Dibutyl phthalate (DBP) promotes Epithelial-Mesenchymal Transition (EMT) to aggravate liver fibrosis into cirrhosis and portal hypertension (PHT) via ROS/TGF-ß1/Snail-1 signalling pathway in adult rats.

OBJECTIVE: The primary objective of this study was to investigate the toxicological impact of Dibutyl phthalate (DBP) on the process of liver fibrosis transitioning into cirrhosis and the subsequent development of portal hypertension (PHT) through the mechanism of epithelial-mesenchymal transition (EMT) mediated by the ROS/TGF-ß/Snail-1 signaling pathway. METHOD: Carbon tetrachloride (CCl4) (1 mg/kg) was introduced in adult rats by oral feeding in CCl4 and CCl4+DBP groups twice a week for 8 weeks, and twice for another 8 week in CCl4 group. DBP was introduced by oral feeding in the CCl4+DBP group twice over the following 8 weeks. We subsequently analyzed hemodynamics measurements and liver cirrhosis degree, hepatic inflammation and liver function in the different groups. EMT related genes expression in rats in the groups of Control, DBP, CCl4 and CCl4+DBP were measured by immunohistochemistry (IHC). Enzyme-linked immunosorbent Assay (ELISA), qRT-PCR, western blot were used to detect the EMT related proteins and mRNA gene expression levels in rats and primary hepatocytes (PHCs). Reactive oxygen species (ROS) were examined with a ROS detection kit. RESULTS: The results showed that the CCl4+DBP group had higher portal pressure (PP) and lower mean arterial pressure (MAP) than the other groups. Elevated collagen deposition, profibrotic factor, inflammation, EMT levels were detected in DBP and CCl4+DBP groups. ROS, TGF-ß1 and Snail-1 were highly expressed after DBP exposure in vitro. TGF-ß1 had the potential to regulate Snail-1, and both of them were subject to regulation by ROS. CONCLUSION: DBP could influence the progression of EMT through its toxicological effect by ROS/TGF-ß1/Snail-1 signalling pathway, causing cirrhosis and PHT in final. The findings of this research might contribute to a novel comprehension of the underlying toxicological mechanisms and animal model involved in the progression of cirrhosis and PHT, and potentially offered a promising therapeutic target for the treatment of the disease.

Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension.

IMPORTANCE: Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.

[The development of portal hypertension and liver failure on the background of long-term intake of vitamin A in a young woman. Case report].

The use of over-the-Counter (OTC) pharmaceuticals is a common phenomenon in today's society. We present a case of liver injury associated with long-term OTC use of vitamin A. The young patient took daily up to 15 capsules of a combined preparation for 2 years containing retinol palmitate 55 mg (100,000 IU) + Alpha-Tocopherol acetate 100 mg, the content of vitamin A in which significantly exceeded the recommended daily dose. Gradually, the patient noted the appearance of arthralgia, skin itching, hyperemia of the palms and feet, exfoliation of the skin on the soles, profuse hair loss, cracks in the corners of the mouth and in the area of the earlobes. Patient's condition worsened with the development of signs of liver cirrhosis in the form of portal hypertension (ascites, splenomegaly) and a decrease in the protein-synthetic function of the organ. Chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson's disease, alcoholic liver disease were exclude. Liver biopsy showed characteristic signs of hypervitaminosis A without fibrosis. A complete regression of symptoms was observe within 8 months after discontinuation of the drug. A toxicity can lead to serious liver injury and should be considere in the differential diagnosis of chronic liver disease. Vitamin A should only be prescribe for medical reasons, for a limited period of time, and under close medical supervision.

Isolated gastric variceal bleeding related to non-cirrhotic portal hypertension following oxaliplatin-based chemotherapy: A case report.

BACKGROUND: Sinusoidal obstruction syndrome has been reported after oxaliplatin-based chemotherapy, but liver fibrosis and non-cirrhotic portal hypertension (NCPH) are rarely reported. CASE SUMMARY: Here, we describe the case of a 64-year-old woman who developed isolated gastric variceal bleeding 16 mo after completing eight cycles of oxaliplatin combined with capecitabine chemotherapy after colon cancer resection. Surprisingly, splenomegaly and thrombocytopenia were not accompanied by variceal bleeding, which has been reported to have predictive value for gastric variceal formation. However, a liver biopsy showed fibrosis in the portal area, suggesting NCPH. The patient underwent endoscopic treatment and experienced no further symptoms. CONCLUSION: It is necessary to guard against long-term complications after oxaliplatin-based chemotherapy. Sometimes splenic size and platelet level may not always accurately predict the occurrence of portal hypertension.

Noncirrhotic Portal Hypertension after Trastuzumab Emtansine in HER2-positive Breast Cancer as Determined by Deep Learning-measured Spleen Volume at CT.

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.

Long-term survival and clinical outcomes following direct-acting antiviral (DAA) treatment in HCV decompensated cirrhosis in Brazil: a real-world study.

INTRODUCTION: The outcomes regarding portal hypertension-related complications and infections after HCV cure in decompensated cirrhosis are scarcely reported. We aimed to identify the predictors of survival and to evaluate the frequency of decompensation events of cirrhosis, including hepatocellular carcinoma (HCC), portal hypertension complications and infections in a cohort of decompensated cirrhotic with sustained virological response (SVR) in a real-world scenario. PATIENTS AND METHODS: This was a prospective study in consecutive HCV-infected patients with decompensated cirrhosis who achieved SVR after direct-acting antiviral (DAA) treatment. At baseline, clinical and laboratory data were recorded. Patients were followed until development of outcomes regarding further decompensation, death, or liver transplant. A Cox-regression analysis was performed and survival curves were constructed using the Kaplan Mayer method. RESULTS: One hundred and thirty patients (age 60 ± 9 years, 64% female, 70% genotype 1) were included and followed-up through three years. SVR was associated with a lower prevalence of ascites and an improvement in Child-Pugh and MELD scores. One and three-year probability of transplant-free survival was 93% and 66%, respectively. Variables related to three-years survival were MELD < 11 (HR 1.24, 95% CI 1.13-1.37) and absence of ascites (HR 2.03, 95% CI 0.99-4.13) after the end of treatment (91% versus 37% in patients with ascites and a higher MELD, p < 0.001). CONCLUSIONS: Decompensated cirrhotics with SVR and a low MELD without ascites have an excellent long-term prognosis. On the contrary, those with higher MELD and ascites have a low probability of survival even in the short term and might be evaluated for liver transplantation.

Oxaliplatin-related Portal Hypertension Complicated with Esophageal Varices and Refractory Massive Ascites.

Oxaliplatin, widely used as a chemotherapy drug for colorectal cancer, is known to cause various adverse reactions. In particular, special attention for the development of portal hypertension associated with porto-sinusoidal vascular disease is necessary, as it is a serious adverse life-threating reaction, although rare. We herein report a case of oxaliplatin-related portal hypertension that developed several years after oxaliplatin administration and led to esophageal varices and refractory massive ascites. Clinical physicians should be aware of the possibility of oxaliplatin-induced portal hypertension and its possible development over a long period after discontinuation of the drug.

Impact of lifestyle interventions targeting physical exercise and caloric intake on cirrhosis regression in rats.

In patients, advanced cirrhosis only regresses partially once the etiological agent is withdrawn. Animal models for advanced cirrhosis regression are missing. Lifestyle interventions (LIs) have been shown to improve steatosis, inflammation, fibrosis, and portal pressure (PP) in liver disease. We aimed at characterizing cirrhosis regression after etiological agent removal in experimental models of advanced cirrhosis and to study the impact of different LI on it. Advanced cirrhosis was induced in rats either by carbon tetrachloride (CCl4) or by thioacetamide (TAA) administration. Systemic and hepatic hemodynamics, liver fibrosis, hepatic stellate cell (HSC) activation, hepatic macrophage infiltration, and metabolic profile were evaluated after 48 h, 4 wk or 8 wk of etiological agent removal. The impact of LI consisting in caloric restriction (CR) or moderate endurance exercise (MEE) during the 8-wk regression process was analyzed. The effect of MEE was also evaluated in early cirrhotic and in healthy rats. A significant reduction in portal pressure (PP), liver fibrosis, and HSC activation was observed during regression. However, these parameters remained above those in healthy animals. During regression, animals markedly worsened their metabolic profile. CR although preventing those metabolic disturbances did not further reduce PP, hepatic fibrosis, or HSC activation. MEE also prevented metabolic disturbances, without enhancing, but even attenuating the reduction of PP, hepatic fibrosis, and HSC activation achieved by regression. MEE also worsened hepatic fibrosis in early-TAA cirrhosis and in healthy rats.NEW & NOTEWORTHY We have developed two advanced cirrhosis regression experimental models with persistent relevant fibrosis and portal hypertension and an associated deteriorated metabolism that mimic what happens in patients. LI, despite improving metabolism, did not enhance the regression process in our cirrhotic models. CR did not further reduce PP, hepatic fibrosis, or HSC activation. MEE exhibited a profibrogenic effect in the liver blunting cirrhosis regression. One of the potential explanations of this worsening could be ammonia accumulation.

Assessment of a biofluid mechanics-based model for calculating portal pressure in canines.

BACKGROUND: Portal hypertension is a severe complication caused by various chronic liver diseases. The standard methods for detecting portal hypertension (hepatic venous pressure gradient and free portal pressure) are available in only a few hospitals due to their technical difficulty and invasiveness; thus, non-invasive measuring methods are needed. This study aimed to establish and assess a novel model to calculate free portal pressure based on biofluid mechanics. RESULT: Comparison of each dog's virtual and actual free portal pressure showed that a biofluid mechanics-based model could accurately predict free portal pressure (mean difference: -0.220, 95% CI: - 0.738 to 0.298; upper limit of agreement: 2.24, 95% CI: 1.34 to 3.14; lower limit of agreement: -2.68, 95% CI: - 3.58 to - 1.78; intraclass correlation coefficient: 0.98, 95% CI: 0.96 to 0.99; concordance correlation coefficient: 0.97, 95% CI: 0.93 to 0.99) and had a high AUC (0.984, 95% CI: 0.834 to 1.000), sensitivity (92.3, 95% CI: 64.0 to 99.8), specificity (91.7, 95% CI: 61.5 to 99.8), positive likelihood ratio (11.1, 95% CI: 1.7 to 72.8), and low negative likelihood ratio (0.08, 95% CI: 0.01 to 0.6) for detecting portal hypertension. CONCLUSIONS: Our study suggests that the biofluid mechanics-based model was able to accurately predict free portal pressure and detect portal hypertension in canines. With further research and validation, this model might be applicable for calculating human portal pressure, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy.

Surgical intervention for portal hypertension caused by oxaliplatin-based chemotherapy: a case report and a review of literature regarding radiological and/or surgical interventions for oxaliplatin-associated portal hypertension.

A 63-year-old man showed massive ascites, massive pleural effusion, severe lower-extremity edema, and repeated esophageal variceal bleeding. Two-year previously, he received 13-courses of oxaliplatin-based chemotherapy (OBC) followed by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for multiple colorectal cancer liver metastases but developed a solitary remaining liver metastasis and multiple lung metastases 2 months after the ALPPS, for which multiple regimens of chemotherapy were conducted. The symptoms were considered attributable to the OBC-associated portal-hypertension. Water-retention symptoms were mitigated by the use of tolvaptan but the variceal bleeding necessitated frequent endoscopic treatments and disallowed restarting antineoplastic treatment. Transjugular intrahepatic portosystemic shunt (TIPS) was considered undesirable because TIPS in this patient might have prohibited future repeat hepatectomy. Thus, the patient underwent splenectomy and surgical portosystemic shunting. Since then, the portal-hypertension symptoms were completely resolved. Thereafter, chemotherapy was able to be recommenced. Moreover, repeat hepatectomy was performed. A literature review demonstrated that radiological and/or surgical interventions for the OBC-associated portal-hypertension have been reported in 31 cases to date. However, this report is the first to show a case of successful treatment of the OBC-associated portal-hypertension with splenectomy and surgical portosystemic shunting, which allowed subsequent chemotherapy followed by repeat hepatectomy.

Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats.

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-ß1 (TGF-ß1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1ß (IL1ß) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1ß and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin-angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

The effects of hepatic steatosis on thromboxane A2 induced portal hypertension / Efectos de la esteatosis hepática en la hipertensión portal inducida por tromboxano A2

Introduction and aim: Thromboxane (TX) A2 was identified as an important vasoconstrictor during Zymosan induced portal perfusion pressure (PP) increase. We aimed at investigating whether hepatic steatosis influences the extent of TXA2-induced portal hypertension. Materials and methods: Sprague-Dawley rats were randomly divided into control and steatosis (induced by the special diet) groups. PP and TXB2 (stable degradation product of TXA2) in the perfusate were measured after in situ liver perfusion with Zymosan (150μg/ml, 40-46min) or U46619 (TXA2 analog, 0.1μM/ml, 40-46min). The number of Kupffer cell (KC) was measured by immunohistochemistry with CD163. Results: Zymosan induced more TXB2 production and a higher PP increase in control group than in steatosis group despite more CD163 positive KCs in fatty livers. PP and TXB2 efflux revealed a strong correlation in control group and a moderate correlation in steatosis group. Contrary to the effect of Zymosan, U46619 induced a much higher PP increase in steatosis group than in control group. Conclusion: Severe steatosis increased number of KCs, however, PP increase and TXB2 efflux caused by Zymosan infusion in fatty livers were lower than those in healthy livers. In contrast, TXA2 analog caused higher PP increase in fatty livers. Targeting the more sensitive response to TXA2 in fatty livers might be a potential therapy of severe steatosis

Introducción y objetivos: Se ha identificado al tromboxano (TX) A2 como importante vasoconstrictor durante el aumento de la presión de perfusión portal (PP) inducida por zymosan. El objetivo ha sido analizar si la esteatosis hepática influye en el grado de hipertensión portal inducida por TXA2. Materiales y métodos: Las ratas Sprague-Dawley(R) se han dividido aleatoriamente en grupos de control y esteatosis (inducida por una dieta especial). Se midieron la PP y el TXB2 (producto de degradación estable de TXA2) en la perfusión después de la perfusión hepática in situ de zymosan (150μg/ml, minuto 40-46) o U46619 (análogo de TXA2, 0,1μM/ml, minuto 40-46). El número de células de Kupffer (CK) se midió mediante inmunohistoquímica con CD163. Resultados: Zymosan provocó más producción de TXB2 y mayor aumento de la PP en el grupo de control que en el grupo de esteatosis a pesar de hallar más CK positivas para CD163 en hígados grasos. El flujo de salida de la PP y el TXB2 reveló una fuerte correlación en el grupo de control y una correlación moderada en el grupo de esteatosis. De manera diferente al efecto de zymosan, U46619 indujo un aumento de la PP mucho mayor en el grupo de esteatosis que en el grupo de control. Conclusión: La esteatosis grave aumentó el número de CK; sin embargo, el aumento de la PP y el flujo de TXB2 provocado por la perfusión de zymosan en hígados grasos fueron menores que en los hígados sanos. En cambio, el análogo de TXA2 provocó un aumento de la PP en hígados grasos. Centrarse en la respuesta más sensible al TXA2 en hígados grasos podría convertirse en un tratamiento potencial de la esteatosis grave

Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats.

BACKGROUND: Portal hypertension (PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome. AIM: To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats. METHODS: Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride (CCl4) in both male and female integral and castrated rats (ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors. RESULTS: No significant difference in portal pressure was observed between integral and castrated male PHT rats (15.2 ± 2.1 mmHg vs 16.7 ± 2.7 mmHg, P > 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats (12.7 ± 2.7 mmHg vs 16.5 ± 2.4 mmHg, P < 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses (Emax) values were decreased and effective concentrations causing half maximum responses (EC50) values were increased, compared to those of non-PHT rats, both in male and female rats. Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased (P > 0.05). However, there was no difference between integral and ORX male rats with PHT. In integral female PHT rats, the concentration response curves were shifted to the left (P < 0.05), and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats. CONCLUSION: Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.

The effects of hepatic steatosis on thromboxane A2 induced portal hypertension.

INTRODUCTION AND AIM: Thromboxane (TX) A2 was identified as an important vasoconstrictor during Zymosan induced portal perfusion pressure (PP) increase. We aimed at investigating whether hepatic steatosis influences the extent of TXA2-induced portal hypertension. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into control and steatosis (induced by the special diet) groups. PP and TXB2 (stable degradation product of TXA2) in the perfusate were measured after in situ liver perfusion with Zymosan (150µg/ml, 40-46min) or U46619 (TXA2 analog, 0.1µM/ml, 40-46min). The number of Kupffer cell (KC) was measured by immunohistochemistry with CD163. RESULTS: Zymosan induced more TXB2 production and a higher PP increase in control group than in steatosis group despite more CD163 positive KCs in fatty livers. PP and TXB2 efflux revealed a strong correlation in control group and a moderate correlation in steatosis group. Contrary to the effect of Zymosan, U46619 induced a much higher PP increase in steatosis group than in control group. CONCLUSION: Severe steatosis increased number of KCs, however, PP increase and TXB2 efflux caused by Zymosan infusion in fatty livers were lower than those in healthy livers. In contrast, TXA2 analog caused higher PP increase in fatty livers. Targeting the more sensitive response to TXA2 in fatty livers might be a potential therapy of severe steatosis.

Carvedilol improves liver cirrhosis in rats by inhibiting hepatic stellate cell activation, proliferation, invasion and collagen synthesis.

Portal hypertension (PHT) is one of the most severe consequences of liver cirrhosis. Carvedilol is a first­line pharmacological treatment of PHT. However, the antifibrogenic effects of carvedilol on liver cirrhosis and the intrinsic mechanisms underlying these effects have not been thoroughly investigated. The present study aimed to investigate the antifibrogenic effects of carvedilol on liver cirrhosis in vivo and in vitro. Liver cirrhosis was induced in rats by carbon tetrachloride (CCl4) administration for 9 weeks; carvedilol was administered simultaneously in the experimental group. Blood samples were collected for serum biochemistry. Liver tissues were used for fibrosis evaluation, histological examination, immunohistochemistry and western blot analysis. The human hepatic stellate cell (HSC) line LX­2 was used for in vitro studies. The effects of carvedilol on LX­2 cell proliferation and invasion were evaluated by Cell Counting Kit­8 assay and Transwell invasion assays, respectively. The effect of carvedilol on transforming growth factor ß1 (TGFß1)­induced collagen synthesis in LX­2 cells and the molecular mechanisms were examined by western blot analysis. The results demonstrated that carvedilol improved CCl4­induced structural distortion and fibrosis in the liver. Carvedilol inhibited HSC activation, proliferation and invasion. Carvedilol inhibited HSC collagen synthesis through the TGFß1/SMAD pathway. In conclusion, carvedilol may alleviate liver cirrhosis in rats by inhibiting HSC activation, proliferation, invasion and collagen synthesis. Carvedilol may be a potential treatment of early­stage liver cirrhosis.

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.

Liver Cirrhosis From Chronic Hypervitaminosis A Resulting in Liver Transplantation: A Case Report.

Herein we report a case of liver dysfunction caused by consumption of vitamin A supplements leading to liver transplantation. The patient was a 48-year-old male with a medical history of congenital ichthyosiform erythroderma in treatment with vitamin A until 12 years of age, at which point he discontinued the supplements because he had developed ascites. Liver cirrhosis was diagnosed as secondary to hypervitaminosis A on the basis of histologic examination of liver biopsy and the absence of other potential causes of chronic liver disease. Despite interruption of administration of vitamin A, the patient continued to deteriorate over the years, with development of portal hypertension signs. His medical conditions were aggravated with the development of hepatic insufficiency manifested by refractory ascites, renal insufficiency, and severe encephalopathy and he underwent orthotopic liver transplantation, followed by disappearance of all signs of portal hypertension. This case highlights the need to take a careful history of consumption of vitamin A when evaluating a patient with liver failure.

Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats.

BACKGROUND: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

Animal models of portal hypertension.

Chronic liver diseases ultimately lead to cirrhosis and portal hypertension (PHT). Indeed, PHT is a major cause of severe complications, while medical treatment is limited to non-selective beta blockers. Sophisticated animal models are needed to investigate novel treatment options for different etiologies of liver disease, effective anti-fibrotic agents as well as vasoactive drugs against PHT. In this review, we present some of the most common animal models of liver disease and PHT - including pre-hepatic, intra-hepatic and post-hepatic PHT in rodents. Methodology for induction, considerations for disease etiology, advantages and limitations and practical issues of these animal models are discussed. The appropriate and sensible use of animal models in preclinical research supporting the 3R concept of replacement, reduction and refinement is highlighted.