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.

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.

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.

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.

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.

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.

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.

Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis.

Autoimmune hepatitis (AIH) in humans arises spontaneously in genetically susceptible individuals and is associated with the presence of Th1 cells in the liver. The understanding of AIH has advanced more slowly than that of other organ-specific autoimmune diseases, however, largely because of the lack of an appropriate animal model. We now describe a new mouse model characterized by spontaneous development of necroinflammatory hepatitis that is restricted by genetic background. Mice deficient in the immunomodulatory cytokine TGF-beta1 were extensively back-bred to the BALB/c background. The BALB/c background dramatically modified the phenotype of TGF-beta1(-/-) mice: specifically, BALB/c-TGF-beta1(-/-) mice developed a lethal necroinflammatory hepatitis that was not observed in TGF-beta1(-/-) mice on a different genetic background. BALB/c background TGF-beta1(-/-) livers contained large numbers of activated CD4(+) T cells that produced large quantities of IFN-gamma, but little IL-4, identifying them as Th1 cells. BALB/c background TGF-beta1(-/-)/IFN-gamma(-/-) double knockout mice, generated by cross-breeding, did not develop necroinflammatory hepatitis, demonstrating that IFN-gamma is mechanistically required for its pathogenesis. This represents the first murine model of hepatitis that develops spontaneously, is restricted by genetic background, and is dependent upon the Th1 cytokine IFN-gamma, and that thus recapitulates these important aspects of AIH.

Inhibition of Fas-mediated fulminant hepatitis in CrmA gene-transfected mice.

Hyperimmune response via Fas/Fas-ligand and perforin/granzyme pathways may be essential in pathogenesis of virus-induced fulminant hepatitis. CrmA inhibits activation of caspases and granzyme B, suggesting it may block these pathways. We investigated whether CrmA expression would inhibit Fas-associated lethal hepatitis in mice. We successfully generated AxCALNLCrmA, a recombinant adenovirus expressing CrmA gene with a Cre-mediated switching cassette. We increased CrmA expression level in the liver transfected with AxCALNLCrmA (10(9) pfu) by increasing administration dose (10(7)-10(9) pfu) of AxCANCre, a recombinant, adenovirus-expressing Cre gene. Injection of anti-Fas antibody into the control mice rapidly led to animal death due to massive liver apoptosis, while the apoptosis was dramatically reduced in the CrmA-expressed mice. The animal survival increased with an increase of CrmA expression. The formation of active caspase-3 was markedly inhibited in the crmA-transfected hepatocytes in vitro. These results suggest that crmA is an effective gene that can inhibit immune-related liver apoptosis.

Hepatoprotective effects of Inula britannica on hepatic injury in mice.

Inula britannica, a Kampo medicine, is prepared from the heads of Compositae plants such as Inula britannica L., which has been used clinically as a remedy for nausea, hiccup and excessive sputum. Here it is shown that administration of Inula britannica improves the survival rate of mice with hepatic injury induced by LPS/PA. It is also suggested that administration of Inula britannica significantly reduces the fluctuation in the amount of cytokine in the spleen of mice with hepatic injuries, and that the Th1/Th2 control effect is related to the inhibitory action of Inula britannica against hepatic injury. In vitro testing suggests that Inula britannica suppresses Th1 differentiation and induces Th2 differentiation by inhibiting the production of macrophage IL-12 and promoting the production of IL-10, thus showing the immunological effect of hepatic injury inhibition by affecting the balance between Th1 and Th2.

Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins.

Lethal hepatitis can be induced by an agonistic anti-Fas Ab in normal mice or by TNF in mice sensitized to d -(+)-galactosamine or actinomycin D. In all three models, we found that apoptosis of hepatocytes is an early and necessary step to cause lethality. In the three models, we observed activation of the major executioner caspases-3 and -7. Two acute-phase proteins, alpha1-acid glycoprotein and alpha1-antitrypsin, differentially prevent lethality: alpha1-acid glycoprotein protects in both TNF models and not in the anti-Fas model, while alpha1-antitrypsin confers protection in the TNF/d -(+)-galactosamine model only. The protection is inversely correlated with activation of caspase-3 and caspase-7. The data suggest that activation of caspase-3 and -7 is essential in the in vivo induction of apoptosis leading to lethal hepatitis and that acute phase proteins are powerful inhibitors of apoptosis and caspase activation. Furthermore, Bcl-2 transgenic mice, expressing Bcl-2 specifically in hepatocytes, are protected against a lethal challenge with anti-Fas or with TNF/d -(+)-galactosamine, but not against TNF/actinomycin D. The acute-phase proteins might constitute an inducible anti-apoptotic protective system, which in pathology or disturbed homeostasis prevents excessive apoptosis.

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.

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.

High-level constitutive expression of alpha 1-acid glycoprotein and lack of protection against tumor necrosis factor-induced lethal shock in transgenic mice.

alpha 1-Acid glycoprotein (AGP) is an acute phase protein produced by hepatocytes. Although its exact biological function remains controversial, it was shown to protect galactosamine-sensitized or normal mice against hepatitis and lethal shock induced by tumor necrosis factor (TNF). Rat-AGP-transgenic mice, constitutively producing several mg AGP per ml serum were tested for their response to a combined challenge with TNF and D-(+)-galactosamine. A previously characterized, single transgenic line (9.5-5) was used. In contrast to our expectations both heterozygous or homozygous transgenic mice were not protected by the endogenously overproduced AGP. However, both transgenic and non-transgenic mice were protected by pretreatment with interleukin-1, an effect which we believe is mediated by the induction of acute phase proteins like AGP. Furthermore, both types of mice were protected by exogenous bovine AGP, suggesting that the lack of protection by endogenous AGP is not because of a repressed response to AGP. Finally, we demonstrate that purified AGP from the serum of transgenic mice is as protective as the AGP from non-transgenic mice or rats. The results suggest that AGP is protective only when its concentration is rapidly induced, perhaps because the endogenous steady state synthesis of AGP, in non-transgenic as well as transgenic mice, is coupled to the production of an AGP-binding factor. This study provides an interesting example of differences in outcome to a lethal challenge between an acute administered and a chronically produced protective protein.

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.

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.

Effects of cyclosporin-A and D-penicillamine on the development of hepatitis and the production of antibody to protein disulfide isomerase in LEC rats.

Long Evans Cinnamon (LEC) rats, which spontaneously develop hepatitis, produce an autoantibody to protein disulfide isomerase (PDI) before the development of clinical signs of hepatitis. Anti-PDI antibody may be associated with immunological hepatitis. Thus, the purpose of this study was to investigate the effects of some drugs on the development of hepatitis and the occurrence of the antibody in LEC rats. Cyclosporin-A, an immunosuppressant, and D-penicillamine, which promotes copper excretion, were orally administered to LEC rats for 23 weeks. Mortality, blood biochemical parameters and the titer of serum anti-PDI antibody were measured. In control LEC rats, four of eight rats died before 20-weeks-old. Only one of seven rats in the cyclosporin-A-treated group died at the age of 20 weeks. When rats were treated with D-penicillamine, the development of clinical signs of hepatitis was inhibited, and all rats survived. Cyclosporin-A-treated rats showed increases in blood biochemical parameters similar to those in control rats. The titer of anti-PDI antibody in control rats was higher the non-survivors than survivors. These findings suggest the association of the anti-PDI antibody with lethality, but not with the apparent development and progression of hepatitis as measured by blood biochemical parameters in LEC rats.