Subacute Liver Injury Research Articles

PAT exposure caused human hepatocytes apoptosis and induced mice subacute liver injury by activating oxidative stress and the ERS-associated PERK pathway

With the widespread use of antimony compounds in synthetic materials and processing, the occupational exposure and environmental pollution caused by antimony have attracted the attention of researchers. Studies have shown that antimony compounds can cause liver damage, but the mechanism has not yet been elucidated. In this study, we used the trivalent potassium antimony tartrate (PAT) to infect L02 hepatocytes and Kunming (KM) mice to establish an antimony-induced apoptosis model of L02 cells and a subacute liver injury model of KM mice. We found that PAT exposure caused hepatocyte apoptosis and was accompanied by oxidative stress and endoplasmic reticulum stress (ERS), and the ERS-associated PERK pathway was activated. Further experimental results showed that N-acetyl-l-cysteine (NAC) pretreatment or silencing of the PERK gene in L02 cells reduced PAT-induced apoptosis. The activity of SOD and CAT in treated L02 cells was increased, the malondialdehyde content in L02 cells and liver tissues was decreased, and the content of ERS-related proteins GRP78 and CHOP, as well as the content of PERK-pathway-related proteins p-PERK/PERK, p-eif2α/eif2α and ATF4 protein were significantly reduced. Overall, PAT exposure triggered hepatocyte apoptosis and liver injury by inducing oxidative stress and activating the ERS-associated PERK pathway; however, this effect could be alleviated by NAC intervention or silencing of PERK in hepatocytes.

Inhibition of Macrophage Pyroptosis─A New Therapeutic Strategy to Alleviate T-2 Toxin-Induced Subacute Liver Injury by Directly Competing with the Key Target.

Multiple compounds are related to the development of liver injury, such as toxins, drugs, and environmental pollutants. Although there are reports that the T-2 toxin can cause liver injury, its toxic mechanism remains unclear, which further impedes the development of effective antidotes. In this study, CRISPR-Cas9 genome-wide screening technology was used to identify transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) as a toxic target of the T-2 toxin. Mechanism studies have shown that the T-2 toxin induced pyroptosis of macrophages (J774A.1 cells) by activating the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, leading to a subacute liver injury. Also, the new drug berberine (BER) identified through virtual screening significantly alleviated the subacute liver injury by competitively binding trp53inp1 via His224; the effect was better than those of the positive control drugs N-acetylcysteine (NAC) and disulfiram (DSF). In summary, the above results indicate that trp53inp1 is a key target for T-2 toxin to induce subacute liver injury and that inhibiting macrophage pyroptosis is a new method for treating liver injury. In addition, this study provides a new method and strategy for the discovery of key disease targets and the search for effective drugs.

Effects of drug-induced liver injury on the in vivo fate of liposomes

Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.

Role of HNF4α-cMyc Interaction in CDE Diet–Induced Liver Injury and Regeneration

Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role during liver regeneration. This study investigated the role of the HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. Wild-type (WT), hepatocyte-specific HNF4α-knockout (KO), cMyc-KO, and HNF4α-cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, normal chow diet was fed for 1 week after CDE diet. WT mice exhibited significant liver injury and decreased HNF4α mRNA and protein expression after CDE diet. HNF4α deletion resulted in significantly higher injury with increased inflammation, fibrosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet but indicated similar recovery. Deletion of cMyc lowered liver injury with activation of inflammatory genes compared with WT and HNF4α-KO mice after CDE diet. DKO mice had a phenotype comparable to that of the HNF4α-KO mice after CDE diet and a complete recovery. DKO mice exhibited a significant increase in hepatic progenitor cell markers both after injury and recovery phase. Taken together, these data show that HNF4α protects against inflammatory and fibrotic changes after CDE diet-induced injury, which is driven by cMyc.

Effect and Mechanism of Fructus Ligustri Lucidi in a Mouse Model of Subacute Liver Injury

We aimed to examine the protective role and mechanism of Fructus Ligustri Lucidi on carbon tetrachloride-induced mouse model of subacute liver injury. The mice were intragastrically injected with 1.2 and 2.4 g/kg of Fructus Ligustri Lucidi water extract after intraperitoneal injection of 0.15% carbon tetrachloride. We found that low-dose or high-dose Fructus Ligustri Lucidi reduced the degree of liver injury, decreased alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels, suppressed malondialdehyde and hydroxyproline contents in the liver tissues of mice, and increased superoxide dismutase content. Additionally, Fructus Ligustri Lucidi decreased concentrations of proinflammatory factors, including tumor necrosis factor-alpha and interleukin-6 and mRNA levels of collagen and fibrosis-associated factors. Fructus Ligustri Lucidi water extract can protect against carbon tetrachloride-induced subacute liver injury in mice. The mechanism is associated with increased antioxidant enzyme activity, reduced lipid peroxidation levels, and suppressed inflammatory and fibrotic responses.

Lipid nanoparticle delivery of siRNA targeting Cyp2e1 gene attenuates subacute alcoholic liver injury in mice.

To investigate the effect and mechanism of lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) targeting Cyp2e1 gene on subacute alcoholic liver injury in mice. siRNA targeting Cyp2e1 gene was encapsulated in LNP (si-Cyp2e1 LNP) by microfluidic technique and the resulting LNPs were characterized. The optimal dose of si-Cyp2e1 LNP administration was screened. Forty female C57BL/6N mice were randomly divided into blank control group, model control group, si-Cyp2e1 LNP group, LNP control group and metadoxine group. The subacute alcoholic liver injury mouse model was induced by ethanol feeding for 10 d plus ethanol gavage for the last 3 d. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and the superoxide dismutase (SOD) activity as well as malondialdehyde, reactive oxygen species, glutathione, triacylglycerol, total cholesterol contents in liver tissue were measured in each group, and liver index was calculated. The expression of genes related to oxidative stress, lipid synthesis and inflammation in each group of mice were measured by realtime RT-PCR. Compared with the model control group, the levels of liver index, serum ALT, AST activities, malondialdehyde, reactive oxygen species, triacylglycerol, total cholesterol contents in liver tissue decreased, but the SOD activity as well as glutathione increased in the si-Cyp2e1 LNP group (all P<0.01). Hematoxylin-eosin staining result showed disorganized hepatocytes with sparse cytoplasm and a large number of fat vacuoles and necrosis in the model control group, while the si-Cyp2e1 LNP group had uniformly sized and arranged hepatocytes with normal liver tissue morphology and structure. Oil red O staining result showed si-Cyp2e1 LNP group had lower fat content of the liver compared to the model control group (P<0.01), and no fat droplets accumulated. Anti-F4/80 monoclonal antibody fluorescence immunohistochemistry showed that the si-Cyp2e1 LNP group had lower cumulative optical density values compared to the model control group (P<0.01) and no significant inflammatory reaction. Compared with the model control group, the expression of catalytic genes P47phox, P67phox and Gp91phox were reduced (all P<0.01), while the expression of the antioxidant enzyme genes Sod1, Gsh-rd and Gsh-px were increased (all P<0.01). The mRNA expression of the lipid metabolism genes Pgc-1α and Cpt1 were increased (all P<0.01) and the lipid synthesis-related genes Srebp1c, Acc and Fasn were decreased (all P<0.01); the expression of liver inflammation-related genes Tgf-β, Tnf-α and Il-6 were decreased (all P<0.01). The si-Cyp2e1 LNP may attenuate subacute alcoholic liver injury in mice mainly by reducing reactive oxygen levels, increasing antioxidant activity, blocking oxidative stress pathways and reducing ethanol-induced steatosis and inflammation.

Protective effect of Lactiplantibacillus pentosus CQZC01 in Kunming mice of subacute alcoholic liver injury.

To decrease the climbing rate of alcoholic liver disease, the protective effect in subacute alcoholic liver injury of newly isolated Lactiplantibacillus pentosus CQZC01 has been investigated. Lactiplantibacillus pentosus CQZC01 (1 × 109 CFU/kgbw) administered orally could keep weight of mice at 30.54±1.15g; alleviate alcoholic damage on hepatic morphology; decrease the activities of hyaluronidase (147±19U/L), procollagen III (4.82±0.54ng/mL), alanine transaminase (10.66±2.32U/L), and aspartate aminotransferase (15.18±1.98U/L); enhance the activities of alcohol dehydrogenase (65.15±3.2 U/mgprot), aldehyde dehydrogenase (16.50±0.96 U/mgprot), superoxide dismutase (623±39 U/mgprot), and glutathione (19.54±2.46µmol/gprot); and decrease liver total cholesterol (3.59±0.50mmol/gprot) and triglyceride (0.88±0.24mmol/gprot) (p<0.05). Moreover, L. pentosus CQZC01 elevated the level of interleukin-10 (IL-10; 807±44 pg/mL) but significantly decreased the levels of IL-1β (29.75±5.27pg/mL), IL-6 (58±8 pg/mL), and tumor necrosis factor-α (TNF-α, 564±13 pg/mL). Liver malondialdehyde was also significantly decreased by treatment with L. pentosus CQZC01 from 3.61±0.14 to 2.03±0.49nmol/mgprot. The relative expression of C-Jun N-terminal kinase, extracellular regulated protein kinases, and cyclooxygenase-1 was downregulated, and the SOD1, SOD2, peroxisome proliferator-activated receptor-α, glutathione peroxidase, catalase, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and nicotinamide adenine dinucleotide phosphate were upregulated by L. pentosus CQZC01. The overall protective effect of L. pentosus CQZC01 was comparable to commercial Lactobacillus delbrueckii subsp. Bulgaricus. Lactobacillus pentosus CQZC01 might be a suitable hepatoprotective measure for people who frequently ingest alcoholic drinks. PRACTICAL APPLICATION: L. pentosus CQZC01 can alleviate subacute alcoholic liver injury by raising the antioxidant status and upregulating the antioxidant-related genes.

Blueberry and cranberry extracts mitigate CCL4-induced liver damage, suppressing liver fibrosis, inflammation and oxidative stress

The current study aims to evaluate potential hepatoprotective effect of lingonberry, cranberry and blueberry polyphenols on carbon tetrachloride (CCL-4)-induced acute and subacute liver injury in rats. A total of 55 male Wistar rats, divided into six experimental and control groups. With the exception of the negative control group, all groups received an intraperitoneal injection of CCl-4, twice a week for 14 days. An extract of lingonberry, cranberry, blueberry polyphenols and the positive control, silymarin were administered daily via intragastric route, for 14 consecutive days. The untreated control group showed characteristic of classical oxidative stress-mediated liver damage with vacuolization of the hepatocyte cytoplasm, infiltration by immune cells and proliferation of collagen fibers, decrease in body weight and increase in liver weight; increased levels of AST and ALT in serum, an increased lipid peroxidation in the liver. However, the use of cranberry and blueberry polyphenols significantly suppressed liver damage, exerting an effect comparable to the hepatoprotective effect of the positive control. The extracts prevented and reduced inflammatory liver damage by reducing IL-6, TNF-α and IFN-γ levels. In conclusion, blueberry and cranberry extracts have a protective effect against acute and subacute CCl4-induced hepatotoxicity in rats.

S3074 Lecithin-Cholesterol Acyltransferase Deficiency From Statin-Induced Autoimmune Hepatitis

Introduction: A 65yr female presented to the hospital with complaints of pruritis and fatigue that had been ongoing for two months. Upon admission she was found to have transaminitis with AST and ALT at 392 and 400 respectively. (reference lab values AST 0-37 ; ALT 0-35) along with a total bilirubin of 25.1 mg/dL. (Ref 0-1.2). She reported that 1 month ago she went to a primary care doctor and was started on insulin, a calcium channel blocker and atorvastatin. A liver biopsy was done which revealed subacute liver injury- autoimmune pattern of injury (de novo versus secondary) +/- medication injury. This was confirmed by further positive autoimmune markers suggestive of autoimmune hepatitis. Case Description/Methods: The patient presented to the ER complaining of intense pruritis, dark urine, pale stools, and jaundice. She had recently started atorvastatin, amlodipine and insulin for newly diagnosed diabetes mellitus and essential hypertension. All home medications were stopped at admission except insulin. She had no prior history of liver disease and no family history of liver disease. She did not take any supplements and had never consumed alcohol. Initial labs revealed a transaminitis with AST and ALT at 392 and 400 IU/L respectively. (reference lab values AST 0-37 ; ALT 0-35 )along with alkaline phosphate at 2147 IU/L. (Ref 44-121). Initial imaging with a right upper quadrant ultrasound was normal. Patient continued to have a transaminitis and elevated alkaline phosphate that were not improving. A MRCP was done which showed hepatomegaly, mild periportal edema, slightly heterogenous enhancement-conglomerate of findings suggests nonspecific hepatitis. An EUS liver biopsy was performed which revealed subacute liver injury- autoimmune pattern of injury (de novo versus secondary) +/- medication injury. Additional laboratory testing revealed positive autoimmune markers; pointing to a drug induced autoimmune hepatitis as the likely diagnosis. Discussion: Patient was started on prednisone and discharged on a steroid taper once her liver function tests began to improve. She followed up in liver clinic and was noted to have developed hypercholesteremia with total cholesterol of 1,375 MG/DL (Ref 170-199 MG/DL), LDL of 1220 Mg/DL and HDL of 162 MG/DL. A cholesterol esters assay was ordered and referral for genetic testing made for likely acquired lecithin cholesterol acyltransferase deficiency in the setting of statin induced autoimmune hepatitis. Previous cholesterol tests prior to starting atorvastatin were normal.

Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.

Stereotactic body radiation therapy (SBRT) has high efficacy for early-stage hepatocellular carcinoma (HCC) and is an accepted alternative to radiofrequency ablation (RFA). However, SBRT for HCC may cause subacute liver injury leading to negative clinical outcomes. In this study, we compared changes of liver function and prognosis after SBRT or RFA in patients with single, small HCC by using a propensity-score matching analysis. We reviewed medical records of 140 patients with single ≤3 cm HCC treated with SBRT or RFA at Kurashiki Central Hospital between January 2014 and February 2019. Changes of albumin-bilirubin (ALBI) score, local recurrence, and overall survival were compared between the propensity-score matched groups (31 patients treated with SBRT and 62 treated with RFA). The ALBI score increased modestly but significantly after SBRT, while it was unchanged in the RFA group; the intergroup difference was statistically significant (P=0.004). No local recurrence was identified in the SBRT group, whereas the cumulative recurrence incidence was 9.7% in the RFA group (P=0.023). Overall survival was not significantly different between the two groups (hazard ratio: 1.32, 95% confidence interval: 0.60-2.89, P=0.401). SBRT had modestly negative impact on liver function but with appraisable local control of HCC. Our findings should contribute to the selection of this modality for treatment of single, small HCC.

Protective mechanism of Astragalus Polysaccharides against Cantharidin-induced liver injury determined in vivo by liquid chromatography/mass spectrometry metabolomics.

Cantharidin (CTD) is a promising anticancer drug; however, its dosage is limited by hepatotoxicity. We previously showed that Astragalus polysaccharides (APS) effectively improved chemical liver injury. In this study, we established a CTD-induced subacute liver injury mouse model and examined the effects of APS on weight, liver indexes, histopathology, serum biochemical indexes and liver metabolism. Compared with the control group, mice in the CTD model group had obvious liver damage, which was partially prevented by APS. Metabolomics demonstrated that CTD caused liver damage mainly by regulating glycerophospholipid metabolism, ABC transporter pathways and choline metabolism in cancer in vivo. APS regulated primary bile acid biosynthesis and glycerophospholipid metabolism, thus decreasing the liver damage caused by CTD. This study revealed the protective mechanism of APS against CTD-induced liver injury from the perspective of metabolomics. The results provide an important basis for analysing the mechanism of CTD-induced liver toxicity and for assessing clinical treatment options to reduce CTD liver toxicity.

Antioxidative and Anti-Inflammatory Effects of Lactobacillus plantarum ZS62 on Alcohol-Induced Subacute Hepatic Damage.

Lactobacillus plantarum ZS62 is a newly isolated strain from naturally fermented yogurt that might offer some beneficial effects in the setting of alcohol-induced subacute liver injury. The liver-protective effect of L. plantarum ZS62 was investigated by gavage feeding of mice with this Lactobacillus strain (1 × 109 CFU/kg BW) before alcohol administration daily for 7 days. We then compared hepatic morphology, liver function indexes, liver lipid levels, inflammation, oxidative stress levels, and mRNA expression of oxidative metabolism- and inflammation-related genes in mice that had been pretreated with Lactobacillus plantarum versus control mice that had not been pretreated. Our results showed that L. plantarum ZS62 attenuated alcohol-induced weight loss; prevented morphological changes in hepatocytes; reduced markers of liver damage including aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), hyaluronidase (HAase), precollagen III (PC III), and inflammatory cytokines; and enhanced the antioxidative status. L. plantarum ZS62 also significantly downregulated inflammation-related genes and upregulated lipid- and oxidative-metabolism genes. Thus, Lactobacillus plantarum pretreatment appears to confer hepatic protection by reducing inflammation and enhancing antioxidative capacity. The protective effect of L. plantarum ZS62 was even better than that of a commonly used commercial lactic acid bacteria (Lactobacillus delbrueckii subsp. Bulgaricus). The L. plantarum ZS62 might be a potentially beneficial prophylactic treatment for people who frequently drink alcoholic beverages.

The Effect of Prolonged Antenatal IVIG Treatment on the Development of Gestational Alloimmune Liver Disease in the Neonate

Introduction: Gestational Alloimmune Liver Disease (GALD) is a rare disease characterized by subacute fetal liver injury and often accompanied by hepatic and extrahepatic iron deposition. Findings include hypoglycemia, coagulopathy, hypoalbuminemia, elevated serum ferritin, elevated alpha-fetoprotein, and ascites. Extrahepatic hemosiderin deposition is often seen in salivary glands. Previously, the mortality rate was close to 80% with all patients needing liver transplantation. With maternal IVIG treatment and changes in neonatal treatment, there is now less than 20% mortality with infrequent need for liver transplantation. Diagnosis of GALD is typically done on a postmortem analysis. Case Description: A term female infant was born via scheduled c-section to a 32 year old G2P1000 mother who had been receiving weekly IVIG during this pregnancy due to the death of her first child at 4 days of life. Autopsy of that female baby demonstrated extensive neuropathological changes, liver steatosis, iron depletion, and ascites, consistent with GALD. Following delivery of our current patient, there was an elevated alpha-fetoprotein (greater than 80,000), decreased fibrinogen, and coagulopathy with peak international normalized ratio of 1.6. The patient received fresh frozen plasma and IVIG on day of life 1 with improvement of these levels. Complete blood count, liver function tests, and ammonia were within normal limits. An MRI of the liver demonstrated normal size, morphology, and normal iron levels based on T2 relaxometry. A buccal biopsy did not demonstrate extrahepatic iron deposition. MRI of the brain showed significant stenosis of the right transverse and sigmoid sinus relating to dural venous sinus thrombosis. There was no evidence of parenchymal infarction and no evidence of iron deposition. At this time, enoxaparin was initiated. The patient was discharged home on day of life nine on enoxaparin therapy. Discussion: There are few reported cases of patients with GALD, especially after maternal IVIG treatment. This case report exemplifies the effect of antenatal IVIG infusions during subsequent pregnancies in women with a history of GALD in prior children. This effect is protective, evidenced by lack of liver injury noted in this patient. This supports the use of immunotherapy during pregnancy to prevent recurrence of alloimmune injury.

Acalypha wilkesiana ‘inferno’ hydroethanolic leaf extract has protective effect on carbon tetrachloride-induced subacute toxicity in animals

Introduction: Liver fibrosis is one of the most common clinical manifestations of hepatic diseases. However, though many synthetic drugs exist for the treatment and prevention of liver diseases, liver injuries still persist. The present study, therefore, sought to investigate the subacute protective effects of Acalphya wilkesiana against carbon tetrachloride (CCl4)-induced toxicity in animals.&#x0D; Methodology: Liver injury was induced in experimental animals by administering CCl4 (1:1 v/v in olive oil, intraperitoneally (i.p.), twice weekly for 8 weeks) after pre-treatment with extract of A. wilkesiana (AWE). AWE (250 mg/kg) and Silymarin (120 mg/kg) were administered orally (daily for 8 weeks). The hepatoprotective effect was studied by assaying the activity of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alpha-fetoprotein. The effect of the treatments on liver prooxidants (e.g. malondialdehyde [MDA]) and antioxidants (e.g. superoxide dismutase [SOD], reduced glutathione [GSH], glutathione peroxidase [GPx], and glutathione transferase [GST]), as well as inflammatory cytokines (e.g. interleukin [IL]-17, IL-23, nuclear factor kappa beta [NF-kB], and cycloxygenase-1 [COX-1]) and the histology of the liver were also examined.&#x0D; Results: The activity of liver function biomarkers changed significantly upon CCl4 administration; increases in ALT, total and direct bilirubin, and some fibrosis indices (e.g. alpha-fetoprotein and APRI [p&lt;0.05-0.001, compared with normal]) were observed. Co-administration of AWE with CCl4 restored these to normal levels. The intensity of structural alterations revealed that the AWE treatment has protective potential against subacute liver injury. AWE treatment also reduced the expression of IL-17, 1L-23, NF-kB and COX-1, underscoring its antiinflammatory properties.&#x0D; Conclusion: The results of the current study generally suggest that hydroethanolic leaf extracts of A. wilkesiana inferno possess some subacute protective activity by improving liver function and inhibition of inflammation, and could be developed as a potent antifibrotic agent.

2409 A Rare Complication of Gastric Bypass in the Setting of Chronic Liver Disease

INTRODUCTION: Porto-mesenteric venous thrombosis (PMVT) is a known and potentially fatal complication of general surgery. However, it has been rarely reported as a complication of worsening liver disease after undergoing bariatric surgery. This is a case of a patient who presented with mesenteric thrombosis following Roux-en-y gastric bypass (RYGB). CASE DESCRIPTION/METHODS: Patient is a 42-year-old African American female with a history of RYGB who presented with episodes of post-operative abdominal pain for 5 years. She was found to have recurrent high-grade small bowel obstruction's (SBO) necessitating a small bowel resection. Her course was further complicated by intra-abdominal abscesses requiring computed tomography (CT)-guided drainage, and wound dehiscence requiring open surgical intervention and debridement. Four months after discharge, she presented with right-sided abdominal pain and acute encephalopathy. Liver enzymes were elevated. Abdominal ultrasound revealed portal vein thrombosis (PVT). Dual-phase CT of the abdomen revealed sub-acute to chronic complete diffuse mesenteric thrombosis with collateralizations involving the portal, splenic, and distal superior mesenteric veins. Given that previous imaging suggested steatosis and hepatomegaly, sub-acute liver injury secondary to thrombosis was established in the setting of chronic liver disease. The patient's underlying non-alcoholic fatty liver disease was likely worsened by severe malnutrition and short gut syndrome following the RYGB. Her hepatic encephalopathy resolved after initiating lactulose and rifaximin. Outpatient hematology evaluation for all causes of thrombophilia remained inconclusive and the patient had no recurrences of thrombosis. DISCUSSION: RYGB remains the gold standard for bariatric surgery as it results in the most durable weight loss. However, complications may occur such as gastrointestinal leak, fistulas, marginal ulcers, SBO, and dumping syndrome. Mechanisms of thrombosis formation in this setting could be related to intra-operative vascular manipulation, increased intra-abdominal pressure, venous stasis, and possibly deteriorating liver function secondary to rapid weight loss and malnutrition. PMVT hasn't been reported consistently as a complication in various bariatric surgery studies, which leads us to conclude that it's either under or mis-diagnosed. It is extremely important to consider PMVT as a complication of RYGB in patients who have evidence of underlying liver disease prior to undergoing RYGB.

Ginsenoside Rg1 attenuates liver injury induced by D-galactose in mice.

The present study investigated the effect and underlying mechanisms of ginsenoside Rg1 (Rg1) in attenuating subacute liver injury induced by D-galactose (D-gal) in mice. Specific Pathogen Free (SPF) male C57BL/6J mice were randomly divided into 3 groups: i) D-gal-administration group (D-gal group), where the mice were intraperitoneally administrated with D-gal (120 mg/kg/day for 42 days); ii) D-gal + Rg1 group where the mice were treated with 120 mg/kg/day D-gal for 42 days and with Rg1 at a dose of 20 mg/kg/day for 35 days. The first dose of Rg1 was administered on the 8th day of treatment with D-gal; and iii) the normal control group, where the mice were injected with an equal volume of saline for 42 days. The day following the final injections in all groups, peripheral blood was collected and serum was prepared to measure the contents of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBiL), advanced glycation end products (AGEs) and 8-hydroxy-2 deoxyguanosine (8-OH-dG). Liver tissue homogenates were prepared to measure the contents of malondialdehyde (MDA) and glutathione (GSH), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Paraffin section were prepared to observe the microscopic structure of the liver. Transmission electron microscopy was used to observe the ultrastructure of hepatocytes. Frozen section were prepared and stained with senescence-associated β-galactosidase to detect the relative optical density value of senescence-associated markers. Compared with the D-gal group, the contents of AST, ALT, TBiL, AGEs and MDA significantly decreased in the D-gal + Rg1 group, while the activities of SOD and GSH-Px markedly increased, and liver injury and degenerative alterations of hepatocytes were reduced. Administration of Rg1 induced a protective effect on D-gal-induced liver injury in mice by inhibiting the oxidative stress, reducing DNA damage and decreasing the AGE content.

Characterizations and hepatoprotective effect of polysaccharides from Mori Fructus in rats with alcoholic-induced liver injury

Crude polysaccharides of Mori Fructus (MFPs) were found to have anti-inflammatory antioxidant, and immuno-enhancing activities. However, the structure of the polysaccharides was ambiguous and its holistic hepatic protection evaluation was defective. This study was conducted to illustrate the characterization of MFPs, and evaluate its hepatoprotective activities. The results found that MFPs contained 67.93±1.18% carbohydrates, 31.03±0.54% uronic acid, and little protein and sulfate. The average molecular weight was ranging from 112.2kDa to 181.9kDa. Monosaccharide component analysis indicated that MFPs was mainly composed of glucose, galacturonic acid, rhamnose and galactose. Both the acute and subacute alcoholic-induced liver injury animal models were adopted to evaluate the MFPs’s hepatoprotective activity. After administration of MFPs, both serological indexes (aspartate aminotransferase and alanine aminotransferase) and hepatic indicators (glutathione, superoxide dismutase, glutathione peroxidase and malondialdehyde) were improved by comparing with the non-MFPs group. The hepatic histopathology results also showed a prominent lipid degeneration and microvesicular steatosis attenuation in the MFPs groups. These outstanding hepatic protecting activities of MFPs might be related to its activation of ethanol dehydrogenase, elimination of free radicals and/or inhibition of lipid peroxidation capacities. MFPs could be important active substances for preventing and remedying liver injury.

Promoting translational research on drug-induced liver injury

Drug-induced liver injury (DILI) is one of the most important drug-induced diseases and an important reason for failure to obtain approval, an increase in warnings, and withdrawal from market. DILI has a complex clinical phenotype and can cause almost all types of acute, subacute, and chronic liver injury, and it may cause liver failure and even death in patients with severe conditions. The diversity of drugs involved and heterogeneity of populations are the main reasons for unpredictability of most DILI cases in clinical practice. Therefore, the prediction, diagnosis, and treatment of DILI become challenging issues in the field of liver disease, and it is of great significance to strengthen clinical translational research in this aspect, so as to transform more achievements into actual diagnostic and treatment methods.

Melatonin attenuates (-)-epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice.

(-)-Epigallocatehin-3-gallate (EGCG), a major constituent of green tea, can ameliorate metabolic syndrome at least in part through reducing gluconeogenesis and lipogenesis. Green tea extracts, of which EGCG is a key constituent, have been used for weight loss in humans. A potential adverse effect of high-dose EGCG or green tea extracts is hepatotoxicity. Melatonin, an endogenous antioxidant with a high safety profile, is effective in preventing various types of tissue damage. The current study investigated the influence of melatonin on EGCG-triggered hepatotoxicity and EGCG-downregulated hepatic genes responsible for gluconeogenesis and lipogenesis in mice. We found that (i) melatonin extended survival time of mice intoxicated with lethal doses of EGCG; (ii) melatonin ameliorated acute liver damage and associated hepatic Nrf2 suppression caused by a nonlethal toxic dose of EGCG; (iii) melatonin reduced subacute liver injury and hepatic Nrf2 activation caused by lower toxic doses of EGCG; and (iv) melatonin did not compromise the action of pharmacological doses of EGCG in downregulating a battery of hepatic genes responsible for gluconeogenesis and lipogenesis, including G6Pc, PEPCK, FOXO1α, SCD1, Fasn, leptin, ACCα, ACCβ, GAPT, and Srebp-1. Taken together, these results suggest that the combination of EGCG and melatonin is an effective approach for preventing potential adverse effects of EGCG as a dietary supplement for metabolic syndrome alleviation and body weight reduction.

Protective effects of C-phycocyanin on alcohol-induced subacute liver injury in mice

Excessive and long-term alcohol consumption leads to liver disease and low immunity. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Arthrospira (Spirulina) platensis, exerts protective effects against chemical-induced organ damage and improves immunity. In this study, we investigated whether C-PC could protect against ethanol-induced subacute liver injury and improve immunity. KM mice with ethanol-induced liver injury were established, and animals were divided into three groups that were treated with high, medium, and low doses of C-PC. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), total bilirubin (TBIL), liver homogenate malondialdehyde (MDA), and superoxide dismutase (SOD) levels were measured. In addition, the number of thymus T cell subsets was assessed, and liver sections were examined pathologically. C-PC exhibited obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL, and MDA levels and increased SOD content significantly in the liver. C-PC also increased serum CD3+ and CD4+ cell activation and T cell proliferation significantly compared with the model group. The structure of the hepatic lobules was clear, the liver sinus returned to normal, and the liver cell cords were arranged in neat rows. Therefore, C-PC could protect against ethanol-induced subacute liver injury significantly.