Characterization of clinical presentation, histological features, ultrasonographic findings, and survival in 29 dogs with granulomatous hepatitis.

BACKGROUND: Granulomatous hepatitis (GH) is a form of chronic hepatitis (CH) in dogs for which limited information is published. HYPOTHESIS: Describe the clinical presentation, clinical pathology, ultrasound, and hepatic histopathology findings and to report survival times in dogs with GH. ANIMALS: Twenty-nine client-owned dogs with GH. METHODS: Retrospective observational study. Pathology records were searched. Inclusion criteria included a histopathologic diagnosis of GH, absence of an identified etiology or evidence of extrahepatic granulomatous disease, and a medical record available for review. Clinical presentation, clinical pathologic findings, treatment protocols, and survival times were recorded. Available hepatic biopsy material was graded and scored, and ultrasound evaluations reviewed. RESULTS: The median age was 7 years (range, 0.66-12 years). Nineteen breeds were represented. Decreased appetite (19/29), lethargy (16/29), and fever (13/29) were seen most commonly. All dogs had increased serum transaminase activities, whereas 21/29 and 12/24 had hyperbilirubinemia and neutrophilia, respectively. Ultrasonographic findings included hepatomegaly (12/22), nodular parenchymal lesions (9/22), and hyperechoic parenchymal bands (8/22). Histopathologic necroinflammatory scores were moderate to severe in 16/19 dogs, and fibrosis scores were mild in 14/19 dogs. Treatments varied and included antibiotics, immunosuppressive drugs, and hepatoprotectants. Overall median survival was 635 days (range, 1-2482 days). CONCLUSION AND CLINICAL IMPORTANCE: Granulomatous hepatitis in dogs is associated with high histopathologic grade, fever, neutrophilia, and a high incidence of hepatomegaly and focal parenchymal lesions on ultrasound examination. Despite disease severity on presentation, dogs with GH can have a good outcome with prolonged survival.

Copper-associated chronic hepatitis in Cavalier King Charles spaniels.

BACKGROUND: Copper-associated chronic hepatitis (CuCH) is poorly characterised in Cavalier King Charles spaniels (CKCS). METHODS: Hepatic copper accumulation was qualitatively and quantitatively assessed, and blood samples were used for genetic testing to screen for known CuCH-associated genetic variants. RESULTS: The study included 13 CKCS with CuCH and eight unaffected controls. Increased transaminase activities, elevated biliary enzyme concentrations and portal hypertension were documented in 100%, 73% and 38% of dogs with CuCH, respectively. Five dogs had three or more abnormalities in measures of liver function. All 11 dogs with CuCh that underwent genetic testing were homozygous negative for the COMMD1 deletion and ATP7A variant but homozygous positive (n = 7) or heterozygous (n = 4) for the ATP7B variant. Liver histology often demonstrated marked architectural distortion by severe, bridging fibrosis and regenerative nodules with lymphoplasmacytic inflammation. Centrilobular copper accumulation characterised early cases with minimal fibrosis. When fibrosis was significant, copper was often differentially concentrated within regenerative nodules. Chelation therapy resolved laboratory derangements and portal hypertension in five of seven dogs. Of the 7 non-surviving dogs with CuCH, 6 had not received chelation therapy. LIMITATIONS: Limitations include a small cohort size and the lack of pedigree analyses to corroborate heritability. CONCLUSIONS: CuCH should be considered in CKCS with suspected liver disease. Long-term prognosis seems favourable in dogs receiving chelation therapy, notwithstanding the presence of previously reported negative prognostic markers.

Mycophenolate mofetil as a treatment for presumed idiopathic chronic hepatitis in dogs: Six cases (2010-2022).

OBJECTIVES: The objectives of this study were to describe the clinical findings, treatment and outcomes of six dogs with presumed idiopathic chronic hepatitis treated with mycophenolate mofetil (MMF). MATERIALS AND METHODS: Medical records were retrospectively searched to identify dogs in which idiopathic chronic hepatitis was diagnosed on histopathology between January 2010 and June 2022 that were treated with MMF for at least two weeks with >2 follow-up examinations. Data recorded from each dog included signalment, clinical signs, diagnostic test results and treatment. RESULTS: Six dogs were treated with MMF at a median initial dosage of 9.6 mg/kg PO q 12 h. Reported adverse effects from MMF included decreased appetite, vomiting and diarrhoea. In all six dogs, MMF was used successfully long term for the treatment of idiopathic chronic hepatitis as determined by 46% or greater improvement of alanine aminotransferase (ALT) between 4 and 18 weeks of starting MMF. Three dogs were also temporarily treated for 4-6 months on a tapering dose of prednisone. In two dogs, ALT remained within the reference interval, and in one dog, it was very mildly elevated when on MMF alone. In all six dogs, owners reported that the medication was well tolerated. CLINICAL SIGNIFICANCE: To the authors' knowledge, this is the first report describing the use of MMF with and without a tapering dose of prednisone for the treatment of idiopathic chronic hepatitis in six dogs. Based on the outcomes of the dogs in this report, MMF can be effective for the long-term treatment of idiopathic chronic hepatitis as measured by reduction in ALT and improvement of clinical signs.

Prevalence of portal vein and splanchnic venous thrombosis in dogs with chronic hepatitis.

OBJECTIVES: Alterations in haemostasis have been described in dogs and humans with chronic hepatitis. Portal vein thrombosis is a recognised complication of chronic hepatitis in humans; however, its prevalence in dogs with chronic hepatitis has not been reported. We aimed to estimate the prevalence of, and describe clinical and laboratory data of dogs with chronic hepatitis and portal vein thrombosis and splanchnic venous thrombosis. MATERIALS AND METHODS: Retrospective cross-sectional study. Medical records of dogs admitted to a veterinary teaching hospital between 2009 and 2019 were reviewed. Dogs were included if chronic hepatitis was histopathologically confirmed, and if diagnostic imaging or necropsy indicated the presence of thrombosis. Clinical and laboratory data (i.e. haematology, biochemistry, coagulation panels) were recorded. Descriptive statistics were used to characterise dogs with and without thrombosis. RESULTS: Records from 136 dogs with chronic hepatitis were identified. Three of these dogs, 2.2% (95% confidence interval: 0.8 to 6.3%) all females, were diagnosed with portal vein thrombosis. Five dogs in total, (3.7%; 95% confidence interval: 1.6 to 8.3%), including three with portal vein thrombosis, all females, were diagnosed with splanchnic venous thrombosis. Dogs with portal vein and splanchnic venous thrombosis often had hyperbilirubinaemia, increased serum gamma-glutamyl transferase activity, and decreased plasma antithrombin 3 activity. They also had relatively high alternative Child-Pugh scores for dogs (median 6 out of 13). CLINICAL SIGNIFICANCE: Portal vein and splanchnic venous thrombosis are potentially serious complications that were identified in a relatively low proportion of dogs with chronic hepatitis.

Correlation of hepatic copper levels, rhodanine scores and histological diagnosis in archived canine liver samples.

The liver is the main storage site for copper. Excess copper accumulation, however, is a risk factor for the development of chronic hepatitis in dogs. Mass spectrometry or rhodanine staining are frequently used methods to assess copper levels in the liver. The association was studied between analytic hepatic copper levels and rhodanine scores in archived canine formalin-fixed-paraffinembedded liver sections from 2014 to 2021 with various diagnoses. Thirty-six (N = 36) liver samples with analytic interpretation of toxic (n = 12), high normal (n = 17), and normal (n = 7) copper levels were selected for the study. Rhodanine staining for each of these samples was graded (scale: 1 to 5), and the association was determined between actual liver copper levels and rhodanine scores and histological diagnoses (chronic hepatitis or other diagnoses). The analytic copper level and rhodanine scores were significantly higher (P < 0.05) in samples designated as toxic compared to normal. There was a significant association between hepatic copper levels and rhodanine scores (P < 0.05). Rhodanine score, but not the actual liver copper levels were significantly (P < 0.05) associated with chronic hepatitis versus other diagnoses. Rhodanine scores of ≥ 1.89 were statistically significant predictors of chronic hepatitis. It was concluded from this study that actual liver copper levels are positively associated with rhodanine scores and rhodanine scores can be a useful predictor of chronic hepatitis.

Le foie est le principal site de stockage du cuivre. Cependant, une accumulation excessive de cuivre est un facteur de risque pour le développement d'une hépatite chronique chez le chien. La spectrométrie de masse ou la coloration à la rhodanine sont des méthodes fréquemment utilisées pour évaluer les niveaux de cuivre dans le foie. L'association entre les niveaux analytiques de cuivre hépatique et les scores de rhodanine a été étudiée dans des sections de foie de chien archivées fixées au formol et incluses dans de la paraffine de 2014 à 2021 avec divers diagnostics. Trente-six (N = 36) échantillons de foie avec interprétation analytique des niveaux de cuivre toxiques (n = 12), normaux élevés (n = 17) et normaux (n = 7) ont été sélectionnés pour l'étude. La coloration à la rhodanine de chacun de ces échantillons a été évaluée (échelle : 1 à 5) et l'association a été déterminée entre les niveaux réels de cuivre dans le foie et les scores de rhodanine et les diagnostics histologiques (hépatite chronique ou autres diagnostics). Les niveaux analytiques de cuivre et les scores de rhodanine étaient significativement plus élevés (P < 0,05) dans les échantillons désignés comme toxiques par rapport à la normale. Il y avait une association significative entre les niveaux de cuivre hépatique et les scores de rhodamine (P < 0,05). Le score de rhodanine, mais pas les niveaux réels de cuivre dans le foie, était significativement (P < 0,05) associé à l'hépatite chronique par rapport à d'autres diagnostics. Les scores de rhodanine ≥ 1,89 étaient des prédicteurs statistiquement significatifs de l'hépatite chronique. Il a été conclu à partir de cette étude que les niveaux réels de cuivre dans le foie sont positivement associés aux scores de rhodanine et que les scores de rhodanine peuvent être un prédicteur utile de l'hépatite chronique.(Traduit par Docteur Serge Messier).

Domestic cat hepadnavirus associated with hepatopathy in cats: A retrospective study.

BACKGROUND: Whether domestic cat hepadnavirus (DCH) infection is associated with clinical disease remains to be determined. OBJECTIVES: To determine the relationship between DCH detection, hematology, serum bichemistry and liver histology in DCH-positive cats. ANIMALS: One thousand twenty-two cats in Thailand without concurrent diseases and not undergoing treatments adversely affecting the liver. METHODS: Retrospective cross-sectional study. Samples derived from cats with concurrent virus detection were excluded. DCH detection was determined in blood and fresh-frozen liver by quantitative polymerase chain reaction (qPCR) and further investigated in liver sections showing histological parenchymal disorders (HPD) and normal liver (HNL) using in situ hybridization (ISH). Proliferative/apoptotic activities were determined using immunohistochemistry and ISH panels. Biochemical variables and risk factors for DCH infection were investigated. RESULTS: Six hundred sixty-one (557 blood and 119 liver samples) cats were included. DCH was detected in 18.50% (103/557), 13.85% (9/65), and 3.70% (2/54) of the blood, HPD, and HNL groups, respectively. Cats with DCH revealed abnormally high activity of aspartate aminotransferase (AST) (P = .001) and alanine aminotransferase (ALT) (P < .001). Among DCH-positive HPD case 2/9 an 7/9 were acute and chronic hepatitis, of which 4/7 had hepatitis. Log viral copy number (LVCN) was positively correlated with ALT (P < .001), triglyceride (P < .001), and gamma-glutamyl transpeptidase (GGT) (P = .022). The LVCN also had a positive association with degree of hepatitis (P < .05). There was hepatocyte proliferation activity in DHC positive cats. CONCLUSION AND CLINICAL IMPORTANCE: Domestic cat hepadnavirus infection was associated with high serum activity of liver enzymes and chronic lymphoplasmacytic hepatitis (LPH).

Serum protein electrophoresis in 26 dogs with chronic hepatitis.

Serum protein electrophoresis (SPE) shows the distribution of protein fractions, helping clinicians to characterize some pathologic processes. Information is lacking in the literature about SPE alterations in dogs with chronic hepatitis (CH). Our aim was to describe SPE alterations in canine CH, to compare SPE results to histologic scores, and to study SPE trends during follow-up. We reviewed retrospectively case data from dogs with a histologic diagnosis of CH. Only cases with SPE, CBC, and serum chemistry results available were included. Dogs were divided into subgroups based on histologic necroinflammatory activity (A) and fibrosis (F) scores (groups A0-1 and A>1; groups F<2 and F≥2). We included 26 dogs; 15 had follow-up SPE. The most common SPE alterations at admission were hypoalbuminemia (n = 16), increases in α1-globulins (n = 11), γ-globulins (n = 11), α2-globulins (n = 8), ß2-globulins (n = 7), and ß1-globulins (n = 6), and decreased albumin:globulin (A:G) ratios (n = 20). Four of 11 dogs had ß-γ bridging. Groups with higher A and F scores had higher ß2-globulins. Eleven of 15 dogs with a post-treatment SPE had a decrease in γ-globulins and increase in A:G ratio compared to their T0, although there was no statistically significant difference. Although further studies are warranted, SPE may be useful for monitoring canine CH.

Immunohistochemical Expression of Oxidative Stress and Apoptosis Markers in Archived Liver Specimens from Dogs with Chronic Hepatitis.

Chronic hepatitis (CH) in dogs is histologically characterized by an inflammatory infiltration of the liver accompanied by hepatocellular apoptosis or necrosis, varying degrees of fibrosis and regeneration. Oxidative stress has been suggested to play a role in the pathogenesis of various liver diseases, including CH. This study assessed the immunohistochemical expression of markers of oxidative stress (4-hydroxynonenal [4-HNE] and malondialdehyde [MDA]) and apoptosis (active caspase-3 [casp-3]) in 35 surplus archived formalin-fixed paraffin-embedded liver biopsies from 25 dogs with CH and 10 control dogs that had no significant hepatic changes. Correlations between immunohistochemical markers and necroinflammatory, fibrosis and histological copper scores, and hepatic copper concentrations were also determined. There were no significant differences in 4-HNE expression between the two groups. Control dogs had lower hepatic MDA scores than dogs with CH. MDA scores were positively correlated with copper scores as well as hepatic copper concentrations. There was no significant difference in casp-3-positive hepatocytes between groups. However, a positive correlation between casp-3 immunoreactivity and copper scores, as well as hepatic copper concentrations, was identified. Necroinflammatory and fibrosis scores were positively correlated with immunoreactivity for MDA and casp-3. MDA and casp-3 are expressed in canine liver and both markers are correlated with necroinflammatory scores, fibrosis scores and hepatic copper accumulation. Our results suggest the utility of immunolabelling for MDA and casp-3 for assessment of hepatic oxidative stress and apoptosis, respectively, in dogs with CH.

Histopathological frequency of canine hepatobiliary disease in the United Kingdom.

OBJECTIVES: Canine hepatobiliary disease is common; however, data determining disease frequency and breed predispositions are lacking. The primary objective was to identify the frequency of different hepatobiliary disease in a United Kingdom population of dogs and consequently determine breeds at both an increased and decreased risk of hepatobiliary disease. MATERIALS AND METHODS: Anonymised histopathology reports from a commercial veterinary diagnostic laboratory, which were submitted between August 2013 and February 2018, were analysed. Data were retrospectively categorised into hepatobiliary diseases according to World Small Animal Veterinary Association Standards and the breed, age and genders recorded. Cases with incomplete data or no definitive diagnosis were excluded. Breed predisposition was calculated using odds ratios and 95% confidence intervals against a United Kingdom-based control population of micro-chipped dogs. RESULTS: Histopathology results from 4584 cases met inclusion criteria. The most frequent histological diagnoses were reactive hepatitis (n=770); chronic hepatitis (n=735) and reversible hepatocellular injury (n=589). A number of breeds were shown to be at an increased or decreased risk of individual liver diseases. CLINICAL SIGNIFICANCE: This is the first study to document the histopathological frequency of hepatobiliary diseases in a large cohort of dogs in the United Kingdom, as well as novel possible breed and age predispositions. Despite multivariable analysis not being performed to account for confounding factors, this information hopes to inform and support future investigations for hepatic disease in particular breeds and potential predispositions.

Hepatic lead and copper concentrations in dogs with chronic hepatitis and their relationship with hematology, serum biochemistry, and histopathology.

BACKGROUND: Although the influence of copper ([Cu]) on chronic hepatitis (CH) has been widely studied in dogs, little information is available about the accumulation of other metals. HYPOTHESIS/OBJECTIVES: We assessed the concentration of lead ([Pb]) in the livers of dogs with CH with or without abnormal hepatic [Cu] to establish if any association existed between [Pb] and either hematologic or biochemical variables, fibrosis, necrosis and inflammation of the liver on histology. ANIMALS: Thirty-four dogs with CH that had hepatic [Cu] and [Pb] determined. METHODS: Retrospective review of medical records of dogs with CH and hepatic [Cu] and [Pb]. Chronic hepatitis was defined using current American College of Veterinary Internal Medicine consensus statement guidelines. Hepatic [Cu] and [Pb] were determined using square wave anodic stripping voltammetry. Dogs were divided into 2 groups based on [Cu]: <400 ppm (LoCu) and ≥400 ppm (HiCu). RESULTS: The median [Cu] and [Pb] were 357 ppm (range, 100-7743 ppm) and 58.7 (range, 6.89-224.4 ppm), respectively. Nineteen dogs had LoCu and 15 dogs had HiCu. Median [Pb] was significantly higher in HiCu compared to LoCu dogs (P < .001). Hepatic [Pb] and [Cu] were significantly correlated (rho = 0.7; P < .001). Dogs with microcytosis had higher [Pb] than did dogs with normal red cell volume (P = .02). Hepatic [Pb] was not correlated with either necroinflammatory or fibrosis scores. CONCLUSIONS AND CLINICAL IMPORTANCE: Although additional studies are needed to better understand the clinical role of hepatic [Pb], dogs with abnormal hepatic [Cu] may also have higher hepatic [Pb]. In addition, in dogs with high hepatic [Pb], microcytosis may be present.

Copper-associated hepatitis in a young Dalmatian dog in Japan.

A male 25-month-old Dalmatian dog attended our veterinary hospital because of anorexia and high circulating liver enzyme activities. Abdominal computed tomography showed a slightly small liver with rounded edges, and laparoscopic examination showed that the liver was yellowish. Histopathological examination revealed multifocal necrosis of hepatocytes and severe chronic hepatitis. Rhodanine staining showed severe copper accumulation in hepatocytes and a quantitative analysis of the copper content of the liver showed substantial accumulation (10.3 mg/g dry mass), suggesting a diagnosis of copper-associated hepatitis. Previously reported canine mutation in the COMMD1, the gene responsible for the copper-associated hepatitis in the Bedlington terrier, was not identified. To our knowledge, this is the first report of copper-associated hepatitis in a Dalmatian in Japan.

Canine copper-associated hepatitis: A retrospective study of 17 clinical cases.

Background: Copper-associated hepatitis (CAH) is a well-documented chronic hepatic disease in dogs. In some breeds, the disease results from an inherited defect in copper metabolism. In others, it is unclear whether its acummulation is a primary or secondary condition. Reports of copper accumulation in dog breeds that are not genetically predisposed are increasing. Aim: To describe the epidemiology, clinical and laboratory findings, liver biopsy techniques, and treatment response in dogs with CAH. Methods: A retrospective study was performed, drawing upon medical records from CAH dogs at a Veterinary Referral Hospital in Paris, France. The diagnosis of CAH had been confirmed in these patients by positive rhodanine staining of hepatic tissue obtained through biopsy. Medical records were mined for the following data: age at presentation, sex, breed, chief presenting complaints, abdominal ultrasound (US) findings, and rhodanine staining pattern. Results: A total of 17 dogs were included in the study. Median age at presentation was 8-year old (4-11). No sex predisposition was found. Terriers (4/17) and German Shepherd Dogs (GSD, 3/17) were overrepresented. American Staffordshire Terriers and Beauceron had not previously appeared in case reports on CAH; two of each breed were identified in this study. Clinical signs of affected dogs were non-specific. An incidental identification of increased liver-enzymes was observed in 5/17 dogs. A heterogeneous, mottled liver was frequently described (5/17) on abdominal US. Liver biopsies were performed by US-guided percutaneous approach in 10/17 dogs, laparoscopy and laparotomy in 6/17 and 1/17, respectively. The rhodanine staining pattern was centrilobular (zone 3) in 8/17 dogs and periportal (zone 1) in 3/17 dogs. The pattern was considered multifocal in 6/17 dogs. Conclusion: Increased liver enzymes may be the only clinical finding in dogs with copper-associated hepatitis, reflecting the silent progression of this disease. Centrilobular pattern of rhodanine staining was observed in the majority of cases suggesting the primary condition of the disease. Results of this study are consistent with the current literature, which reports that terriers and GSD are predisposed to CAH. This is the first description of CAH in Beauceron and American Staffordshire Terrier dogs.

Prednisolone therapy for chronic hepatitis in English springer spaniels: a prospective study of 12 cases.

BACKGROUND: English springer spaniels (ESS) show an increased risk of chronic hepatitis (CH). In a previous study of 68 ESS with CH, in which only one dog received corticosteroids, a median survival time of 189 days was noted. Some ESS with CH appear to improve with prednisolone treatment; therefore, we aimed to investigate the response to prednisolone in this breed. PARTICIPANTS: ESS with histologically confirmed idiopathic CH were treated with prednisolone 1-2 mg/kg/day. Nine female and three male ESS were enrolled (median age at diagnosis of five years). Patients were monitored clinically and had biochemistry samples taken to assess markers of hepatocellular damage and function. RESULTS: The mean starting dose of prednisolone was 1.1 mg/kg/day. All symptomatic patients showed an initial clinical improvement. Two cases were euthanased while receiving prednisolone. The median time since diagnosis is 1715 days (range: 672-2105 days) and the remaining patients are clinically well, with seven patients still receiving a mean dose of 0.4 mg/kg prednisolone every other day. Statistical analysis demonstrated significant (P<0.05) reductions in serum alkaline phosphatase, alanine aminotransferase and bilirubin following 2-4 weeks of prednisolone treatment. CONCLUSION: This study demonstrates improved clinical and biochemical parameters when some ESS with CH are managed with prednisolone and standard supportive treatments.

Neutrophilia is associated with a poorer clinical outcome in dogs with chronic hepatitis.

BACKGROUND: Liver disease is a common cause of morbidity and mortality in dogs. Currently, it is challenging to prognosticate in these cases. The aim of this study was to evaluate the utility of the haematological variables in dogs with chronic hepatitis. METHODS: Dogs with chronic hepatitis confirmed on histopathology had presenting haematological values retrospectively obtained and evaluated against survival time. Eighty-two dogs met the inclusion criteria and their data analysed. RESULTS: Neutrophilic patients, with a count greater than 12×109/l, controlled for sex and age, had a shorter survival time (P≤0.01). In dogs, neutrophilia at presentation predicted a poor outcome, whereas the other haematological parameters were not prognostically informative. When the dogs were split into even quarters on the basis of their neutrophil count, those within the higher quartiles had poorer survival times. Neutrophilia was associated with a poorer survival time in comparison to those patients with a lower count. CONCLUSION: The relationship between neutrophils, inflammation and clinical outcome is deserving of future study in dogs with chronic hepatitis.

Plasma renin activity and aldosterone concentration in dogs with acquired portosystemic collaterals.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is activated in humans with portal hypertension (PH) associated with liver disease. However, involvement of RAAS in dogs with intrahepatic PH is not clear. OBJECTIVE: To measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in dogs with PH (chronic hepatitis [CH] and primary hypoplasia of the portal vein [PHPV]), dogs with extrahepatic congenital portosystemic shunt (EH-CPSS), and healthy dogs and to determine whether the RAAS is activated in dogs with PH. ANIMALS: Twenty-seven dogs with acquired portosystemic collaterals (APSCs; 15 dogs with CH, 12 dogs with PHPV), 9 dogs with EH-CPSS, and 10 healthy dogs. METHODS: Retrospective study. Plasma renin activity and PAC were measured by radioimmunoassay. RESULTS: Plasma renin activity was significantly higher in the CH group (median, 4.4 ng/mL/h) than in the EH-CPSS (median, 1.0 ng/mL/h; P < .01) and the healthy (median, 1.1 ng/mL/h; P < .01) groups. No significant differences were found between the PHPV group (median, 2.2 ng/mL/h) and other groups. Plasma aldosterone concentration was significantly higher in the CH (median, 111.0 pg/mL) and PHPV (median, 89.5 pg/mL) groups than in the EH-CPSS (median, 1.0 pg/mL; P < .001, P < .01, respectively) and healthy (median, 14.5 pg/mL; P < .001, P < .05, respectively) groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Activation of the RAAS contributes to the pathophysiology of intrahepatic PH in dogs, suggesting that spironolactone may not only be effective for the treatment of ascites but also for the suppression of intrahepatic PH.

A Novel Hepadnavirus is Associated with Chronic Hepatitis and Hepatocellular Carcinoma in Cats.

In 2015, over 850,000 people died from chronic hepatitis and hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV). A novel hepatitis B-like virus has recently been identified in domestic cats. The pathogenic potential of domestic cat hepadnavirus (DCH), for which 6.5% to 10.8% of pet cats are viremic, is unknown. We evaluated stored formalin-fixed, paraffin-embedded biopsies of diseased and normal feline liver for the presence of DCH using PCR and in situ hybridization (ISH). DCH was detected in 43% (6/14) of chronic hepatitis cases and 28% (8/29) of HCCs, whereas cholangitis (n = 6), biliary carcinoma (n = 18) and normal liver (n = 15) all tested negative for DCH. Furthermore, in DCH-associated cases, the histologic features of inflammation and neoplasia, and the viral distribution on ISH were strikingly similar to those seen with HBV-associated disease. Several histological features common in human HBV-associated hepatitis, including piecemeal necrosis and apoptotic bodies, were identified in DCH-positive cases of chronic hepatitis. In two cases of HCC examined, the proliferation index in regions that were ISH-positive was higher than in ISH-negative regions. The intracellular distribution of virus in both hepatitis and HCC demonstrated that viral nucleic acid is present in both nuclear and cytoplasmic forms. Collectively, these findings demonstrate a compelling association between DCH and some cases of chronic hepatitis and hepatocellular carcinoma in the cat that mirrors features of HBV-associated hepatopathies. Future investigations of viral epidemiology and natural history are needed to establish the impact of DCH on feline health.

Retrospective evaluation of cyclosporine in the treatment of presumed idiopathic chronic hepatitis in dogs.

BACKGROUND: The etiology of idiopathic chronic hepatitis (ICH) in dogs is poorly understood, but evidence supports an immune-mediated pathogenesis in some dogs. OBJECTIVES: To describe a case series of dogs with presumed ICH treated with cyclosporine (CsA) with or without concurrent medications and to document the incidence of biochemical remission and factors associated with failure to attain remission. ANIMALS: Forty-eight client-owned dogs diagnosed with presumed ICH, treatment of which included CsA. METHODS: Two-institution, retrospective case series of dogs between 2010 and 2017. All dogs were treated with CsA with or without concurrent medications for ≥2 weeks. Data were collected from medical records. RESULTS: Biochemical remission (<1.1 times the upper limit of normal for alanine aminotransferase activity) was attained in 79% of dogs (38/48). Median dose of CsA at remission was 7.9 mg/kg/d (range, 2.5-12.7 mg/kg/d) and median time to remission was 2.5 months (range, 0.75-18 months). Concurrent hepatoprotectant treatment was not associated with likelihood of remission. Clinical score, ascites, hypoalbuminemia, hyperbilirubinemia, prolonged coagulation times, dose, and duration of treatment were not associated with the probability of remission or time to remission. Common adverse effects of CsA were gastrointestinal signs in 38% (18/48) and gingival hyperplasia in 25% (12/48) of treated dogs. CONCLUSION AND CLINICAL IMPORTANCE: A treatment regimen including CsA and frequent hepatoprotectant use resulted in biochemical remission of ICH in most dogs. None of the evaluated factors, including hepatoprotectant use, were significantly associated with likelihood of remission. Future prospective studies are indicated to evaluate CsA monotherapy in ICH dogs.

Development, validation, and application of a liquid chromatography-tandem mass spectrometry method for quantitative determination of trans-4-hydroxy-l-proline concentration in the serum of dogs with chronic hepatitis.

OBJECTIVE: To develop and analytically validate a liquid chromatography-tandem mass spectrometry method for measurement of endogenous trans-4-hydroxy-l-proline concentrations in canine serum and to assess serum trans-4-hydroxy-l-proline concentrations in dogs with chronic hepatitis. SAMPLE: Serum samples obtained from 20 dogs with histopathologically confirmed chronic hepatitis and 20 healthy control dogs. PROCEDURES: A liquid chromatography-tandem mass spectrometry method for quantification of trans-4-hydroxy-l-proline concentration was developed and assessed for analytic sensitivity, linearity, accuracy, precision, and reproducibility. Serum concentration of trans-4-hydroxy-l-proline in dogs with chronic hepatitis and healthy control dogs was measured. RESULTS: Observed-to-expected ratios for dilutional parallelism ranged from 72.7% to 111.5% (mean ± SD, 91.3 ± 19.6%). Intra-assay and interassay coefficients of variation ranged from 2.1% to 3.0% and 3.2% to 5.3%, respectively. Relative error ranged from -2.3% to 7.8%. Trans-4-hydroxy-l-proline concentrations were significantly lower in serum obtained from dogs with chronic hepatitis (median, 0.24 ng/mL; range, 0.06 to 1.84 ng/mL) than in serum obtained from healthy control dogs (median, 0.78 ng/mL; range, 0.14 to 4.90 ng/mL). CONCLUSIONS AND CLINICAL RELEVANCE: The method described here for the quantification of trans-4-hydroxy-l-proline concentration in canine serum was found to be sensitive, specific, precise, accurate, and reproducible. Dogs with chronic hepatitis had significantly lower serum trans-4-hydroxy-l-proline concentrations than did healthy control dogs, possibly as a result of altered hepatic metabolism of amino acids.

ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs.

This consensus statement on chronic hepatitis (CH) in dogs is based on the expert opinion of 7 specialists with extensive experience in diagnosing, treating, and conducting clinical research in hepatology in dogs. It was generated from expert opinion and information gathered from searching of PubMed for manuscripts on CH, the Veterinary Information Network for abstracts and conference proceeding from annual meetings of the American College of Veterinary Medicine and the European College of Veterinary Medicine, and selected manuscripts from the human literature on CH. The panel recognizes that the diagnosis and treatment of CH in the dog is a complex process that requires integration of clinical presentation with clinical pathology, diagnostic imaging, and hepatic biopsy. Essential to this process is an index of suspicion for CH, knowledge of how to best collect tissue samples, access to a pathologist with experience in assessing hepatic histopathology, knowledge of reasonable medical interventions, and a strategy for monitoring treatment response and complications.

Untargeted metabolomic profiling of serum from dogs with chronic hepatic disease.

BACKGROUND: Chronic hepatopathies present a diagnostic challenge, with different diseases being associated with similar clinical and laboratory findings. Characterization of dogs with chronic hepatopathies can be difficult and require costly diagnostic procedures such as acquisition of a liver biopsy specimen. Noninvasive and inexpensive biomarkers that reliably characterize chronic hepatopathies such as chronic hepatitis or a congenital portosystemic vascular anomaly may decrease the need for costly or invasive diagnostic testing and guide novel therapeutic interventions. OBJECTIVE: To investigate differences in the serum metabolome among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis. ANIMALS: Stored serum samples from 12 healthy dogs, 10 dogs with congenital portosystemic shunts, and 6 dogs with chronic hepatitis were analyzed. METHODS: The serum metabolome was analyzed with an untargeted metabolomics approach using gas chromatography-quadrupole time of flight mass spectrometry. RESULTS: Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering among individuals in each group. Random forest analysis showed differences in the abundance of various metabolites including increased aromatic amino acids and xylitol in dogs with congenital portosystemic shunts. Based on the univariate statistics, 50 metabolites were significantly different among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: The serum metabolome varies among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis. Statistical analysis identified several metabolites that differentiated healthy dogs from dogs with vascular or parenchymal liver disease. Further targeted assessment of these metabolites is needed to confirm their diagnostic reliability.