Journal articles: 'Hepatic and Periportal fibrosis'

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Ferraz, Álvaro Antônio Bandeira, Pedro Cavalcanti de Albuquerque, Edmundo Pessoa de Almeida Lopes, José Guido Corrêa de Araújo Jr., Anderson Henrique Ferreira Carvalho, and Edmundo Machado Ferraz. "The influence of periportal (pipestem) fibrosis on long term results of surgical treatment for schistosomotic portal hypertension." Arquivos de Gastroenterologia 40, no. 1 (March 2003): 4–10. http://dx.doi.org/10.1590/s0004-28032003000100002.

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AIM: To evaluate the degree of influence that periportal fibrosis has on clinical development and the long term results of surgical treatment on patients with hepatic-splenic schistosomiasis with previous gastrointestinal hemorrhages. METHODS: During the period of 1992-1998, 111 patients underwent surgical treatment for the treatment of hepatic-splenic schistosomiasis with previous gastrointestinal hemorrhages. The degree of fibrosis was classified as: degree I - the portal spaces show a rich increase of young connective cells, a slight collagen production and a varying presence of inflammatory infiltrate. The periportal blade unchangeable (29/111); degree II - there is an expansion of the connective tissue with the emission of radial collagen septa, producing a star shaped aspect (38/111); degree III - the connective septa form bridges with other portal spaces or with the vein, with evident angiomatoid neo-formation (44/111). CONCLUSION: The patients with periportal fibrosis degree I present recurrent hemorrhages statistically less than patients with periportal fibrosis degrees II and III, and that the intensity of the periportal fibrosis is not the only pathophysiological factor of the esophageal varices, gastric varices, prevalence of post-operative portal vein thrombosis and hematological and biochemical alterations of the patients with pure mansoni schistosomiasis.

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Bindseil, Erling, Tine Iburg, Maria H. Hurst, and Maria V. Johansen. "Distinguishing periportal fibrosis from portal fibrosis in hepatic schistosomiasis." Trends in Parasitology 20, no. 8 (August 2004): 361–62. http://dx.doi.org/10.1016/j.pt.2004.05.009.

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Ruiz-Guevara, Raiza, Belkisyolé Alarcón de Noya, Sharon Kay Valero, Pablo Lecuna, Miguel Garassini, and Oscar Noya. "Clinical and ultrasound findings before and after praziquantel treatment among Venezuelan schistosomiasis patients." Revista da Sociedade Brasileira de Medicina Tropical 40, no. 5 (October 2007): 505–11. http://dx.doi.org/10.1590/s0037-86822007000500003.

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Abdominal ultrasound can be a useful tool for diagnosing periportal fibrosis related to Schistosoma mansoni infection, and also for planning and monitoring the evolution of hepatic morbidity following control measures. We evaluated the standardized ultrasound methodology proposed by the World Health Organization for detecting periportal fibrosis and portal hypertension, among patients from an endemic area in Venezuela, and the impact of praziquantel treatment 3-5 years later. After chemotherapy, complete reversal of periportal lesions was observed in 28.2% of the cases and progression of the disease in 5.1%. Improvement in the hepatic disease started with a reduction in the periportal thickening followed by a decrease in the size of the left hepatic lobe, spleen and mesenteric and spleen veins. Ultrasound confirmed the clinical findings after chemotherapy among the patients with reversal of the disease. However, in patients with more advanced disease, these findings were contradictory. There was no correlation between evolution of the disease seen on ultrasound and age, intensity of infection or serological findings.

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Christen, Urs, Edith Hintermann, Selina Christen, and Monika Bayer. "Activation of hepatic stellate cells during fibrosis: Comparison of the CYP2D6 model for autoimmune hepatits and CCl4 injection (130.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S227. http://dx.doi.org/10.4049/jimmunol.178.supp.130.2.

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Abstract Only little is known about the mechanisms of periportal fibrosis in the pathogenesis of human autoimmune hepatitis. We used the virus induced CYP2D6 model system to investigate the activation of hepatic stellate cells (HSC) and the kinetics of fibrosis in comparison with the CCl4-induced fibrosis model. CYP2D6 transgenic mice express the human Cytochrome P450 in the liver and develop liver damage upon Adenovirus-CYP2D6 infection. In the CYP2D6 model we found mostly subcapsular fibrosis resulting in the fusion of individual lobules (Sirius Red, Collagen I). At 10–12 weeks post-infection, weak periportal fibrosis became apparent. In contrast, in CCl4-treated mice the kinetic of extracellular matrix deposition was accelerated resulting in periportal fibrosis after 3–4 week of CCl4 administration. At later times, fibrosis was much more pronounced in CCl4-treated mice compared to virus-infected CYP2D6 mice but subcapsular fibrosis was not as dominat. Activation of HSCs could be detected by staining for α-smooth muscle actin (αSMA) in liver sections of both CCl4-treated mice and virus-infected CYP2D6 mice. In addition, isolation of HSCs revealed an enhanced activation status (decreased amount of oil droplets, de novo αSMA expression) in CCl4-treated mice and virus-infected CYP2D6 mice. Our data indicate that virus-infected CYP2D6 mice display subcapsular and periportal fibrosis that correlates with an activation of HSCs similar to CCl4-induced fibrosis. Thus, the CYP2D6 mouse is a good model system to further investigate the molecular mechanisms involved in fibrotic events during autoimmune hepatitis.

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Thompson, Michael D., Alaina Derse, Jeremie LA Ferey, Michaela Reid, Yan Xie, Miranda Christ, Deyali Chatterjee, et al. "Transgenerational impact of maternal obesogenic diet on offspring bile acid homeostasis and nonalcoholic fatty liver disease." American Journal of Physiology-Endocrinology and Metabolism 316, no. 4 (April 1, 2019): E674—E686. http://dx.doi.org/10.1152/ajpendo.00474.2018.

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Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F1 and F2 female offspring to lean males to develop F2 and F3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F1, but not F2 or F3, offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F1 offspring, a trend continued in F2 and F3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet.

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Andrade, Zilton A., and Ediriomar Peixoto. "Pathology of periportal fibrosis involution in human schistosomiasis." Revista do Instituto de Medicina Tropical de São Paulo 34, no. 4 (August 1992): 263–72. http://dx.doi.org/10.1590/s0036-46651992000400001.

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Optical and electron microscopical evidences of focal matrix degradation were frequently seen in liver sections of periportal fibrosis caused by schistosomiasis mansoni in man. The material came from 14 wedge hepatic biopsies taken from patients with chronic advanced hepatosplenic disease and undergoing operations for the relief of portal hypertension. Besides the presence of focal areas of rarefaction, fragmentation and dispersion of collagen fibers, the enlarged portal spaces also showed hyperplasia of elastic tissue and disarray of smooth muscle fibers following destruction of portal vein branches. Eggs were scanty in the tissue sections, and matrix degradation probably represented involuting changes related to the progressive diminution of parasite-related aggression, which occurs spontaneously with age or after cure by chemotherapy. The changes indicative of matrix degradation now described are probably the basic morphological counterpart of periportal fibrosis involution currently being documented by ultrasonography in hepatosplenic patients submitted to curative chemotherapy.

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Abou Basha, L. M. "Hepatic fibrosis due to fascioliasis and/or schistosomiasis in Abis 1 village, Egypt." Eastern Mediterranean Health Journal 6, no. 5-6 (December 15, 2000): 870–78. http://dx.doi.org/10.26719/2000.6.5-6.870.

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An epidemiological study of fascioliasis and/or schistosomiasis was conducted in Abis 1 village. Stool specimens were collected from 2492 individuals and examined. Fascioliasis, alone or combined with schistosomiasis, was more prevalent among children aged between 5 years and 15 years than in adults. Serum procollagen III peptide [PIIIP]levels were determined as an indicator of active fibrosis, and liver histopathology and ultrasonography used as indicators of established fibrosis. PIIIP levels were significantly higher in children than in adults, and in mixed infections than in fascioliasis alone. In adults, fibrosis around granulomata detected by histopathology and grade 3 periportal fibrosis detected by sonography were encountered more frequently in dual than in single infections.

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Sebastian, Kimberley, Rebecca C. Smedley, Alexander Bartel, and Matti Kiupel. "Patterns of Lymphocytic Infiltrates Can Differentiate Feline Hepatic Lymphoma from Lymphocytic Portal Hepatitis." Veterinary Sciences 10, no. 2 (February 7, 2023): 127. http://dx.doi.org/10.3390/vetsci10020127.

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Hepatic lymphoma is poorly characterized in cats and differentiating between inflammation and lymphomas is often difficult. The diagnosis of hepatic lymphoma in humans relies on recognition of specific patterns of lymphocytic infiltrates and clonality testing of antigen receptors. Herein, we defined similar patterns of lymphocytic infiltrates in hepatic biopsies of cats and correlated them with clonality to determine which patterns are predictive of lymphoma. A retrospective study was performed on surgical biopsies from 44 cats. The immunophenotype was characterized using CD3 and CD20 on all 44 samples. All 44 samples were tested using PCR for T-cell receptor gamma-gene rearrangements. PCR for immunoglobulin heavy chain gene rearrangements was performed on 24 of these cats. Four patterns of lymphocytic infiltrates were characterized: (1) tightly periportal, (2) periportal and centrilobular, (3) nodular, and (4) periportal with sinusoidal extension. Other histomorphologic features (fibrosis, biliary hyperplasia, bile ductopenia, bile duct targeting, hepatic hematopoiesis, lipogranulomas, lymphonodular aggregates, other inflammatory cells) were also evaluated. The sensitivity and specificity of the lymphocytic patterns to diagnose lymphomas were determined using Bayesian Hui–Walter analysis (BLCM) against clonality results. Lymphocytic patterns 2, 3, and 4 accurately diagnosed hepatic lymphomas with a sensitivity and specificity of 82% (CI 95%: 0.65, 0.96) and 77% (CI 95%: 0.54, 1.00), respectively. None of the other microscopic features evaluated were predictive of a lymphoma or inflammation. Our study identified specific patterns of lymphocytic infiltration that differentiate feline hepatic lymphoma from inflammation while other histologic features were not associated with an accurate diagnosis.

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Andrade, Zilton A., Ana Paula Baptista, and Thaynã Souto Santana. "Remodeling of hepatic vascular changes after specific chemotherapy of schistosomal periportal fibrosis." Memórias do Instituto Oswaldo Cruz 101, suppl 1 (October 2006): 267–72. http://dx.doi.org/10.1590/s0074-02762006000900041.

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Lee, Myung Hwan, Hyun Joo Shin, Haesung Yoon, Seok Joo Han, Hong Koh, and Mi-Jung Lee. "Periportal thickening on magnetic resonance imaging for hepatic fibrosis in infantile cholestasis." World Journal of Gastroenterology 26, no. 21 (June 7, 2020): 2821–30. http://dx.doi.org/10.3748/wjg.v26.i21.2821.

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Hegazy, Sahar K. "Antifibrotic effect of aloe vera in viral infection-induced hepatic periportal fibrosis." World Journal of Gastroenterology 18, no. 17 (2012): 2026. http://dx.doi.org/10.3748/wjg.v18.i17.2026.

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S. A. Jung, Y.-H. Chung, N. H. Park. "Experimental Model of Hepatic Fibrosis Following Repeated Periportal Necrosis Induced by Allylalcohol." Scandinavian Journal of Gastroenterology 35, no. 9 (January 2000): 969–75. http://dx.doi.org/10.1080/003655200750023057.

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Ryu, Soo Hyung, Young-Hwa Chung, Jae Kyun Lee, Jeong A. Kim, Jung Woo Shin, Myoung Kuk Jang, Neung Hwa Park, Han Chu Lee, Yung Sang Lee, and Dong Jin Suh. "Antifibrogenic effects of tamoxifen in a rat model of periportal hepatic fibrosis." Liver International 29, no. 2 (February 2009): 308–14. http://dx.doi.org/10.1111/j.1478-3231.2008.01811.x.

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Popovych, O. O., L. V. Moroz, Yu V. Avdosiev, F. A. Chabanov, and O. O. Voinalovych. "Congenital hepatic fibrosis (a case report)." Zaporozhye Medical Journal 23, no. 6 (October 29, 2021): 882–88. http://dx.doi.org/10.14739/2310-1210.2021.6.229102.

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Congenital hepatic fibrosis (CHF) is an autosomal recessive disorder of intrauterine morphogenesis of the portobiliary system, characterized by periportal fibrosis and defective remodeling of the bile ducts. The article describes the features of the clinical course, diagnosis and treatment of type I CHF in the different terms of a patient’s life: from birth to her pregnancy, during pregnancy and after childbirth. The aim of this work is to familiarize specialists with the problem of diagnosis and treatment of type I CHF in a patient with a provisional misdiagnosis of cryptogenic liver cirrhosis. Results. The features of type I CHF that determine a wider diagnostic testing in long-term unspecified liver pathology cases were identified. First-time decompensation of portal hypertension (PH) occurred at 35 weeks of gestation with the development of ascitic-edematous syndrome, hypersplenism, preeclampsia without signs of hepatic encephalopathy (HE). Cesarean section was performed at 37 weeks’ gestation and healthy baby was born. One year and 9 months after delivery, hypersplenism compensation was achieved by performing splenic artery embolization (SAE). There were no clinical manifestations of HE throughout the follow-up period. Conclusions. The diagnostic algorithm for a long-term compensated unspecified liver pathology with PH should confirm or rule out CHF. Type I CHF patients can give birth to a healthy child. SAE successfully compensates for hypersplenism and PH in type I CHF. Transient elastography is an effective method for the assessment of liver fibrosis progression in patients with type I CHF.

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Biswas, Ayan, Suman Santra, Debasree Bishnu, Gopal Krishna Dhali, Abhijit Chowdhury, and Amal Santra. "Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism." International Journal of Hepatology 2020 (April 23, 2020): 1–12. http://dx.doi.org/10.1155/2020/6987295.

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Background & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. We sought evidence of the production of hepatic fibrosis on long-term INH-RMP treatment through experiments in BALB/c mice exposed to INH-RMP. Methods. A combined dose of INH (50 mg) and RMP (100 mg) per kg body weight per day was administered to mice by oral gavage, 6 days a week, for 4 to 24 weeks for the assessment of liver injury, oxidative stress, and development of hepatic fibrosis, including demonstration of changes in key fibrogenesis linked pathways and mediators. Results. Progressive increase in markers of hepatic stellate cell (HSC) activation associated with changes in matrix turnover was observed between 12 and 24 weeks of INH-RMP treatment along with the elevation of liver collagen content and significant periportal fibrosis. These were associated with concurrent apoptosis of the hepatocytes, increase in hepatic cytochrome P450 2E1 (CYP2E1), NADPH oxidase (NOX) activity, and development of hepatic oxidative stress. Conclusions. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis.

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Lima, Leila Maria Soares Tojal de Barros, Celina Maria Costa Lacet, Mônica Salum Valverde Borsoi Viana, Bernadete de Lourdes Novais da Costa, and Edison Roberto Parise. "Evaluation of hepatic fibrosis by elastography in patients with schistosomiasis mansoni." Transactions of The Royal Society of Tropical Medicine and Hygiene 114, no. 7 (June 2, 2020): 531–37. http://dx.doi.org/10.1093/trstmh/traa035.

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Abstract Background Periportal fibrosis is associated with the main complications of schistosomiasis mansoni. The usefulness of hepatic transient elastography (TE) in its evaluation remains to be clarified. Methods We conducted a cross-sectional study of schistosomal patients, where the measurements obtained by FibroScan TE were correlated with the degree of liver fibrosis according to the Niamey sonographic protocol, adopted as the gold standard, and its performance was calculated as the area under the receiver operating characteristics curve (AUROC). Results A total of 117 of 141 adult schistosomiasis patients from endemic areas were selected between May and August 2015. Applying the Niamey protocol, the patients were regrouped into absent fibrosis (A; 34.2%), mild to moderate fibrosis (MM; 27.4%) and intense fibrosis (I; 38.5%). The median of the TE values in the patients of group A was 4.7 kPa, the group MM 9.3 kPa and the group I 10.3 kPa. There was a difference in the TE values between the group A and the groups MM and I (p < 0.05). The TE also presented strong and direct correlation with the clinical form (r ≥ 0.77). The AUROC value to define the presence of fibrosis was 0.92 and for significant fibrosis was 0.79, with cut-offs of 6.1 kPa and 8.9 kPa, respectively. Conclusions In this study, the TE was effective in the diagnosis of schistosomal fibrosis, being able to identify the advanced forms of the disease and thus predict the risk of clinical complications in endemic regions.

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Mak, Ki M., Priya Sehgal, and Cynthia K. Harris. "Factor VIII-Related Antigen Detects Phenotypic Change of Sinusoidal to Vascular Endothelium in Hepatic Fibrosis of Elderly Cadavers." International Scholarly Research Notices 2014 (September 22, 2014): 1–10. http://dx.doi.org/10.1155/2014/839560.

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In advanced stages of hepatic fibrosis, the liver sinusoidal endothelium transforms to vascular endothelium with accompanying expression of factor VIII-related antigen (FVIIIRAg), a phenotypic marker of vascular endothelial cells. Liver fibrosis has been shown to be associated with aging and was found to be prevalent in elderly cadavers. Using immunohistochemistry, we studied FVIIIRAg expression in the livers of elderly cadavers with progressive stages of fibrosis. The vascular endothelium of portal tracts and central veins was stained for FVIIIRAg, providing an internal positive control. The incidence of FVIIIRAg expression was low in the sinusoids of livers that showed minimal fibrosis or perisinusoidal fibrosis but was increased in livers with advanced fibrosis (i.e., septa formation, bridging fibrosis, and cirrhosis). FVIIIRAg positive sinusoidal endothelial cells were distributed in loose aggregates in the periportal, periseptal, and midlobular parenchyma and were found less frequently in the centrilobular area. FVIIIRAg immune deposits appeared patchy and discontinuous along the sinusoidal lining, likely representing focalized transformation of sinusoidal to vascular endothelium. There was a discrete localization of FVIIIRAg immunoreactivity in the foci of severe parenchymal fibrosis. Conclusion. FVIIIRAg is a reliable marker for detecting the transformation of sinusoidal to vascular endothelium in advanced liver fibrosis in elderly cadavers.

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Parkkila, S., O. Niemela, R. S. Britton, K. E. Brown, S. Yla-Herttuala, R. O'Neill, and B. R. Bacon. "Vitamin E decreases hepatic levels of aldehyde-derived peroxidation products in rats with iron overload." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 2 (February 1, 1996): G376—G384. http://dx.doi.org/10.1152/ajpgi.1996.270.2.g376.

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Hepatic iron overload can cause lipid peroxidation with the formation of aldehydic products, hepatocellular injury, and fibrosis. Vitamin E (alpha-tocopherol) may prevent peroxidation-induced hepatic damage. We used confocal laser scanning microscopy, digital image analysis, and immunohistochemical methods to quantitate aldehyde-derived peroxidation products in the liver of rats with experimental iron overload with or without supplemental vitamin E. A strong autofluorescent reaction colocalizing with iron deposits was present in the livers of iron-loaded rats. Fluorescent granules were unevenly distributed in the cytosol of both hepatocytes and Kupffer cells in the periportal regions. Immunohistochemical studies revealed the presence of malon-dialdehyde adducts in the periportal regions of the ironloaded rats. Vitamin E supplementation markedly reduced the fluorescence intensity and the amount of aldehyde-derived peroxidation products and changed the distribution of stainable iron and iron-associated peroxidation products such that their levels were much decreased in Kupffer cells. These results indicate that aldehyde-derived covalent chemical addition products are formed in the liver in iron overload. Vitamin E supplementation markedly reduces the amount of these compounds and changes their cellular distribution. These findings should be implicated in the role of antioxidant therapy in conditions causing iron overload and lipid peroxidation.

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Ludwig, Daniel R., Tyler J. Fraum, David H. Ballard, Vamsi R. Narra, and Anup S. Shetty. "Imaging Biomarkers of Hepatic Fibrosis: Reliability and Accuracy of Hepatic Periportal Space Widening and Other Morphologic Features on MRI." American Journal of Roentgenology 216, no. 5 (May 2021): 1229–39. http://dx.doi.org/10.2214/ajr.20.23099.

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Lotowska, Joanna Maria, Maria Elzbieta Sobaniec-Lotowska, Dariusz Marek Lebensztejn, Urszula Daniluk, Piotr Sobaniec, Krzysztof Sendrowski, Jaroslaw Daniluk, Joanna Reszec, and Wojciech Debek. "Ultrastructural Characteristics of Rat Hepatic Oval Cells and Their Intercellular Contacts in the Model of Biliary Fibrosis: New Insights into Experimental Liver Fibrogenesis." Gastroenterology Research and Practice 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/2721547.

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Purpose. Recently, it has been emphasized that hepatic progenitor/oval cells (HPCs) are significantly involved in liver fibrogenesis. We evaluated the multipotential population of HPCs by transmission electron microscope (TEM), including relations with adherent hepatic nonparenchymal cells (NPCs) in rats with biliary fibrosis induced by bile duct ligation (BDL). Methods. The study used 6-week-old Wistar Crl: WI(Han) rats after BDL for 1, 6, and 8 weeks. Results. Current ultrastructural analysis showed considerable proliferation of HPCs in experimental intensive biliary fibrosis. HPCs formed proliferating bile ductules and were scattered in periportal connective tissue. We distinguished 4 main types of HPCs: 0, I, II (bile duct-like cells; most common), and III (hepatocyte-like cells). We observed, very seldom presented in literature, cellular interactions between HPCs and adjacent NPCs, especially commonly found transitional hepatic stellate cells (T-HSCs) and Kupffer cells/macrophages. We showed the phenomenon of penetration of the basement membrane of proliferating bile ductules by cytoplasmic processes sent by T-HSCs and the formation of direct cell-cell contact with ductular epithelial cells related to HPCs. Conclusions. HPC proliferation induced by BDL evidently promotes portal fibrogenesis. Better understanding of the complex cellular interactions between HPCs and adjacent NPCs, especially T-HSCs, may help develop antifibrotic therapies in the future.

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Feldbrügge, Linda, Katrin Splith, Ines Kämmerer, Sandra Richter, Anna Riddermann, Santiago Andres Ortiz Galindo, Felix Krenzien, et al. "Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity." International Journal of Molecular Sciences 21, no. 17 (August 20, 2020): 5998. http://dx.doi.org/10.3390/ijms21175998.

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Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.

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Cannito, Stefania, Chiara Milani, Andrea Cappon, Maurizio Parola, Mario Strazzabosco, and Massimiliano Cadamuro. "Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies." International Journal of Molecular Sciences 19, no. 12 (December 4, 2018): 3875. http://dx.doi.org/10.3390/ijms19123875.

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The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli’s disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.

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Gava, Aldo, and Claudio S. L. Barros. "Senecio spp. POISONING OF HORSES IN SOUTHERN BRAZIL." Pesquisa Veterinária Brasileira 17, no. 1 (January 1997): 36–40. http://dx.doi.org/10.1590/s0100-736x1997000100006.

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Cases of seneciosis in horses occurring in four farms in the state of Santa Catarina and in another in the state of Rio Grande do Sul, southern Brazil, are reported. S. brasiliensis or S. oxyphyllus or both were detected in four of the five properties. Five horses (one on each property) were necropsied, and tissues for histopathological examination were collected from four horses. Neurological signs, such as depression, ataxia, aimeless walking, circling, head pressing, faulty prehension of food, dysphagia and blindness were consistently observed. Other signs included inappetence, loss of weight, colic, subcutaneous edema, icterus and photodermatitis. At necropsy the livers were firmer and darker than normal and had accentuation of lobular pattern. Edema of the mesentery and ascites were observed in one horse. Main histopathological changes consisted of hepatic chiefly periportal fibrosis, hepatomegalocytosis and biliary hyperplasia. Marked cholestasis and morphological evidence of hepatic encephalopathy were seen respectively in the liver and brain of one of the horses.

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Avni, Fred E., Valerie Segers, Viviane De Maertelaer, Sammy Cadranel, Martine Dassonville, Marc-Henri DeLaet, Nicole Nicaise, and Thierry Metens. "The evaluation by magnetic resonance imaging of hepatic periportal fibrosis in infants with neonatal cholestasis: Preliminary report." Journal of Pediatric Surgery 37, no. 8 (August 2002): 1128–33. http://dx.doi.org/10.1053/jpsu.2002.34457.

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Xie, Guanhua, Lin Wang, Xiangdong Wang, Lei Wang, and Laurie D. DeLeve. "Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 5 (November 2010): G1204—G1210. http://dx.doi.org/10.1152/ajpgi.00302.2010.

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Many liver sinusoidal endothelial cell (LSEC)-dependent processes, including drug-induced liver injury, ischemia-reperfusion injury, acute and chronic rejection, fibrosis, and the HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome, may have a lobular distribution. Studies of the mechanism of this distribution would benefit from a reliable method to isolate LSEC populations from different regions. We established and verified a simple method to isolate periportal, midlobular, and centrilobular LSEC. Three subpopulations of LSEC were isolated by immunomagnetic separation on the basis of CD45 expression. Flow cytometry showed that 78.2 ± 2.3% of LSEC were CD45 positive and that LSEC could be divided into CD45 bright (28.6 ± 2.7% of total population), dim (49.6 ± 1.0%), and negative populations (21.8 ± 2.3%). Immunohistochemistry confirmed that in vivo expression of CD45 in LSEC had a lobular distribution with enhanced CD45 staining in periportal LSEC. Cell diameter, fenestral diameter, number of fenestrae per sieve plate and per cell, porosity, and lectin uptake were significantly different in the subpopulations, consistent with the literature. Endocytosis of low concentrations of the LSEC-specific substrate, formaldehyde-treated serum albumin, was restricted to CD45 bright and dim LSEC. Acetaminophen was more toxic to the CD45 dim and negative populations than to the CD45 bright population. In conclusion, CD45 is highly expressed in periportal LSEC, low in midlobular LSEC, and negative in centrilobular LSEC, and this provides an easy separation method to isolate LSEC from the three different hepatic regions. The LSEC subpopulations obtained by this method are adequate for functional studies and drug toxicity testing.

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Lee, Sung Won, Sung Min Kim, Wonhee Hur, Byung-Yoon Kang, Hae Lim Lee, Heechul Nam, Sun Hong Yoo, et al. "Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K/Akt/mTOR signaling pathway." PLOS ONE 16, no. 12 (December 8, 2021): e0261067. http://dx.doi.org/10.1371/journal.pone.0261067.

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Background Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis. Methods Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice. Results After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF. Conclusions TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.

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Stegelmeier, Bryan L., Dale R. Gardner, Lynn F. James, and Russell J. Molyneux. "Pyrrole Detection and the Pathologic Progression of Cynoglossum Officinale (Houndstongue) Poisoning in Horses." Journal of Veterinary Diagnostic Investigation 8, no. 1 (January 1996): 81–90. http://dx.doi.org/10.1177/104063879600800113.

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Houndstongue ( Cynoglossum officinale), a noxious weed that contains pyrrolizidine alkaloids (PAs), infests pastures and fields in the western United States and Europe. The purpose of this study was to develop techniques to better diagnose PA poisoning and describe the progression of gross and microscopic lesions caused by houndstongue intoxication. Six horses were gavaged daily with a suspension of houndstongue containing 5 or 15 mg/kg total PA for 14 days. Two horses were treated similarly with ground alfalfa as controls. Liver biopsy samples and serum biochemical and hematologic values were evaluated biweekly. Within 7 days after dosing, horses treated with 15 mg/kg PA developed severe liver disease characterized by altered bile acid metabolism, elevated serum enzymes, and extensive hepatocellular necrosis with minimal periportal fibrosis and biliary hyperplasia. The condition of these animals continued to deteriorate, and they were euthanized. For several weeks after dosing, horses treated with 5 mg/kg PA were depressed, had transient elevations of serum enzymes and bile acids, and developed minimal periportal hepatocellular necrosis with fibrosis. The biochemical changes resolved by 6–8 weeks; however, the histologic disease persisted with extensive megalocytosis by week 14. Throughout the study, the rate of hepatocellular proliferation remained constant. Biliary cells had an increase in mitotic rate that correlated with the histologic changes. Hepatic tissue-bound pyrroles (PA metabolites) were identified in necropsy samples of treated animals using gas chromatography/mass spectrometry and photometrically with Ehrlich's reagent. These findings suggest that pyrrole extraction and identification are useful in documenting PA exposure and that houndstongue is extremely toxic to horses.

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Wanless, Ian R., Eisuke Nakashima, and Morris Sherman. "Regression of Human Cirrhosis." Archives of Pathology & Laboratory Medicine 124, no. 11 (November 1, 2000): 1599–607. http://dx.doi.org/10.5858/2000-124-1599-rohc.

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Abstract Context.—Cirrhosis is widely regarded as being irreversible. Recent studies have demonstrated that fibrosis may decrease with time in humans and experimental animals if the disease activity becomes quiescent. The histologic appearance of regressing cirrhosis in the human has not been described in detail. Objectives.—To define histologic parameters that indicate regression of cirrhosis and to provide an interpretation of how regression occurs from a histologic point of view. Design.—A patient who underwent a series of biopsies that showed apparent regression of hepatitis B cirrhosis is presented. In addition, 52 livers removed at transplantation having cirrhosis or incomplete septal cirrhosis were graded for histologic parameters that suggest progression or regression of fibrosis. Progression parameters were steatohepatitis, inflammation, bridging necrosis, and piecemeal necrosis. The regression parameters (collectively called the hepatic repair complex) were delicate perforated septa, isolated thick collagen fibers, delicate periportal fibrous spikes, portal tract remnants, hepatic vein remnants with prolapsed hepatocytes, hepatocytes within portal tracts or splitting septa, minute regenerative nodules, and aberrant parenchymal veins. Results and Conclusions.—Regression parameters were found in all livers and were prominent in the majority. Livers with micronodular cirrhosis, macronodular cirrhosis, and incomplete septal cirrhosis demonstrate a histologic continuum. A continuum of regressive changes was also seen within individual livers. These appearances allow one to understand visually how fibrous regions of hepatic parenchyma can be returned toward a normal appearance. Many examples of incomplete septal cirrhosis could be the product of regressed cirrhosis.

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Silva, Luciana Cristina dos Santos, Luciene Mota Andrade, Ivie Braga de Paula, Leonardo Campos de Queiroz, Carlos Maurício Figueiredo Antunes, and José Roberto Lambertucci. "Ultrasound and magnetic resonance imaging findings in Schistosomiasis mansoni: expanded gallbladder fossa and fatty hilum signs." Revista da Sociedade Brasileira de Medicina Tropical 45, no. 4 (July 26, 2012): 500–504. http://dx.doi.org/10.1590/s0037-86822012005000008.

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INTRODUCTION: There is no study relating magnetic resonance imaging (MRI) to ultrasound (US) findings in patients with Schistosomiasis mansoni. Our aim was to describe MRI findings inpatients with schistosomal liver disease identified by US. METHODS: Fifty-four patients (mean age 41.6±13.5years) from an area endemic for Schistosomiasis mansoni were selected for this study.All had US indicating liver schistosomal fibrosis and were evaluated with MRI performed witha 1.5-T superconducting magnet unit (Sigma). RESULTS: Forty-seven (87%) of the 54 patientsshowing signs of periportal fibrosis identified through US investigation had confirmed diagnosesby MRI. In the seven discordant cases (13%), MRI revealed fat tissue filling in the hilar periportalspace where US indicated isolated thickening around the main portal vein at its point of entryto the liver. We named this the fatty hilum sign. One of the 47 patients with MRI evidence ofperiportal fibrosis had had his gallbladder removed previously. Thirty-five (76.1%) of the other46 patients had an expanded gallbladder fossa filled with fat tissue, whereas MRI of the remainingeleven showed pericholecystic signs of fibrosis. CONCLUSIONS: Echogenic thickening of thegallbladder wall and of the main portal vein wall heretofore attributed to fibrosis were frequentlyidentified as fat tissue in MRI. However, the gallbladder wall thickening shown in US (expandedgallbladder fossa in MRI) is probably secondary to combined hepatic morphologic changes inschistosomiasis, representing severe liver involvement.

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Wybraniec-Zaręba, Aldona, Julia Tuchalska-Czuroń, Gabriela Półtorak-Szymczak, Mariusz Furmanek, Jerzy Walecki, and Katarzyna Sklinda. "Magnetic Resonance Imaging in Primary Sclerosing Cholangitis." Wiedza Medyczna 3, no. 2 (November 22, 2021): 20–24. http://dx.doi.org/10.36553/wm.92.

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Primary sclerosing cholangitis (PSC) is a chronic liver disease in which there are inflammation and scarring of the bile ducts leading to fibrosis, destruction and narrowing of the bile ducts, resulting in cholestasis. In the long run, PSC can cause liver cirrhosis and failure. In clinical practice, the diagnosis of PSC is generally based on blood tests and imaging studies (currently preferably magnetic resonance cholangiopancreatography). To make a diagnosis of PSC it is necessary to exclude secondary causes of sclerosing cholangitis. The most common MRI features of PSC concerning bile ducts are: bile duct dilatation, beading, extrahepatic bile duct stenosis, wall enhancement and thickening. The most common MRI features of PSC concerning hepatic parenchyma are: rounded shape of the liver caused by hypertrophy of caudate lobe and left liver lobe, atrophy of the right lobe, enlargement of portal and/or portacaval lymph nodes, peripheral parenchymal inflammation, wedge-shaped confluent fibrosis, heterogeneity of the liver parenchyma, periportal oedema, cirrhosis with indirect signs of portal hypertension such as splenomegaly, ascites and collateral vasculature.

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Pogoriler, Jennifer, Allison F. O’Neill, Stephan D. Voss, Robert C. Shamberger, and Antonio R. Perez-Atayde. "Hepatocellular Carcinoma in Fanconi-Bickel Syndrome." Pediatric and Developmental Pathology 21, no. 1 (April 6, 2017): 84–90. http://dx.doi.org/10.1177/1093526617693540.

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Fanconi-Bickel syndrome is a rare autosomal recessive disorder due to mutations in the facilitative glucose transporter 2 ( GLUT2 or SLC2A2) gene resulting in excessive glycogen storage predominantly in the liver and kidney. Previous case reports of this condition have described liver biopsies with glycogen storage and variable steatosis and/or fibrosis. Unlike in other types of glycogen storage disease, hepatocellular adenomas and carcinomas have not been described to date in this syndrome. A 6-year-old boy with consanguineous parents had short stature, poorly controlled rickets, hepatosplenomegaly, and renal tubular dysfunction clinically consistent with Fanconi-Bickel Syndrome. Sequencing of the SLC2A2 gene showed a homozygous variant of unknown significance [c.474A > C (p.Arg158Ser)] causing a missense mutation in an evolutionarily conserved residue. An incidental single hepatic lesion was discovered on imaging, and subsequent resection showed a 2.6 cm well-differentiated hepatocellular carcinoma with moderate atypia, diffuse immunoreactivity for glypican-3, and nuclear b-catenin, and with focal complete loss of the reticulin framework. The non-neoplastic liver showed marked glycogen accumulation with mild periportal fibrosis, rare bridging fibrosis, and no regenerative or adenomatous nodules. By electron microscopy, tumor cells had pleomorphic nuclei, prominent nucleoli, and scant cytoplasm with numerous mitochondria. Well-developed canaliculi were occasionally seen. The non-neoplastic liver showed glycogenosis with abundant cytoplasmic free (non-membrane bound) glycogen. Hepatocellular carcinoma should be considered as a possible complication of Fanconi-Bickel syndrome. This well differentiated carcinoma did not appear to be associated with hepatic adenomatosis as has been described in some hepatocellular carcinomas associated with other hepatic glycogen storage disorders. The nuclear beta-catenin immunoreactivity indicates a role for the Wnt signaling pathway in the pathogenesis of this tumor.

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Tomanovic, Nada, Ivan Boricic, and Dimitrije Brasanac. "Immunohistochemical analysis of α-SMA and GFAP expression in liver stellate cells." Vojnosanitetski pregled 63, no. 6 (2006): 553–57. http://dx.doi.org/10.2298/vsp0606553t.

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Background/Aim. Liver stellate cells play an important role in hepatic fibrosis, and its progression to cirrhosis. These cells show immunoreactivity with different monoclonal antibodies amongst which the commonest are ?-smooth muscle actin (?-SMA) and glial fibrillary acid protein (GFAP). The aim of this study was to analyze stellate cell immunoreactivity for ?-SMA and GFAP in tissue sections showing the signs of chronic viral B-hepatitis and compare it with those without histopathological changes. Methods. We included 12 tissue samples showing chronic viral B hepatitis in the different stages of fibrosis and 7 tissue samples showing no histopathological changes. Immunohistochemical staining was performed using the streptavidinbiotin method. Results. There was a regular presence of ?-SMA immunoreactivity in tissue sections without histopathological changes in the portal tracts and also in liver parenchyma, while GFAP expression was noted in the periportal cavity. Tissue sections with the signs of chronic viral B hepatitis displayed very strong ?-SMA expression in the portal tracts. A statistical analysis showed a positive correlation between the degree of liver fibrosis and ?-SMA expression along the fibrous septa, whereas a negative correlation between the degree of liver fibrosis and ?-SMA expression was present in the portal zone. Conclusion. This study showed the existance of two different stellate cell subpopulations in liver tissue. Differentiation between them was possible on the basis of SMA/GFAP expression.

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Marcos, Ricardo, Eduardo Rocha, and Rogério AF Monteiro. "STEREOLOGICAL ESTIMATION OF ITO CELLS FROM RAT LIVER USING THE OPTICAL FRACTIONATOR - A PRELIMINARY REPORT." Image Analysis & Stereology 21, no. 1 (May 3, 2011): 1. http://dx.doi.org/10.5566/ias.v21.p1-6.

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In the last two decades, much light has been shed on hepatic fibrosis, and the activation / proliferation of Ito cells (IC) emerged to play a central role. Therefore, it is essential to have solid quantitative data in nonpathological statuses; yet, this data is scarce and confined to "number per area" or semiquantitative information. Moreover, the supposed heterogeneous distribution of IC in the hepatic lobule was never analysed with design-based (unbiased) stereology. In the present study, the total number (N) of IC in rat liver was estimated for the first time, by combining immunocytochemistry with the optical fractionator. Quantification was extended to the hepatocytes, to disclose the IC index, an often-used ratio in hepatology. Systematic uniform random liver sections were obtained from male Wistar rats (n = 3), and immunostained against glial fibrillary acidic protein (GFAP), a known specific marker for hepatic IC. For the first time, these were marked against GFAP in thick (30 μm) paraffin sections. The estimated N of IC was 224E06; with a coefficient of error of 0.04 or 0.06, depending on the particular equation used (based on the so-called "quadratic approximation"). The IC index was 91 IC/1000 hepatocytes. Concerning the lobular heterogeneity, it was proved the liver harbours a larger total number of periportal IC and hepatocytes.

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GUERRA, Juliana Arrais, Kátia Cristina KAMPA, Maurício ZAPPAROLI, Venâncio AF ALVES, and Cláudia Alexandra Pontes IVANTES. "CONGENITAL HEPATIC FIBROSIS AND OBLITERATIVE PORTAL VENOPATHY WITHOUT PORTAL HYPERTENSION - A REVIEW OF LITERATURE BASED ON AN ASYMPTOMATIC CASE." Arquivos de Gastroenterologia 55, no. 4 (December 2018): 324–28. http://dx.doi.org/10.1590/s0004-2803.201800000-91.

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ABSTRACT The disease and the case reported here are relevant especially because of their varied clinical presentation, possibility of being associated with other disorders affecting several organs and possible differential diagnoses. Congenital Hepatic Fibrosis is an autosomal recessive disease due to mutation in the PKHD1 gene, which encodes the fibrocystin/polyductine protein. It is a cholangiopathy, characterized by varying degrees of periportal fibrosis and irregular proliferation of bile ducts. Affected patients are typically diagnosed in childhood, but in some cases the disease may remain asymptomatic for many years. The exact prevalence and incidence of the disease are not known, but it is consider a rare disease, with a few hundred cases described worldwide. It can affect all ethnic groups and occur associated with various hereditary and non-hereditary disorders. The clinical presentation is quite variable, with melena and hematemesis being initial symptoms in 30%-70% of the cases. More rarely, they may present episodes of cholangitis. The disease has been classified into four types: portal hypertension, cholestasis / cholangitis, mixed and latent. Diagnosis begins with imaging tests, but the definition is made by the histopathological sample. So far, there is no specific therapy that can stop or reverse the pathological process. Currently, the therapeutic strategy is to treat the complications of the disease.

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Lucchesi, Amanda Natália, Lucas Langoni Cassettari, and César Tadeu Spadella. "Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans." Journal of Diabetes Research 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/494578.

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Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver.Methods. Thirty nondiabetic control rats (NC) and 30 untreated diabetic (UD) rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed.Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed.Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

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Milani, Luiz, Tuane Moura, Mirna Porto, Guilherme Blume, André Santos, Letícia Oliveira, and Rômulo Eloi. "Crotalaria spectabilis poisoning in a horse." Brazilian Journal of Veterinary Pathology 14, no. 2 (July 30, 2021): 111–16. http://dx.doi.org/10.24070/bjvp.1983-0246.v14i2p111-116.

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Plant poisoning is an important cause of death in horses and cattle in Brazil. Crotalaria sp. has stood out in this scenario due to its toxic potential caused by monocrotaline, a pyrrolizidine alkaloid found throughout the plant, mainly in seeds. Here is reported a case of Crotalaria spectabilis poisoning a horse. A horse consumed oats contaminated with Crotalaria spectabilis seed and presented clinical signs of toxicosis characterized by jaundice, progressive weight loss, hemoglobinuria, subcutaneous edema in the pectoral region and neurological symptoms typical of hepatic encephalopathy. In the serum evaluation, there was an increase in the activity of the enzymes alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and aspartate transaminase (AST), urea, creatinine and creatine phosphokinase (CPK). At necropsy, the main macroscopic findings were opaque and congested liver with capsular irregularity and accentuated the lobular pattern, trachea with foamy and pinkish fluid and congested and edematous pulmonary lobes. The main histopathological findings were hepatic fibrosis, periportal ductal hyperplasia, centrilobular necrosis, megalocytosis and binucleated hepatocytes. The brain parenchyma showed perivascular edema and Alzheimer type II astrocytes. Crotalaria sp. is among the main plants that cause acute or chronic mortality after exposure to the toxic compound in horses and farm animals.

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Pereira, Haydée Marina do Valle, Norma de Paula Cavalheiro, Fátima Mitiko Tengan, Carlos Eduardo Melo, Evandro Sobroza Mello, and Antônio Alci Barone. "Patients with chronic hepatitis C and normal transaminases." Revista do Instituto de Medicina Tropical de São Paulo 47, no. 5 (October 2005): 247–51. http://dx.doi.org/10.1590/s0036-46652005000500002.

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Hepatitis C virus infection evolves progressively persisting in the majority of patients (85%). Most patients have high ALT (alanine aminotransferase) levels and approximately 25% normal ALT. The latter are usually female and there is no association between genotype and severity of hepatic lesion. Histologic analysis usually shows small lesion and absence or low amount of fibrosis, despite cirrhosis having been reported. Aiming at assessing prevalence, demographic, genotypical and anatomopathological characteristics in patients with normal ALT levels, we have carried out a study of 68 chronic hepatitis C patients between January 1997 and April 2000. There was a prevalence of 13.8% chronic hepatitis C patients with normal ALT levels, 45.6% of which were male and 54.4% female, the mean age being 38 +/- 13 years. We found a predominance of genotype 1 in 84.7% of the patients, genotype 2 in 6.8% and genotype 3 in 10.7%. In 52.9% of the cases liver biopsies revealed liver reaction, periportal activity score 0-1 was observed in 85.3% of the patients and score 2-4 was seen in 14.7%. Structural activity score 0-1 was seen in 73.5% of the patients and score 2-4 in 26.5% of them. Periportal activity > 2 and structural activity > 1 was seen in 29%, but steatosis was not seen in 73.5%. Our results suggest the need to revisit for liver biopsy practice in patients with Chronic Hepatitis C and normal transaminases.

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Ramm, G. A., S. C. Li, L. Li, R. S. Britton, R. O'Neill, Y. Kobayashi, and B. R. Bacon. "Chronic iron overload causes activation of rat lipocytes in vivo." American Journal of Physiology-Gastrointestinal and Liver Physiology 268, no. 3 (March 1, 1995): G451—G458. http://dx.doi.org/10.1152/ajpgi.1995.268.3.g451.

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Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.

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Eboumbou Moukoko, Carole, Nasureldin El Wali, O. K. Saeed, Qurashi Mohamed-Ali, Jean Gaudart, Alain J. Dessein, and Christophe Chevillard. "No Evidence for a Major Effect of Tumor Necrosis Factor Alpha Gene Polymorphisms in Periportal Fibrosis Caused by Schistosoma mansoni Infection." Infection and Immunity 71, no. 10 (October 2003): 5456–60. http://dx.doi.org/10.1128/iai.71.10.5456-5460.2003.

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ABSTRACT Hepatic periportal fibrosis (PPF), associated with portal hypertension, is a major pathological consequence of infections with Schistosoma mansoni and Schistosoma japonicum. Indeed, affected subjects may die from portal hypertension. Previous studies have indicated that tumor necrosis factor alpha (TNF-α) may aggravate fibrosis. We therefore investigated whether PPF was associated with certain polymorphisms of the TNF-α gene. Four polymorphisms (TNF-α −376 G/A, −308 G/A, −238 G/A, and +488 G/A) were investigated in two Sudanese populations living in an area in which S. mansoni is endemic. These polymorphisms were analyzed for 105 Sudanese subjects with various grades of PPF, from mild to advanced; all subjects were from two neighboring villages (Taweela and Umzukra). They were then analyzed for 70 subjects with advanced liver disease and for 345 matched controls from the Gezira region. We found no evidence of associations between these four polymorphisms and PPF in both of these studies. Thus, these four polymorphisms, two of which (TNF-α −376 and −308) were found to increase TNF-α gene transcription, are unlikely to have a major effect on PPF progression in these populations. However, this result does not exclude the possibility that these polymorphisms have a minor effect on PPF development.

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Ederli, N. B., I. de Oliveira, C. Demarque, S. S. Mello Gallo, H. J. Leandro, L. S. da Silveira, and F. C. R. de Oliveira. "First report of Athesmia foxi Goldberger and Crane, 1911 (Digenea, Dicrocoeliidae) from Chrysocyon brachyurus (Illiger, 1815) (Carnivora, Canidae) and pathological findings." Helminthologia 55, no. 3 (September 1, 2018): 240–46. http://dx.doi.org/10.2478/helm-2018-0017.

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Summary Chrysocyon brachyurus, the largest South American canid, is a native species of the Brazilian cerrado. The present study is aimed to report the occurrence of the trematode, Athesmia foxi, in the liver of a new host, C. brachyurus, and to describe its morphology and pathology. One C. brachyurus individual was necropsied and examined for the presence of parasites. Worms were collected from the bile ducts and based on morphological and morphometrical characteristics, such as a relatively large, slender, aspinose, elongated shape with vitellarium present on the upper left side of the body were identified as A. foxi. On the host, hepatic lesions limited to the bile ducts and periportal regions, were characterized as chronic-active cholangitis, biliary hyperplasia, and fibrosis. This is the first report of A. foxi parasitizing C. brachyurus, demonstrating that this parasite has no host specificity and can be widely distributed. A. foxi lesions noted in C. brachyurus are similar to those noted in various other mammalian hosts.

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Marinho, Carolina Coimbra, Aline Joice Pereira Gonçalves Nicolato, Vivian Walter Reis, Rosiane Cristina dos Santos, Jaime Costa Silva, Henrique Pereira Faria, and George Luiz Lins Machado-Coelho. "Ultrasound evaluation of schistosomiasis-related morbidity among the Xakriabá people in the state of Minas Gerais, Brazil." Radiologia Brasileira 53, no. 1 (February 2020): 7–13. http://dx.doi.org/10.1590/0100-3984.2019.0047.

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Abstract Objective: To use ultrasound to investigate the morbidity related to schistosomiasis in the Xakriabá indigenous population. Materials and Methods: This was a field-based census study conducted in the territory of the Xakriabá people. A total of 166 individuals were invited, and 148 (≤ 77 years of age) agreed to participate. Most participants underwent abdominal ultrasound, physical examination, and stool examination. Mann-Whitney U and chi-square tests were used for comparisons. We determined risk by calculating odds ratio (OR) and performed logistic regression analysis. Results: Schistosoma mansoni eggs were found in 31 (26.7%) of the 116 stool samples examined, 22 (70.9%) of the 31 being from individuals 4-16 years of age. The median count was 144 eggs/g of feces (interquartile range, 264). Of the 105 participants examined with ultrasound, 68 (64.8%) had hepatomegaly (left lobe), 6 (5.7%) had splenomegaly, and 4 (3.8%) had portal hypertension. Egg-positive stool samples were more common in those with an enlarged left lobe (OR = 3.4; 95% confidence interval (CI): 1.1-11.2; p = 0.043). Periportal fibrosis was found in 30 participants (28.6%), of whom 9 (30%) had pattern C, 10 (33.3%) had pattern D, and 11 (36.7%) had pattern Dc. Age was the only independent risk factor for fibrosis (p = 0.007). Fibrosis was up to nine-fold more common in alcohol drinkers than in nondrinkers (OR = 9.28; 95% CI: 2.60-33.06; p < 0.001). Among the 138 participants in whom the clinical form was classified, the chronic hepatic form was identified in 54 (39.1%), of whom 32 (59.2%) were under 30 years of age and one (1.8%) was hepatosplenic. Conclusion: Schistosomiasis in the Xakriabá population is characterized by a high frequency of egg-positive stool samples, predominantly in children/adolescents, and by chronic hepatic form in the young, especially among alcohol drinkers.

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Ravikanth, Reddy, DenverSteven Pinto, and Pooja Majumdar. "Extensive periportal fibrosis due to hepatic iron overload masquerading as mass lesions in a beta-thalassemia major patient: Sonological appearances." Apollo Medicine 17, no. 2 (2020): 124. http://dx.doi.org/10.4103/am.am_35_20.

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Elhakeim, Suzan, Sami Madani, and Sarra Hussein. "Studying the left hepatic lobe(lt lobe) sonographic morphometry in bilharzial periportal fibrosis(ppf). Is the it lobe enlargement exaggerated?" Ultrasound in Medicine & Biology 45 (2019): S90. http://dx.doi.org/10.1016/j.ultrasmedbio.2019.07.300.

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McDyre, B. Claire, Mohamed Diwan M. AbdulHameed, Matthew G. Permenter, William E. Dennis, Christine E. Baer, Jason M. Koontz, Molly H. Boyle, Anders Wallqvist, John A. Lewis, and Danielle L. Ippolito. "Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats." Toxicologic Pathology 46, no. 2 (January 29, 2018): 202–23. http://dx.doi.org/10.1177/0192623317747549.

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The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4′-methylenedianiline (4,4′-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4′-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4′-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.

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Maida, Ivana, Pilar Garcia-Gasco, Giovanni Sotgiu, María José Rios, María Eugenia Vispo, Luz Martin-Carbonero, Pablo Barreiro, et al. "Antiretroviral-Associated Portal Hypertension: A New Clinical Condition? Prevalence, Predictors and Outcome." Antiviral Therapy 13, no. 1 (January 2008): 103–8. http://dx.doi.org/10.1177/135965350801300111.

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Background Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddI) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddI removal. Methods From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified. Results Thirty-two individuals (prevalence ∼1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddI for a median of 44 months; removal of ddI in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan®. Conclusions Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddI seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.

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Araújo, Rebekah Rank, Rayane Chitolina Pupin, Renata Cunha Madureira, Luiz Gustavo de Morais, Lucas De Souza Quevedo, Ricardo Antônio Amaral de Lemos, Ana Lúcia Schild, Edson Moleta Colodel, and Márcio Botelho de Castro. "Characterization and Frequency of Histological Changes in Bovine Livers from Slaughterhouses in Brazil kept on Brachiaria spp." Acta Scientiae Veterinariae 45, no. 1 (April 19, 2017): 9. http://dx.doi.org/10.22456/1679-9216.79385.

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Background: Brachiaria spp. is the main pasture for ruminant productions in Brazil, but the limiting factor for its use is the toxicity due to the presence of steroidal saponins. Chronic ingestion of Brachiaria spp. by cattle may cause liver changes such as fibrosis, bile duct proliferation and clusters of foamy macrophages in the hepatic parenchyma. The main objective of the present study was to evaluate the most frequent histological changes and their frequencies in livers collected in abattoirs in Brazil from beef cattle raised exclusively on Brachiaria spp. and compare them with those observed in animals kept in Andropogon spp. grass and native pastures in Rio Grande do Sul.Materials, Methods & Results: Liver samples without macroscopic changes were collected in abattoirs from 561 healthy Nelore and Nelore crossbred cattle raised in Brachiaria spp. pastures from Mato Grosso (MT), Mato Grosso do Sul (MS), Minas Gerais (MG) and Pará (PA) States. Liver samples from 84 Angus cattle (Bos taurus) kept on native pastures in Rio Grande do Sul (RS) and from 60 Nelore and Nelore crossbreed cattle raised in Andropogon spp. pastures in Tocantins State (TO) were collected as control. Semi-quantitative analysis of the histopathological changes were proceeded: (-) = no change; (+) = slight or discreet change; (++) = moderate change and (+++) = marked change. The main histopathological changes evaluted in the liver samples were the presence of foamy macrophages and its location, parenchymal fibrosis and its location, proliferation of bile ducts, periportal mononuclear infiltrate, presence of crystals in macrophages and within the bile ducts. Foamy macrophages clusters in the liver parenchyma were the most frequent histological changes exclusively observed in samples of animals kept in Brachiaria spp. and it was more frequent in cattle from MS State (P < 0.0001). The periportal hepatic fibrosis was another relevant finding in cattle kept in Brachiaria spp. and was also more frequent in MS animals (P ≤ 0.0001), and was not present in control groups. Proliferation of the bile ducts rate was similar between animals raised in Brachiaria spp. (P > 0.05), though it was higher in cattle kept on native pasture in RS (P < 0.0001). The mononuclear periportal inflammatory infiltrate was more frequent in MS and MG samples than in MT and PA (P < 0.0002).Discussion: The most significant histopathological changes observed in liver samples of cattle from the states of MT, MS, PA and MG kept in Brachiaria spp. pastures from the birth to slaughter, was the presence of foamy macrophages in quantities and variables distribution showing the strengthen association between clusters of foamy macrophages in the liver parenchyma and grazing on this grass. These macrophages could be found in healthy animals kept in Brachiaria spp. pastures and in intoxicated animals. This change was considered frequent and characteristic in animals kept in pastures containing steroidal lithogenic saponins in its composition, and it was frequently observed in ruminants that growed in Brachiaria spp. pastures. Beef cattle kept in Andropogon spp. grass pastures in the state of Tocantins and native pastures in Rio Grande do Sul did not showed foamy macrophages in liver samples. On the other hand, in susceptible sheep kept in Andropogon spp. grass pastures that contains low amount of lithogenic steroidal saponins, are insufficient to induce toxicity and morphological changes in the liver, including aggregates of foamy macrophages.

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Chedid, Antonio, Selma Arain, Ann Snyder, Philippe Mathurin, Frédérique Capron, and Sylvie Naveau. "The Immunology of Fibrogenesis in Alcoholic Liver Disease." Archives of Pathology & Laboratory Medicine 128, no. 11 (November 1, 2004): 1230–38. http://dx.doi.org/10.5858/2004-128-1230-tiofia.

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Abstract Context.—Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic fibrogenesis are available, but extrapolation of those findings to human ethanol-induced liver injury is difficult. Hepatic ethanol-induced fibrosis in humans has often been studied in relatively small patient populations. During the past decade, several animal models and human studies have attributed fibrogenesis in the liver to the role played by hepatocytes, Kupffer cells, endothelial cells, and especially stellate cells. Objective.—To determine the contribution of the main liver cell types to ethanol-induced fibrogenesis. For that purpose, we studied the expression of the following immunologic parameters: smooth muscle–specific α actin (SMSA), CD68, CD34, transforming growth factor β1, intercellular adhesion molecule 1, and collagen types 1 and 3. The Dako LSAB+ kit (peroxidase method) was used. Design.—We recently studied a large cohort of patients with alcoholic liver disease in France. In this cohort, we found 87 cases in which liver biopsies revealed only pericentral injury with nonpathologic portal areas. We compared cases in which the portal areas were nonpathologic with 324 patients in whom staging ranged from F0 to F3. Patients with cirrhosis (F4) were excluded from evaluation. To stage fibrosis, we used the METAVIR system. Furthermore, we selected 40 cases in which the biopsies measured at least 25 mm in length for further histochemical evaluation. Ten additional normal cases from our archives were used as controls. We divided this patient population into the following 5 groups of 10 patients each: group 1A, F0 with steatosis; group 1B, F0 without steatosis; group 2, F0 to F1, central injury; group 3, F3, fibrosis with multiple septa; and group 4, nonpathologic livers (controls). Results.—Smooth muscle–specific α actin was expressed by stellate cells, pericentrally, with increasing severity and intensity in the advanced stage of fibrosis of group 3, less intense expression was noted in group 2, and expression was practically absent in group 1 and in nonpathologic controls. CD68 was the best marker for Kupffer cells and was expressed diffusely within the lobules in all groups. Its expression correlated directly with the degree of disease severity, progressing from stage I through stage III, but was absent in nonpathologic livers. CD34 was consistently expressed by endothelial cells in the periportal areas in all groups. The expression of collagen type 1 was intense in the bands of fibrosis or bridging, while type 3 expression was poor. Transforming growth factor β1 and intercellular adhesion molecule 1 were not expressed in any group. Conclusions.—In this study, stellate cell activation (SMSA) was most intense pericentrally in the early stages and diffusely with progression to fibrosis and maximum intensity in stage III. Kupffer cell activation, as determined by CD68 expression, was intense and diffuse, while endothelial cells expressed CD34 periportally in a similar manner in all stages. Fibrogenesis in human ethanol injury is due to the activity of stellate cells, Kupffer cells, and to a lesser extent, to endothelial cells.

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Unrau, Ludmilla, Jessica Endig, Diane Goltz, Paulina Sprezyna, Hanna Ulrich, Julia Hagenstein, Bernd Geers, et al. "Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl4 Exposure in Mice." International Journal of Molecular Sciences 22, no. 21 (October 27, 2021): 11575. http://dx.doi.org/10.3390/ijms222111575.

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Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction and progression. TGF-β signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-β-signalling pathway, rendering cells that express high levels of it resistant to TGF-β-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl4)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smadfl/fl mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl4 induces severe liver injury, with elevated serum alanine transaminase (ALT)/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl4-treated animals. In summary, our results suggest that, during long-term application of CCl4, Smad7 expression in myeloid cells and its potential effects on the TGF-β-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.

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Vogel, Erika, Jeffrey D. Lebensburger, Shuting Bai, Naomi Fineberg, Lee Hilliard, Naren Vadlamudi, Reed Dimmit, David Kelly, and Thomas H. Howard. "Liver Histology, Liver Iron Concentration (LIC), and Serum Ferritin in a Large Cohort of Chronically Transfused Children with Sickle Cell Anemia: Limitations of LIC As a Marker for Hepatic Injury and Ferritin as An Indicator for Chelation Initiation." Blood 118, no. 21 (November 18, 2011): 2142. http://dx.doi.org/10.1182/blood.v118.21.2142.2142.

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Abstract Abstract 2142 Chronic blood transfusion therapy reduces clinical events and prevents recurrent brain injury in children with sickle cell anemia. The benefit of administering chronic transfusion is weighed against the risk of an increased iron burden leading to chronic organ injury. The gold standard technique for evaluating the adverse effect of iron is to perform a liver biopsy for quantification of hepatic iron content and evaluation of liver pathology. Surrogate evaluations for iron overload include monitoring liver enzymes, serum ferritin and performing r2* MRI of the liver. In order to evaluate the role for utilizing surrogate markers to monitor liver injury, we conducted a retrospective review of 262 liver biopsies in 109 children with sickle cell anemia on chronic transfusion therapy over a nine year period at a single center. Ninety one patients had HbSS, 17 had HbSB0 thalassemia, and one patient had HbSD. Chronic transfusion therapy was performed by either simple transfusion (65%) or erythrocytapheresis (35%) primarily for stroke prevention (n=236), with a few for other indications (n=26) including lung injury and acute vascular necrosis. Patients were initiated on chronic transfusion at a mean age of 6.2 ± 3.6 yrs (0.75–17yrs) with initial biopsy obtained at a mean age of 14.6 ± 5.3 yrs (3–34 yrs). Chelation with deferoxamine or deferasirox was determined by the physician with a practice standard of initiation of chelation once ferritin increased to > 1000ng/mL. All patients at the time of liver biopsy were treated with chelation therapy with either deferoxamine (30%) or deferasirox (70%). Two pathologists reviewed the biopsies and utilized a standardized hepatic scoring system to evaluate the degree of portal/periportal and lobular inflammation and hepatic fibrosis (0= none, 1= mild, 2= moderate, 3= severe). Portal/periportal inflammation was scored 0–3 respectively in 132, 89, 38, and 0 patients and lobular inflammation in 29, 226, 4, and 0 patients. Fibrosis was scored 0–3 respectively in 23, 107, 103, and 26 patients. Ferritin and ALT were recorded prior (median of 3 days) to the liver biopsy. Seven biopsies performed as part of a therapeutic clinical trial were excluded from this analysis. Results show that the mean (± SD) serum ferritin, liver iron concentration (LIC), and ALT were 3509 ± 2617ng/mL, 17.12 ± 13.0 mg Fe/gm dry weight, and 40.2 ± 40.2 IU/L. With respect to histology, ferritin and LIC levels were significantly increased with higher periportal inflammation score (F= 21, p<0.001. F= 20, p<0.001) and severe fibrosis (score 3) (F=36, p<0.001, F=10.4, p<0.001), but not for lower fibrosis scores (0–2), or lobular inflammation score (p=0.20). Despite this significant histologic correlation with surrogate markers, individual overlap exists between ferritin, LIC and liver pathology. A strong linear correlation exists between ferritin and LIC (r=0.74, p<0.001) but with a spread in LIC (R2=55%). With respect to ferritin as a predictor of LIC, all patients with ferritin >1000ng/mL, a standard value for initiation of chelation therapy, had abnormally high LICs, and surprisingly 11 patients were identified with an abnormal LIC despite a ferritin <1000ng/ml. Furthermore, patients with a high LIC (≥ 7 mg Fe/gm dry weight) demonstrate a significantly higher ferritin as compared to patients with lower LIC< 7 (p<0.001) and this positive relationship between LIC and ferritin was replicated in a population with a higher LIC (LIC ≥ 30mg Fe/g dry weight vs. <30) (p<0.001). ROC curves demonstrate an AUC of.88 ± 0.02 (p<0.001) utilizing a LIC of ≥7 or <7 and 0.91± 0.02 (p<0.001) utilizing a LIC of ≥30 or <30. A weak association was noted between ferritin and alanine aminotransferase (ALT) (r=0.27, p<0.001, R2=8%). The results show that although strong statistical correlations exist between liver histology and ferritin or LIC, variability exists. Additionally, a ferritin >1000ng/mL always predicts abnormal LIC, but is inadequate as an indicator for initiation of chelation. The results suggest caution when using surrogate markers alone to predict histological changes in the liver and to initiate chelation therapy in individual patients on chronic blood transfusion therapy. Disclosures: Lebensburger: University of Alabama at Birmingham: Employment.

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Airik, Merlin, Markus Schüler, Blake McCourt, Anna-Carina Weiss, Nathan Herdman, Timo H. Lüdtke, Eugen Widmeier, et al. "Loss of Anks6 leads to YAP deficiency and liver abnormalities." Human Molecular Genetics 29, no. 18 (September 4, 2020): 3064–80. http://dx.doi.org/10.1093/hmg/ddaa197.

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Abstract ANKS6 is a ciliary protein that localizes to the proximal compartment of the primary cilium, where it regulates signaling. Mutations in the ANKS6 gene cause multiorgan ciliopathies in humans, which include laterality defects of the visceral organs, renal cysts as part of nephronophthisis and congenital hepatic fibrosis (CHF) in the liver. Although CHF together with liver ductal plate malformations are common features of several human ciliopathy syndromes, including nephronophthisis-related ciliopathies, the mechanism by which mutations in ciliary genes lead to bile duct developmental abnormalities is not understood. Here, we generated a knockout mouse model of Anks6 and show that ANKS6 function is required for bile duct morphogenesis and cholangiocyte differentiation. The loss of Anks6 causes ciliary abnormalities, ductal plate remodeling defects and periportal fibrosis in the liver. Our expression studies and biochemical analyses show that biliary abnormalities in Anks6-deficient livers result from the dysregulation of YAP transcriptional activity in the bile duct-lining epithelial cells. Mechanistically, our studies suggest, that ANKS6 antagonizes Hippo signaling in the liver during bile duct development by binding to Hippo pathway effector proteins YAP1, TAZ and TEAD4 and promoting their transcriptional activity. Together, this study reveals a novel function for ANKS6 in regulating Hippo signaling during organogenesis and provides mechanistic insights into the regulatory network controlling bile duct differentiation and morphogenesis during liver development.

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Journal articles on the topic 'Hepatic and Periportal fibrosis'

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