-Peter Sowa, Paul Manka, Alexander Dechêne, Patrick Gerner, Elke Lainka, Peter F. Hoyer, Ariel E. Feldstein, Ali Canbay Page 722-728

    Pediatric acute liver failure (PALF) is a progressive, potentially fatal clinical syndrome occurring in previously healthy children. Our study aimed to determine the current leading causes of PALF in a single center in Germany, identifying possible prognostic markers. Thirty-seven pediatric patients with PALF were included. Medical records were reviewed for demographic, laboratory and clinical data. Laboratory results on admission and at peak value, PELD and MELD score on admission, and intensive care support were assessed. Fifteen patients recovered spontaneously, 14 died without transplantation, and 8 received a liver transplant. Patients who survived were significantly older than patients who died. Specific causes of PALF could be identified as infectious diseases (16%), metabolic diseases (14%), toxic liver injury (11%), immunologic diseases (8%), or vascular diseases (8%). Causes of PALF remained indeterminate in 43%. High ammonia, low albumin, and low ALT levels on admission were associated with worse outcome. Absence of need of ventilation, hemodialysis, and circulatory support predicted spontaneous recovery. In conclusion, infections are the most common known cause of PALF. However, in a large proportion of patients the cause for PALF remains cryptic. Ammonia and albumin levels may be of prognostic value to predict outcomes.

  • Association of a novel TAS2R38 haplotype with alcohol intake among Mexican-Mestizo population Omar Ramos-Lopez, Sonia Roman, Erika Martínez-López, Karina González-Aldaco, Claudia Ojeda-Granados, Maricruz Sepulveda-Villegas, Arturo Panduro Page 729-734

    Background. Alcohol intake has been associated with the bitter taste receptor T2R38. TAS2R38 gene expresses two common haplotypes: PAV and AVI. It has been reported that AVI homozygotes consume more alcohol than heterozygotes and PAV homozygotes. The aim of this study was to determine the prevalence of the TAS2R38 haplotypes among Mexican-Mestizo population and to analyze its association with alcohol intake. Material and methods. In a cross-sectional study, a total of 375 unrelated Mestizo individuals were genotyped for TAS2R38 polymorphisms (A49P, V262A and I296V) by a Real-Time PCR System (TaqMan). Haplotype frequencies were calculated. Association of TAS2R38 haplotypes with alcohol intake was estimated in drinkers (DRS) and nondrinkers (NDRS). Results. Two haplotypes accounted for over 96% of all haplotypes (AVV, 60%, and PAI, 36.5%). The frequency of AVV homozygotes was significantly higher in DRS than NDRS (47.2 vs. 32.2%, respectively; p < 0.05). Additionally, the AVV/AVV genotype was associated with alcohol intake when compared with heterozygotes and PAI homozygotes (OR = 1.79, 95% CI 1.13-2.84, p < 0.05 and OR = 2.23, 95% CI 1.11-4.48; p < 0.05, respectively). Conclusions. In conclusion, two TAS2R38 haplotypes (AVV and PAI) prevailed in Mexican-Mestizo population. The novel AVV haplotype was associated with alcohol intake. The high prevalence of this allelic profile in our population could help to explain, at least in part, the preference for alcohol among the Mexicans.

Basic studies

  • Development of steatohepatitis in Ob/Ob mice is dependent on Toll-like receptor 4 Alton G. Sutter, Arun P. Palanisamy, Julie H. Lench, Alex P. Jessmore, Kenneth D. Chavin Page 735-743

    Background and aim. The etiology of non-alcoholic fatty liver disease (NAFLD) progression, and why some patients develop non-alcoholic steatohepatitis (NASH) vs. uncomplicated NAFLD, is not well understood. Obesity and NAFLD are thought to be associated with high circulating levels of leptin; however, the role of leptin in NASH has been controversial. Secondly, as ob/ob mice are known to have elevated circulating levels of TLR4-stimulating endotoxin secondary to increased intestinal permeability. Material and methods. We evaluated the long-term effects of steatosis on the livers of aleptinemic (OB) mice and the role of TLR4 in the development of hepatic sequelae in these animals. Results. At 20 weeks of age OB animals displayed grossly steatotic livers, but also features of early stage NASH including hepatocellular ballooning and numerous necroinflammatory foci with associated changes in serum aspartate aminotransferase (AST) and alanine transaminase (ALT). TLR4 KO did not affect the development of obesity or steatosis in ob/ob mice, but protected these animals from hepatitis and liver injury. Conclusions. In conclusion, the data presented here indicate that steatohepatitis develops in the absence of leptin, and that TLR4 is integral to the development NASH secondary to hyperphagia.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MDR3 Bernardo Frider, Amalia Castillo, Raquel Gordo-Gilart, Andrés Bruno, Marcelo Amante, Luis Alvarez, Verónica Mathet Page 745-751

    Introduction. Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a severe liver disorder associated with inherited dysfunction of multidrug resistance protein 3 (MDR3/ABCB4), which functions as a phospholipid floppase, translocating phosphatidylcholine from the inner to the outer hemileaflet of the canalicular membrane of hepatocytes. MDR3 deficiency results in a disbalanced bile which may damage the luminal membrane of cells of the hepatobiliary system. We evaluated clinical, biochemical and histological improvement in a genetically proven PFIC-3 patient after long-term ursodeoxycholic acid (UDCA) administration. Material and methods. A PFIC-3 patient and a relative with cholestatic liver disease were studied. Hepatic MDR3 expression was analyzed by immunohistochemistry and ABCB4 mutations were identified. The effect of the mutations on MDR3 expression and subcellular localization was studied in vitro. Results. A 23-year-old man presented cholestasis with severe fibrosis and incomplete cirrhosis. Canalicular staining for MDR3 was faint. Sequence analysis of ABCB4 revealed two missense mutations that reduce drastically protein expression levels. After 9 years of treatment with UDCA disappearance of fibrosis and cirrhosis was achieved. Conclusion. These data indicate that fibrosis associated with MDR3 deficiency can be reversed by long-term treatment with UDCA, at least when there is residual expression of the protein.

  • Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach Jorge Martínez, Santiago Besa, Juan P. Arab, Juan C. Quintana, Carlos Regonesi, Alvaro Huete, Nicolás Jarufe, Juan F. Guerra, Carlos Benítez, Marco Arrese Page 752-755

    Gastrointestinal neuroendocrine tumors (NET) frequently present with unresectable hepatic metastases, which poses a barrier for curative treatment. Resection of the primary tumor and subsequent orthotopic liver transplantation (OLT) has been proposed as a treatment approach but available data in this regard is limited. We present a clinical case of an otherwise asymptomatic 44-yo man complaining of abdominal pain and dyspepsia that was diagnosed of a 10 cm duodenal tumor with multiple hepatic metastases. A CT-guided biopsy confirmed a NET. He underwent first a Whipple’s procedure, and then was listed for liver transplantation. During the waiting time a multimodal therapeutic approach was used including the use of radioactive 177lutetium-labeled somatostatin analogues, long-acting somastostatin analogues and antiangiogenic antibodies (bevacizumab) in order to keep neoplastic disease under control. Two years after Whipple’s procedure and given disease stability he underwent OLT with an uneventful postoperative evolution. Patient condition and graft function are optimal after a 4-year follow-up period with no evidence of recurrence. This case report underscores how a multimodal approach involving careful patient selection, resective surgery as well as use of somatostatin analogues and antiangiogenic biological therapy followed by liver transplantation can achieve excellent long-term results in this difficult patient population.

  • Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma Adriano M. Pellicelli, Cecilia D’Ambrosio, Maria L. Dessanti, Roberto Villani, Lucia Fondacaro, Lucia Miglioresi, Lucia R. Grillo, Arnaldo Andreoli Page 756-761

    Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.

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