Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-κB activation.

Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A-induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α-induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3ß/ß-catenin cascade. Increased ß-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced ß-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3ß/ß-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.

A single strain of Tetratrichomonas gallinarum causes fatal typhlohepatitis in red-legged partridges (Alectoris rufa) to be distinguished from histomonosis.

Typhlohepatitis was observed in a flock of 2500 red-legged partridges in Great Britain, characterized by the sudden deaths of 15 birds within 2 days. Necropsy of five dead birds revealed severe lesions in the caeca with thickened caecal walls, a reddened lining and bloody contents. The livers contained multiple miliary lesions and similar pathological changes were found in the spleens of some birds. Microscopic examination of intestinal contents showed the occurrence of coccidial oocysts in two partridges. Different methods for the detection of bacteria from liver and intestine samples were conducted without positive results. Histopathological examination revealed the presence of protozoan parasites in the caecum, liver and spleen of the affected birds. In situ hybridization (ISH) for the detection of trichomonads resulted in positive findings and polymerase chain reaction (PCR) confirmed the presence of Tetratrichomonas gallinarum in the lesions. Additionally, archived tissues of red-legged partridges from different flocks suffering from severe typhlohepatitis in Great Britain in 2008 and 2009 were re-investigated by ISH and PCR. Beside the sporadic occurrence of histomonosis, in most of the cases trichomonads were detected by ISH in the caecum and liver of affected birds. Furthermore, dissemination of the flagellate into the lung and bursa of Fabricius could be demonstrated. Analyses of T. gallinarum DNA obtained from the different cases resulted in homologous nucleotide sequences. Altogether, the results demonstrate the circulation of a virulent strain of T. gallinarum in reared red-legged partridges.

SOCS1 regulates type I/type II NKT cell balance by regulating IFNgamma signaling.

Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγ in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery.

Polychlorinated biphenyl: interaction with duck hepatitis virus.

Ten-day-old mallard ducklings fed a polychlorinated biphenyl at concentrations of 25, 50, and 100 parts per million for 10 days suffered no apparent clinical intoxication. Five days later these birds were challenged with duck hepatitis virus, and they suffered significantly higher mortality than birds which were not exposed to the polychlorinated biphenyl.

Primary hepatitis in dogs: a retrospective review (2002-2006).

BACKGROUND: Little is known about etiology, disease progression, treatment outcome, survival time, and factors affecting prognosis in dogs with primary hepatitis (PH). OBJECTIVES: To review retrospectively different forms of hepatitis in a referral population, by the World Small Animal Veterinary Association Standardization criteria. ANIMALS: One-hundred and one dogs examined for histologically confirmed PH between 2002 and 2006. Dogs with nonspecific reactive hepatitis were excluded. METHODS: Retrospective study. Medical records were reviewed for prevalence, signalment, clinical and clinicopathologic manifestation, outcome, survival time, and prognostic factors for shortened survival. RESULTS: PH occurred in 0.5% of dogs in this referral population. Acute (AH) and chronic hepatitis (CH) were diagnosed in 21 and 67 dogs, respectively. Progression from AH to CH occurred in 5/12 of the repeatedly sampled dogs. CH was idiopathic in 43 (64%) dogs, and was associated with copper accumulation in 24 (36%) dogs. Median survival time was longer in dogs with AH than in dogs with CH (either idiopathic or copper associated), and dogs with lobular dissecting hepatitis had the shortest survival time. Prognostic factors predicting shortened survival were associated with decompensated liver function and cirrhosis at initial examination. CONCLUSIONS AND CLINICAL IMPORTANCE: The majority of PH in dogs is CH. Previous studies appear to have underestimated the etiologic role of copper in both AH and CH. Prognosis is reduced in dogs with hepatic cirrhosis or cirrhosis-related clinical findings. Further research into etiology and treatment effectiveness in all PH forms is needed.

Typhlohepatitis and Amyloidosis Associated with High Mortality in Chukar Partridges (Alectoris chukar).

Twelve chukar partridges (Alectoris chukar) from a farm experiencing poor uniformity and increased mortality of up to 65% were submitted for diagnosis. Several birds had mild to moderate multifocal white foci or multifocal petechial hemorrhages throughout the liver. Livers and spleens of older birds were moderate to severely diffusely enlarged. In addition, some birds had caseous cores mixed with blood within the ceca as well as segmentally thickened cecal walls. Histopathology showed acute, multifocal, severe, often coalescing foci of necrosis with accumulation of fibrin and/or fibrinosuppurative inflammation in livers and spleens. Scattered within exudate were protozoa that were spherical or round and measured 12-20 µm in diameter. In the ceca, acute necrosis of the mucosa was observed, often with ulceration and fibrinosuppurative inflammation. Immunohistochemistry using an antiserum against Tritrichomonas foetus revealed round protozoa in ceca, small intestines, liver, spleen, and lung. Quantitative PCR to detect DNA of Histomonas meleagridis was negative. Non-species-specific PCRs amplifying the partial rDNA, the internal transcribed spacer (ITS) region, and the partial beta-tubulin gene yielded products of the expected size. Sequences of the PCR products had the highest homology to sequences of Tetratrichomonas gallinarum and less homology to sequences of H. meleagridis. In addition there was accumulation of amyloid in the space of Disse in the liver, splenic sinuses, and walls of the blood vessels. The typhlohepatitis and other inflammatory processes that were diagnosed might be the underlying cause of the amyloidosis. Other findings were clusters of Clostridium perfringens associated with the lesions in the ceca; multifocal granulomas in the lungs, occasionally associated with fungal hyphae; hyperkeratosis associated with bacteria and Candida sp. cells in the crop; mild infection of the bursal mucosa with Cryptosporidium.

Tiflohepatitis y amiloidosis asociadas con alta mortalidad en perdices chukar (Alectoris chukar). Doce perdices chukar (Alectoris chukar) de una granja con baja uniformidad y alta mortalidad de hasta el 65% se presentaron para diagnóstico. Varias aves presentaron áreas blancas multifocales de leves a moderadas o hemorragias petequiales multifocales en todo el hígado. Los hígados y los bazos de las aves con mayor edad estuvieron agrandados de tamaño de manera difusa y de moderado a severo. Además, algunas aves tenían contenidos caseosos mezclados con sangre dentro de los ciegos, así como paredes cecales engrosadas de manera segmentaria. La histopatología mostró focos de necrosis agudos, multifocales, graves, a menudo coalescentes con acumulación de fibrina y/o inflamación fibrinosupurativa en hígados y bazos. Dispersos dentro del exudado se encontraban protozoarios que eran esféricos o redondos y que medían de 12 a 20 µm de diámetro. En el ciego, se observó necrosis aguda de la mucosa, a menudo con ulceración e inflamación fibrinosupurativa. La inmunohistoquímica con un antisuero contra Tritrichomonas foetus reveló protozoarios redondos en el ciego, intestino delgado, hígado, bazo y pulmón. El método de PCR cuantitativo para detectar el ADN de Histomonas meleagridis fue negativo. Los métodos de PCR no específicos de especie que amplifican parcialmente al rDNA de la región espaciadora transcrita interna (ITS) y el gene parcial de la beta-tubulina dieron productos del tamaño esperado. Las secuencias de los productos de PCR tuvieron la mayor similitud con las secuencias de Tetratrichomonas gallinarum y menos similitud con las secuencias de H. meleagridis. Además, se observó acumulación de amiloide en el espacio de Disse en el hígado, en senos esplénicos y paredes de los vasos sanguíneos. La tiflohepatitis y otros procesos inflamatorios que se diagnosticaron pueden ser la causa subyacente de la amiloidosis. Otros hallazgos incluyeron grupos de Clostridium perfringens asociados con las lesiones en el ciego; granulomas multifocales en los pulmones, ocasionalmente asociados con hifas fúngicas; hiperqueratosis asociada a bacterias y Candida spp. en el buche, e infección leve de la mucosa bursal con Cryptosporidium.

Acute, fatal Sarcocystis calchasi-associated hepatitis in Roller pigeons (Columba livia f. dom.) at Philadelphia Zoo.

Four Roller pigeons (Columba livia f. dom.) at the Philadelphia Zoo died suddenly. Necropsy examination revealed macroscopic hepatitis. Microscopically, the predominant lesions were in liver, characterized with necrosis and mixed cell inflammatory response. Sarcocystis calchasi-like schizonts and free merozoites were identified in liver. Transmission electron microscopy confirmed that schizonts were in hepatocytes. A few schizonts were in spleen. PCR using S. calchasi-specific primers confirmed the diagnosis. Neither lesions nor protozoa were found in brain and muscles. This is the first report of acute visceral S. calchasi-associated sarcocystosis in naturally infected avian hosts.

Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice.

Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1ß as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1ß and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1ß in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose.

Rift Valley fever virus infection in golden Syrian hamsters.

Rift Valley fever virus (RVFV) is a formidable pathogen that causes severe disease and abortion in a variety of livestock species and a range of disease in humans that includes hemorrhagic fever, fulminant hepatitis, encephalitis and blindness. The natural transmission cycle involves mosquito vectors, but exposure can also occur through contact with infected fluids and tissues. The lack of approved antiviral therapies and vaccines for human use underlies the importance of small animal models for proof-of-concept efficacy studies. Several mouse and rat models of RVFV infection have been well characterized and provide useful systems for the study of certain aspects of pathogenesis, as well as antiviral drug and vaccine development. However, certain host-directed therapeutics may not act on mouse or rat pathways. Here, we describe the natural history of disease in golden Syrian hamsters challenged subcutaneously with the pathogenic ZH501 strain of RVFV. Peracute disease resulted in rapid lethality within 2 to 3 days of RVFV challenge. High titer viremia and substantial viral loads were observed in most tissues examined; however, histopathology and immunostaining for RVFV antigen were largely restricted to the liver. Acute hepatocellular necrosis associated with a strong presence of viral antigen in the hepatocytes indicates that fulminant hepatitis is the likely cause of mortality. Further studies to assess the susceptibility and disease progression following respiratory route exposure are warranted. The use of the hamsters to model RVFV infection is suitable for early stage antiviral drug and vaccine development studies.

Occurrence of autoimmune antibodies to liver microsomal proteins associated with lethal hepatitis in LEC rats: effects of TJN-101 ((+)-(6S,7S,R-biar)- 5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy-6,7-dimethyl-10,11- methylenedioxy-6-dibenzo[a,c]cyclooctenol) on the development of hepatitis and the autoantibodies.

Long Evans Cinnamon (LEC) rats, that spontaneously develop hepatitis, were found to possess autoantibodies to liver microsomal proteins (anti-LM) before the development of hepatitis. Anti-LM antibody was assumed to appear in association with the lethal hepatitis in the LEC rats. Thus, the purpose of this study was to investigate the effects of an anti-hepatitis drug on the development of hepatitis and the occurrence of the antibody in LEC rats. Mortality, blood biochemical parameters and the titer of serum anti-LM antibody were measured. In control LEC rats, 4 of 8 rats died before 20 weeks of age. In rats treated with TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11 - methylenedioxy-6-dibenzo[a,c]cyclooctenol), 4 of 7 rats died of hepatitis, but the time of death was delayed by 7-10 weeks compared to the control rats. The titer of the anti-LM antibody increased 3-7 weeks before death in the non-survivors in control and TJN-101-treated rats, supporting the idea that anti-LM antibody occurs in association with acute lethal hepatitis.

An outbreak of infectious hepatitis in commercially reared ostriches associated with Campylobacter coli and Campylobacter jejuni.

A disease causing high morbidity and mortality was observed in young ostriches from six properties in southeast Queensland, Australia. The disease affected birds from 2-8 weeks of age and was characterised clinically by bright-green urates and pathologically by severe necrotic hepatitis. The liver lesions resembled those of vibrionic hepatitis in other avian species. Campylobacter coli was isolated from the livers of affected ostriches from five of the six properties. Campylobacter jejuni subsp. jejuni was isolated from birds from the remaining property. Pulsed-field gel electrophoresis-based (PFGE) typing of representative isolates indicated that trade of infected birds between farms was an important factor in the spread of C. coli. Phenotypic and genotypic data suggest a clonal variant of the principal outbreak type may account for the remaining cases from which C. coli was found. Conventional biochemical test results and PFGE clearly distinguished the C. jejuni strain isolated from the geographically remote farm from the outbreak of C. coli type. We believe this to be the first definitive report of avian hepatitis associated with C. coli.

Effect of oxymatrine on murine fulminant hepatitis and hepatocyte apoptosis.

OBJECTIVE: To evaluate the protective effects and mechanism of action of oxymatrine (OM) on the experimental fulminant hepatitis (FH) and early hepatocyte apoptosis in murine liver tissue. METHODS: Fulminant hepatitis mice were induced by injecting lipopolysaccharide (LPS) intraperitoneally (ip) in galactosamine (GalN) sensitized mice. Two separate experiments were designed, including saline control group, fulminant hepatitis group and oxymatrine pretreated group (50 mg/kg, intraperitoneally, bid x 3 days). The levels of serum tumor necrosis factor alpha (TNFa) in mice from two experiments were determined at 5-hour and 7.5-hour after injecting galactosamine/lipopolysaccharide. Mouse liver samples at 5-hour time point were obtained for in situ end labeling (ISEL) staining and ultrastructural observation of apoptotic cells under transmission electron microscope (TEM). Liver samples at 7.5-hour time point were taken for hematoxylin-eosin (HE) staining and immunohistochemical staining of Fas and its ligand (FasL). RESULTS: As compared with the fulminant hepatitis group, the levels of serum tumor necrosis factor alpha in mice from the OM pretreated group at 5-hour and 7.5-hour time point were all significantly decreased (P < 0.05 and P < 0.01 respectively). Hepatocyte apoptosis in mice at 5-hour time point was significantly inhibited (P < 0.01). Both the degree of liver injury and the degree of Fas and Fas ligand expression in the OM pretreated group were reduced remarkably (P < 0.01 and 0.05 respectively) when compared with the saline control group. CONCLUSIONS: Oxymatrine protects mice from fulminant hepatitis induced by GalN/LPS and may block hepatocyte apoptosis and subsequent necrosis through downregulating the production of serum tumor necrosis factor alpha and the expression of Fas and Fas ligand in liver tissue.

Effects of corticosteroid treatment on survival time in dogs with chronic hepatitis: 151 cases (1977-1985)

Medical records of 151 dogs with chronic hepatitis were reviewed. Corticosteroid treatment had a statistically significant (P less than 0.005) effect on improving survival time when corticosteroid-treated dogs were compared with untreated dogs. Dogs dying within 1 week of examination represented 37.1% of the cases, and when compared with those living more than 1 week, serum glucose concentration was significantly lower (P less than 0.001); prothrombin time and partial thromboplastin time were significantly longer (P less than 0.001); blood ammonia concentration after oral administration of ammonium chloride was significantly higher (P less than 0.05); and necrosis severity and fibrosis severity were significantly greater (P less than 0.05 and P less than 0.022, respectively). The best predictors of early death were low normal serum glucose concentration (P less than 0.001) and prolonged prothrombin time (P less than 0.030), which was abnormal in 60.0% of dogs dying early. Partial thromboplastin time, which was increased in 92.0% of dogs dying early and in 42.6% of dogs living more than 1 week, was a less reliable predictor. Plasma ammonia concentration after oral administration of NH4Cl was least reliable in predicting early death. In dogs living more than 1 week, hypoalbuminemia was a predictor of shorter survival time (P less than 0.003). Of all the histologic features evaluated, only necrosis severity and fibrosis severity were accurate predictors of early death. The presence of bridging fibrosis was a predictor of shorter survival time in dogs living more than 1 week (P less than 0.0002).

Clinical features of inflammatory liver disease in cats: 41 cases (1983-1993).

OBJECTIVE: To compare the clinical and clinicopathologic findings in and prognosis for cats with lymphocytic portal hepatitis (LPH) versus cats with acute or chronic cholangiohepatitis (CH). DESIGN: Retrospective study. ANIMALS: 25 cats with LPH; 16 cats with CH (7 acute, 9 chronic). PROCEDURE: Cats with LPH and CH were selected by evaluating records from liver biopsy specimens submitted to the University of Minnesota Veterinary Teaching Hospital during a 10-year period. Clinical and clinicopathologic data were retrieved. RESULTS: Cats with CH had higher segmented and band neutrophil counts, alanine aminotransferase activities, and total bilirubin concentrations than did cats with LPH. Cats with acute CH had higher segmented and band neutrophil counts and lower serum alkaline phosphatase activities and total bilirubin concentrations than did cats with chronic CH. Twelve of 14 cats with LPH or CH had coarse or nodular texture to the liver on ultrasonography, with loss of portal vein wall clarity noticed in 4 of 8 cats with LPH. Sixteen of 23 cats with LPH and 8 of 15 cats with CH survived > 1 year. Of those cats living < 1 year, all cats with LPH and 5 of 7 cats with CH had a serious concurrent illness that may have been responsible for their deaths. CLINICAL IMPLICATIONS: LPH and CH can be detected and tentatively differentiated through evaluation of clinical laboratory test results, but histologic evaluation of liver specimens is necessary for definitive differentiation. Survival time was good regardless of the type of inflammatory liver disease.

Suspected hepatotoxicity in neonatal foals: preliminary report of an emerging syndrome.

An apparently new and emerging fatal hepatic disease affecting foals is described. Characteristics included evidence of hepatic failure, marked biliary hyperplasia, hepatocellular necrosis and occasionally fibrosis. Generally, the features of the disease appear to differ markedly from other hepatic diseases of neonatal foals.

Disease-husbandry associations in farmed crocodiles in Queensland and the Northern Territory.

To investigate husbandry-disease associations in farmed crocodiles 7 farms in Queensland and the Northern Territory were visited and details of past and present farm design and husbandry practices were recorded. In addition pathological examination of 300 (mostly young) crocodiles was carried out (85 necropsied, one biopsied and 214 examined retrospectively). Mortality rate and occurrence of disease, especially opportunistic infections with bacteria and fungi, were highest during winter months and in farms located at greater latitudes. A difference in the presence and prevalence of disease between the initial establishment phase of Northern Territory crocodile farms (1984-87) and currently (1988-91) was apparent; parasitic infections are now relatively infrequent and bacterial septicaemias and mycoses less common as a result of some provision of artificial heating for juveniles. Gross and microscopic changes observed in visceral and periarticular gout, bacterial hepatitis/septicaemia, deep and superficial mycosis, pentastomiasis and other parasitic infections are described.

Diagnosis and prognosis of chronic hepatitis and cirrhosis in dogs.

The purpose of this investigation was to evaluate the significance of enzymatic and biochemical analyses in the classification of chronic inflammatory liver disease and to evaluate the prognosis of these diseases. Chronic hepatitis and cirrhosis were diagnosed by histopathological examination in 79 dogs. Decreased appetite and lethargy were the most common owner complaints (46/79). Vomiting and, or, diarrhoea were reported in 27/79 dogs. Ascites was the most common clinical sign (43/79), whereas icterus was a more unusual finding demonstrated in 16/79 dogs. Liver cirrhosis was diagnosed most frequently, in 33/79 dogs, followed by chronic progressive hepatitis (22/79), chronic cholangiohepatitis (13/79), and chronic non-specific hepatitis (11/79). Hypoalbuminaemia was the most consistent biochemical aberration in liver cirrhosis (25/26) and in chronic progressive hepatitis (13/18). These diseases also showed normal to mildly increased concentrations of serum alanine aminotransferase (ALT) and serum gamma-glutamyl transferase (GGT) and a moderate to marked increase of serum alkaline phosphatase (ALP) and fasting serum bile acid (SBA) concentrations. As expected, icterus and markedly elevated ALT, ALP, GGT and SBA levels were demonstrated in chronic cholangiohepatitis. In this disease hypoalbuminaemia was shown in 6/12 dogs, whereas in dogs with chronic non-specific hepatitis, mean SBA and albumin concentrations were normal. In liver cirrhosis the prognosis was poor, with 94 per cent of the dogs dead within one week of established diagnosis. For dogs with the other types of chronic hepatitis the prognosis was more favourable with the mean survival time ranging from 21.1 to 36.4 months.