Protective effects of glutamine on lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice.

Fulminant hepatitis remains a critical health problem owing to its high mortality rate and the lack of effective therapies. An increasing number of studies have shown that glutamine supplementation provides protective benefits in inflammation-related disorders, but the pharmacological significance of glutamine in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced fulminant hepatitis remains unclear. In the present study, the potential effects of glutamine on LPS/D-Gal-induced fulminant hepatitis were investigated. Pretreatment with glutamine decreased plasma activities of alanine and aspartate aminotransferases, and ameliorated hepatic morphological abnormalities in LPS/D-Gal-exposed mice. Glutamine pretreatment also inhibited LPS/D-Gal-induced tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production. In addition, glutamine pretreatment decreased the level of cleaved cysteinyl aspartate-specific proteinase 3 (caspase-3), suppressed the activities of caspase-3, caspase-8, and caspase-9, and reduced the number of cells positive for TdT-mediated dUTP nick-end labeling in LPS/D-Gal-challenged mice. Interestingly, post-treatment with glutamine also provided protective benefits against LPS/D-Gal-induced acute liver injury, although these effects were less robust than those of glutamine pre-treatment. Thus, glutamine may have potential value as a pharmacological intervention in fulminant hepatitis.

Fibroblast growth factor 9 attenuates sepsis-induced fulminant hepatitis in mice.

Sepsis-induced fulminant hepatitis (FH) is a fatal syndrome that has a worse prognosis in clinical practice. Hence, seeking effective agents for sepsis-induced FH treatment is urgently needed. Fibroblast growth factors (FGFs) are vital for tissue homeostasis and damage repair in various organs including the liver. Our study aims to investigate the protective effects and potential mechanisms of FGF9 on lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced FH in mice. We found that pre-treatment with FGF9 exhibited remarkable hepaprotective effects on liver damage caused by LPS/D-Gal, as manifested by the concomitant decrease in mortality and serum aminotransferase activities, and the attenuation of hepatocellular apoptosis and hepatic histopathological abnormalities in LPS/D-Gal-intoxicated mice. We further found that FGF9 alleviated the infiltration of neutrophils into the liver, and decreased the serum levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS/D-Gal-challenged mice. These effects can be explained at least in part by the inhibition of NF-κB signaling pathway. Meanwhile, FGF9 enhanced the antioxidative defense system in mice livers by upregulating the expression of NRF-2-related antioxidative enzymes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H: quinone oxidoreductase 1 (NQO-1), and heme oxygenase-1 (HO-1). These data indicate that FGF9 represents a promising therapeutic drug for ameliorating sepsis-induced FH via its anti-apoptotic and anti-inflammatory capacities.

Forsythia Fruit Prevents Fulminant Hepatitis in Mice and Ameliorates Inflammation in Murine Macrophages.

Forsythia Fruit (FF), the fruit of Forsythia suspensa, has been used since ancient times as an herbal medication in East Asia to treat inflammation, gonorrhea, and pharyngitis. However, the efficacy of FF against liver damage due to inflammation has not been studied. Here, we explored the protective effects of FF in a mouse hepatitis model induced by lipopolysaccharide (LPS)/D-galactosamine (GalN) treatment. We measured inflammatory cytokine and aminotransferase levels in mouse blood and analyzed the effects of FF on inflammatory gene and protein expression levels in liver tissue. Our results show that FF treatment effectively lowers inflammatory cytokine and serum aminotransferase levels in mice and inhibits the expression of hepatic cytokine mRNA and inflammatory proteins. Furthermore, treatment with FF activated the antioxidant pathway HO-1/Nrf-2 and suppressed severe histological alteration in the livers of LPS/D-GalN-treated mice. Further investigation of the effects of FF on inflammatory reactions in LPS-stimulated macrophages showed that pretreatment with FF inhibits inflammatory mediator secretion and activation of inflammatory mechanisms both in a mouse macrophage RAW 264.7 cells and in primary peritoneal macrophages. These results show that FF has potential worth as a candidate for the treatment of fulminant inflammatory reactions and subsequent liver injury.

Withaferin A alleviates fulminant hepatitis by targeting macrophage and NLRP3.

Fulminant hepatitis (FH) is an incurable clinical syndrome where novel therapeutics are warranted. Withaferin A (WA), isolated from herb Withania Somnifera, is a hepatoprotective agent. Whether and how WA improves D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced FH is unknown. This study was to evaluate the hepatoprotective role and mechanism of WA in GalN/LPS-induced FH. To determine the preventive and therapeutic effects of WA, wild-type mice were dosed with WA 0.5 h before or 2 h after GalN treatment, followed by LPS 30 min later, and then killed 6 h after LPS treatment. To explore the mechanism of the protective effect, the macrophage scavenger clodronate, autophagy inhibitor 3-methyladenine, or gene knockout mouse lines NLR family pyrin domain containing 3 (Nlrp3)-null, nuclear factor-erythroid 2-related factor 2 (Nrf2)-null, liver-specific AMP-activated protein kinase (Ampk)a1 knockout (Ampka1ΔHep) and liver-specific inhibitor of KB kinase ß (Ikkb) knockout (IkkbΔHep) mice were subjected to GalN/LPS-induced FH. In wild-type mice, WA potently prevented GalN/LPS-induced FH and inhibited hepatic NLRP3 inflammasome activation, and upregulated NRF2 and autophagy signaling. Studies with Nrf2-null, Ampka1ΔHep, and IkkbΔHep mice demonstrated that the hepatoprotective effect was independent of NRF2, hepatic AMPKα1, and IκκB. Similarly, 3-methyladenine cotreatment failed to abolish the hepatoprotective effect of WA. The hepatoprotective effect of WA against GalN/LPS-induced FH was abolished after macrophage depletion, and partially reduced in Nlrp3-null mice. Consistently, WA alleviated LPS-induced inflammation partially dependent on the presence of NLRP3 in primary macrophage in vitro. Notably, WA potently and therapeutically attenuated GalN/LPS-induced hepatotoxicity. In conclusion, WA improves GalN/LPS-induced hepatotoxicity by targeting macrophage partially dependent on NLRP3 antagonism, while largely independent of NRF2 signaling, autophagy induction, and hepatic AMPKα1 and IκκB. These results support the concept of treating FH by pharmacologically targeting macrophage and suggest that WA has the potential to be repurposed for clinically treating FH as an immunoregulator.

Fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma.

Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Hepatocyte CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration through upregulation of NF-κB p65 in mice.

Fulminant hepatitis is a serious inflammatory condition of the liver characterized by massive necrosis of liver parenchyma following excessive immune cell infiltration into the liver, and possibly causing sudden hepatic failure and medical emergency. However, the underlying mechanisms are not fully understood. Here, we investigated the role of cyclic AMP-responsive element-binding protein, hepatocyte specific (CREBH) in concanavalin A (ConA)-driven hepatitis-evoked liver injury. C57BL/6J (WT) and Crebh knockout (KO) mice injected with ConA (7.5 or 25 mg/kg) and bone marrow (BM) chimeric mice, generated by injection of BM cells into sub-lethally irradiated recipients followed by ConA injection (22.5 or 27.5 mg/kg) 8 weeks later, were used for in vivo study. Primary mouse hepatocytes and HEK293T cells were used for a comparative in vitro study. Crebh KO mice are highly susceptible to ConA-induced liver injury and prone to death due to increased neutrophil infiltration driven by enhanced hepatic expression of neutrophil-attracting chemokines. Notably, BM chimera experiment demonstrated that Crebh-deficient hepatocytes have an enhanced ability of recruiting neutrophils to the liver, thereby promoting hepatotoxicity by ConA. Intriguingly, in vitro assays showed that p65, a subunit of NF-κB and common transcription factor for various chemokines, dependent transactivation was inhibited by CREBH. Furthermore, p65 expression was inversely correlated with CREBH level in ConA-treated mice liver and TNFα-stimulated primary mouse hepatocytes. This is the first demonstration that CREBH deficiency aggravates inflammatory liver injury following chemokine-dependent neutrophil infiltration via NF-κB p65 upregulation. CREBH is suggested to be a novel therapeutic target for treatment of fulminant hepatitis.

The hepatoprotective effect of myricetin against lipopolysaccharide and D-galactosamine-induced fulminant hepatitis.

Fulminant hepatitis (FH) is a severe liver disease characterized by extensive hepatic necrosis, oxidative stress, and inflammation. Myricetin (Myr), a botanical flavonoid glycoside, is recognized to exert antiapoptosis, anti-inflammatory, and antioxidant properties. In the current study, we focused on exploring the protective effects and underlying mechanisms of Myr against lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FH. These data indicated that Myr effectively protected from LPS/D-GalN-induced FH by lowering the mortality of mice, decreasing ALT and AST levels, and alleviating histopathological changes, oxidative stress, inflammation, and hepatic apoptosis. Moreover, Myr could efficiently mediate multiple signaling pathways, displaying not only the regulation of caspase-3/9 and P53 protein, inhibition of toll-like receptor 4 (TLR4)-nuclear factor-kappa B (NF-κB) activation, and -mitogen-activated protein kinase (MAPK), but also the increase of heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, as well as induction of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in mice with LPS/D-GalN-induced FH. Importantly, our further results in vitro suggested that Myr remarkably attenuated H2O2-triggered hepatotoxicity and ROS generation, activated Keap1-Nrf2/HO-1 and AMPK/ACC signaling pathway. However, Myr-enhanced the expression of HO-1 and Nrf2 protein was reversed by Keap1-overexpression, Nrf2-null and AMPK inhibitor. Meanwhile, Myr-relieved hepatotoxicity excited by H2O2 was blocked by Nrf2-null and AMPK inhibitor. Taken together, Myr exhibits a protective role against LPS/D-GalN-induced FH by suppressing hepatic apoptosis, inflammation, and oxidative stress, likely involving in the regulation of apoptosis-related protein, TLR4-NF-κB/-MAPK and NLRP3 inflammasome, and AMPK-Nrf2/HO-1 signaling pathway.

Drug-Induced Fulminant Hepatitis in a Child Treated for Latent Multidrug-Resistant Tuberculosis With Dual Therapy Combining Pyrazinamide and Levofloxacin.

We report the case of a 10-year-old child treated for latent tuberculosis infection (LTBI) with pyrazinamide (PZA) and levofloxacin after contact with a smear-positive multidrug-resistant tuberculosis adult. Over the course of the treatment, the patient developed a drug-induced fulminant hepatitis attributed to the combination of PZA and levofloxacin. This case highlights the hepatotoxicity of the association of second-line anti-TB treatment in children.

Clinical and histologic outcome in a dog surviving massive hepatic necrosis.

This report describes the clinical and histologic recovery of a 2-year-old mixed-breed dog presented with hypovolemic shock, markedly increased serum alanine amino transferase activity, and hemoabdomen. Emergency exploratory surgery revealed a friable liver with multiple capsule hemorrhages necessitating removal of the left lateral lobe. Histologic evaluation showed acute massive hepatic necrosis with centrilobular and midzonal distribution. The dog survived, and all monitored laboratory values normalized within 7 weeks. A liver biopsy taken 8 weeks after presentation revealed normal hepatic architecture with a few, randomly distributed neutrophilic foci. Follow-up included intermittent determination of liver variables including liver function tests for a period of 7 years. The dog's health status, and all test results remained normal during this time. Complete recovery and good long-term quality of life after life-threatening acute liver failure secondary to massive hepatic necrosis is possible in dogs.

Autoimmune acute liver failure and seronegative autoimmune liver disease in children: Are they different from classical disease?

OBJECTIVES: Presentation as autoimmune acute liver failure (AI-ALF) and seronegative autoimmune liver disease (SN-AILD) represents two uncommon variants of AILD. We compared the clinical profile and outcome of AI-ALF with autoimmune-non-acute liver failure (AI-non-ALF) and also SN-AILD with seropositive autoimmune liver disease (SP-AILD). MATERIALS AND METHODS: Children managed as AI-ALF and AI-non-ALF including SN-AILD and SP-AILD were enrolled and compared. AI-non-ALF was diagnosed by simplified diagnostic criteria and AI-ALF by Pediatric Acute Liver Failure Study Group criteria with positive autoantibody, exclusion of other etiologies, elevated immunoglobulin G and histology when available. RESULTS: Seventy children [AI-ALF=15 and AI-non-ALF=55 (SN-AILD=11, SP-AILD=44)] were evaluated. Age at presentation [7 (1.2-16) vs. 9 (2-17) years] percentage of female patients (67 vs. 62%), and AILD type (type II, 53 vs. 31%) were similar in AI-ALF and AI-non-ALF patients], respectively. 8/15 AI-ALF cases were treated with steroids (improved-4, liver transplant-1, and death-3) and 7/15 died before initiation of therapy. Hepatic encephalopathy (100 vs. 16.3%; P<0.001), massive hepatic necrosis (60 vs. 0%; P<0.001), and higher pediatric end-stage liver disease [n=53, 29.9 (13.1-56.9) vs. 9.8 (-10-28.7) P<0.001], model for end-stage liver disease [n=17, 38.5 (24-46) vs. 18 (6-24); P=0.005], and Child-Turcotte-Pugh [n=70, 13 (8-13) vs. 9 (5-13); P<0.001] scores were features of AI-ALF. Poorer response to immunosuppression (4/8 vs. 48/55; P=0.02) and higher mortality (11/15 vs. 4/55; P=0.0001) were seen in AI-ALF than in AI-non-ALF patients. Clinicolaboratory profile, therapeutic response, and outcome were similar in SN-AILD and SP-AILD. CONCLUSION: AI-ALF is characterized by poorer liver function, lower response to immunosuppression, and higher mortality compared with SP or SN AI-non-ALF, which are similar.

Hematological and pathological features of massive hepatic necrosis in two radiated tortoises (Astrochelys radiata).

Two radiated tortoises (Astrochelys radiata) exhibited anorexia and hypokinesia. In both cases, hematological and serum biochemical examinations revealed high alkaline phosphatase levels, moderately high aspartate aminotransferase levels and white blood cell counts approximately within the normal range. Despite being treated, the tortoises died 9 and 43 days after the first clinical examination. Gross pathological examinations revealed that the livers of both animals were extremely swollen and contained pale yellow necrotic tissue. Histopathological assessment revealed that the livers contained a massive area of hepatic necrosis surrounded by migration of macrophages and multinucleated giant cells. In one of the cases, severe fibrosis was observed. The present study provides reference information for similar cases in the future.

Lethal hepatocellular necrosis associated with herbal polypharmacy in a patient with chronic hepatitis B infection.

Following a short treatment for irritable bowel with the following herbs: Astragalus propinquus, Codonopsis pilosula, Paeonia sp., Atractylodes macrocephala, Pueraria sp., Poria cocos, Dioscorea opposita, Patriniae, Psoralea corylifolia, Alpinia katsumadai, Glycyrrhiza uralensis and Dolomiaea souliei sp. a 43-year-old woman developed acute severe liver failure requiring liver transplantation. Histopathological examination of the liver showed massive hepatic necrosis in keeping with drug/chemical toxicity. Surgery was followed by multiorgan failure and death. While numerous studies have evaluated the effect of polypharmacy, the study of multiple concurrent herb use is only just emerging, despite the popularity of herbal medicine use in the western world. As this case demonstrates that fulminant hepatic failure and death may be caused by the concomitant use of a number of herbal products, the possibility of untoward effects from herbal polypharmacy must be increasingly considered in the evaluation of medicolegal cases.

Fatal methanol poisoning: features of liver histopathology.

Methanol poisoning has become a considerable problem in Iran. Liver can show some features of poisoning after methanol ingestion. Therefore, our concern was to examine liver tissue histopathology in fatal methanol poisoning cases in Iranian population. In this study, 44 cases of fatal methanol poisoning were identified in a year. The histological changes of the liver were reviewed. The most striking features of liver damage by light microscopy were micro-vesicular steatosis, macro-vesicular steatosis, focal hepatocyte necrosis, mild intra-hepatocyte bile stasis, feathery degeneration and hydropic degeneration. Blood and vitreous humor methanol concentrations were examined to confirm the proposed history of methanol poisoning. The majority of cases were men (86.36%). In conclusion, methanol poisoning can cause histological changes in liver tissues. Most importantly in cases with mean blood and vitreous humor methanol levels greater than 127 ± 38.9 mg/dL more than one pathologic features were detected.

Intoxicação por Trema micrantha (Ulmaceae) em caprinos no Estado de Santa Catarina / Poisoning by Trema micrantha (Ulmaceae) in goats in the State of Santa Catarina

Vinte e cinco caprinos, criados em piquetes, morreram nos cinco dias subsequentes ao fornecimento de folhas de Trema micrantha (fam.Ulmaceae), uma árvore com nome comum de grandiúva. Quatro caprinos foram necropsiados e amostras de vísceras foram coletadas para exame histológico. As principais alterações clínicas foram: apatia, anorexia, cabeça apoiada contra obstáculos, decúbito e morte. Achados macroscópicos incluíram sufusões no epicárdio e endocárdio; fígado levemente amarelado e com padrão lobular evidente e, em um caso, acompanhado de hemorragias multifocais. Na histologia observou-se necrose hepática, que variava de centrolobular a massiva, compatível com hepatopatia tóxica. No SNC havia satelitose, tumefação neuronal, edema periaxonal, perivascular. O diagnóstico de intoxicação por Trema micrantha foi baseado no quadro clínico e lesional de hepatite tóxica associado ao uso da planta para alimentação de caprinos.

Twenty five goats, maintained in paddocks, had died in five subsequent days after have been offered leaves, mixed in the ration, of Trema micrantha, a tree commonly called grandiúva. Four animals were necropsied and samples were collected for histopathology. Clinical signs included apathy, anorexia, head pressing against obstacles, decubitus and death. Macroscopic findings included suffusions in the epi- and endocardium, a yellowish liver with pronounced lobular pattern, in one goat, the liver presented additionally multiple visible hemorrhages. Histological examination revealed centrilobular to massive hepatic necrosis consistent with acute liver toxicosis. In the brain, satelitosis, neuronal swelling, and perineuronal and perivascular edema was found. The diagnosis of poisoning by Trema micrantha was based in the clinical picture characteristic of toxic hepatitis associated in the feeding of the plant to the goats.

Intestinal volvulus with coagulative hepatic necrosis in a chicken.

A 7-week-old SPF chicken inoculated at 4 weeks of age with chicken anemia virus was puffed up depressed and had ruffled feathers and a good body condition. Intestinal volvulus involving the jejunum and part of the duodenum forming two loops with one knob was observed. Microscopically, venous infarction of the obstructed loops, periportal and sublobular multifocal coagulative hepatic necrosis and granulomatous inflammation of the cecal tonsils were observed. Gram staining revealed no bacteria in hepatic tissue; however, gram-positive bacilli were detected in the necrotic debris in the intestinal lumen. Immunosuppression might have predisposed the chicken to intestinal and cecal tonsil infection that then progressed to volvulus. Loss of the mucosal barrier in infarction might allow bacterial toxins and vasoactive factors to escape into the systemic circulation (toxemia) and be responsible for the hepatic necrosis.

Massive hepatic necrosis with large regenerative nodules / 대한간학회지

No abstract available.