Clinical manifestations of chronic pancreatitis in English cocker spaniels.

BACKGROUND: Chronic pancreatitis (CP) is common in English cocker spaniels (ECS). It is histologically similar to IgG4-related disease (IgG4-RD) in humans and is characterized by duct destruction, interlobular fibrosis, and dense periductular and perivenous lymphocytic aggregates. However, the clinical manifestations of CP in ECS have not been previously described. OBJECTIVES: Characterize the clinical manifestations of CP in a group of ECS, including similarities and differences to IgG4-RD in humans. ANIMALS: One-hundred four ECS with CP and 44 client owned control ECS without CP (both healthy and diseased controls). METHODS: Affected dogs were divided into 2 groups according to the methods used to diagnose CP. Case records were searched for signalment, clinical, and clinicopathological findings, and evidence of keratoconjunctivitis sicca (KCS), proteinuria, other immune-mediated diseases, and anal sacculitis. RESULTS: Involvement of other organs was common. Affected ECS presented with a high frequency of KCS (n = 49), proteinuria (n = 47), anal gland disease (n = 36), atopy (n = 21), and other immune-mediated diseases (n = 16). Those with parti-color hair coats, particularly blue roan, had a strong association with CP, suggesting a link between coat color and autoimmune conditions in this breed. CONCLUSIONS AND CLINICAL IMPORTANCE: English cocker spaniels with CP show clinical similarities to humans with IgG4-RD and common involvement of other organs. Clinicians should evaluate affected Cocker Spaniels for proteinuria, keratoconjunctivitis sicca, and other potential immune-mediated diseases.

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.

Copper toxicosis in Bedlington terriers is associated with multiple independent genetic variants.

BACKGROUND: Bedlington terrier copper toxicosis (CT) is due to a homozygous exon deletion in COMMD1. CT also occurs in Bedlingtons lacking this deletion. An association with two ABCA12 single nuceotide polymorphism (SNP) splice variants was reported. Labrador retriever CT is associated with a missense mutation in ATP7B, and with a protective mutation in ATP7A. METHODS: Liver and DNA samples from 24 affected and 10 unaffected Bedlingtons were assessed for copper and genetic variants. Allelic frequencies were compared. The ATP7B mutation frequency was investigated in 144 dogs of other breeds. RESULTS: The ABCA12 SNPs showed no differences between groups. The COMMD1 deletion was less frequent in unaffected than in affected dogs and in affected dogs post-2001 than pre-2001. The ATP7B mutation was more frequent in affected than unaffected Bedlingtons. Thirty-five of 144 dogs of other breeds were homo- or heterozygous for the ATP7B mutation. The ATP7A mutation was absent from Bedlingtons. LIMITATIONS: Clinical information and qualitative copper measurements were unavailable for most dogs. CONCLUSION: The COMMD1 deletion remains present in Bedlington terriers but is no longer the primary cause of CT. ABCA12 SNPs were not associated with CT. The ATP7B:c.4358G>A mutation was significantly associated with Bedlington CT and was more common in dogs of this breed than in the 144 dogs of other breeds.

A multicenter retrospective study assessing progression of biliary sludge in dogs using ultrasonography.

BACKGROUND: Biliary sludge (BS) frequently is identified on ultrasonographic examination and is described as incidental. It is hypothesized that biliary stasis and hypersecretion play a role in both BS and gallbladder mucocele (GBM) formation. Recent studies have documented similarities in composition of BS and GBM, and there are several examples of progression from BS to GBM in the veterinary literature. OBJECTIVES: To assess the relationship between the presence of BS and later development of GBM in dogs, over time periods >12 months. ANIMALS: A total of 154 dogs with BS and ultrasonographic follow-up >12 months. METHODS: Medical records were retrospectively collected from 9 UK-based referral centers for all available time points. A semiobjective scoring system was used to track volume of BS within the gall bladder (GB) over time. RESULTS: Twenty dogs developed GBM during the study period. Shetland Sheepdogs (odds ratio [OR], 40.99; 95% confidence interval [CI], 3.61-465.95; P = .003) and Border Terriers (OR, 11.66; 95% CI, 3.28-46.63; P < .001) were independent risk factors for the development of GBM. Non-gravity-dependent BS (NDBS) was noted to form before GBM development in 9/20 dogs, and breeds at-risk for GBM were more likely to have NDBS. Odds for the development of GBM increased with BS score. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with NDBS may be at risk for the development of GBM and a stratified BS scoring system could allow for semiobjective monitoring over time, particularly in at-risk breeds.

Clinical features and outcomes in 38 dogs with cholelithiasis receiving conservative or surgical management.

BACKGROUND: Ursodeoxycholic acid is used in human medicine for litholytic management of choleliths, but the efficacy of medical management in dogs with cholelithiasis is unknown. OBJECTIVES: To describe the clinical features and outcomes of dogs with cholelithiasis, focusing on cases that received medical treatment, and to identify patient factors that influenced decision-making for surgical or medical management. ANIMALS: Thirty-eight dogs with cholelithiasis identified on abdominal ultrasonography (AUS). METHODS: Medical records of dogs with cholelithiasis on AUS between 2010 and 2019 were retrospectively reviewed. Cases were classified as symptomatic (n = 18) or incidental (n = 20) and divided into medically treated (n = 13), surgically treated (n = 10), and no treatment (n = 15) groups. Biochemical variables and cholelith location were compared between symptomatic and incidental groups using Mann-Whitney U and chi-squared tests, respectively. Survival times were compared using Kaplan-Meier survival analysis. RESULTS: Symptomatic cases had higher alkaline phosphatase (P = .03), gamma-glutamyl transferase (P = .03), and alanine transferase (P = .02) activities than did incidental cases. A higher proportion of symptomatic cases (44.4%) had choledocholithiasis than did incidental cases (0%; P = .003). Seventy percent of surgically managed dogs, 7.7% of medically managed dogs, and 0% of nontreated dogs had choledocholiths at presentation. Seventeen dogs had follow-up AUS: cholelithiasis completely resolved in 4/8 medically treated, 5/7 of surgically treated, and 1/2 nontreated dogs. Median survival time was 457.4 days, with no significant difference between incidental and symptomatic dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Medical treatment can be effective for management of cholelithiasis in dogs, with clinical presentation and cholelith location playing important roles in treatment decision-making.

Increased canine pancreatic lipase immunoreactivity (cPLI) and 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) lipase in dogs with evidence of portal hypertension and normal pancreatic histology: a pilot study.

The clinical presentations of both liver disease and pancreatitis are nonspecific and overlapping, which may cause difficulty in diagnosis. In our retrospective pilot study, we assessed whether dogs with evidence of portal hypertension and absence of pancreatitis on pancreatic histology have increases in canine pancreatic lipase immunoreactivity (cPLI) and 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) lipase. We included dogs that had been presented between 2008 and 2019 if they had normal pancreatic histology, histologically confirmed hepatopathy, and if canine pancreas-specific lipase (Spec cPL; Idexx) or DGGR lipase had been measured. Only dogs with portal hypertension were included. Six dogs fulfilled the inclusion criteria. Four of 6 and 2 of 6 dogs had Spec cPL and DGGR lipase exceeding the upper reference limit, respectively. From the 4 dogs with increased Spec cPL, 2 had concentrations of 200-400 µg/L and 2 had concentrations ≥ 400 µg/L. Our results suggest that canine portal hypertension might lead to increased Spec cPL and DGGR lipase values in the absence of pancreatitis on histology. Until more evidence in a larger number of dogs with portal hypertension is available, both tests should be interpreted cautiously in the presence of portal hypertension.

Breed-related expression patterns of Ki67, γH2AX, and p21 during ageing in the canine liver.

Cellular senescence is a molecular hallmark of ageing that is associated with multiple pathologies, and DNA damage marker γH2AX, together with cell cycle inhibitor p21, have been used as senescence markers in multiple species including dogs. Idiopathic canine chronic hepatitis has recognised breed-related differences in predisposition and prognosis, but reasons behind this are poorly understood. This retrospective study using archived post mortem tissue aimed to provide insight into liver ageing in 51 microscopically normal canine livers across seven breed categories, including those with and without increased risk of chronic hepatitis. Immunohistochemistry was conducted for γH2AX, p21, and cell proliferation marker Ki67, and the mean number of positive hepatocytes per high power field was determined. All three markers were strongly correlated to each other, but no age-dependent expression was seen in the combined study population. Overall expression levels were low in most dogs, with median values representing less than 1.5% of hepatocytes, but this increased to 20-30% in individual dogs at the upper end of the range. Individual breed differences were noted in two breeds that have increased risk of chronic hepatitis, with English Springer Spaniels having lower expression of Ki67 than other dogs, and Labradors having higher expression of Ki67 and γH2AX than other dogs. These results warrant further investigation in these breeds and highlight a need to validate reliable markers of cellular senescence in dogs.

Clinical features and long-term follow-up of 70 cases of canine idiopathic eosinophilic lung disease.

BACKGROUND: Canine idiopathic eosinophilic lung disease (ELD) is sparsely documented in the literature. METHODS: Clinical presentation and outcome of dogs diagnosed with ELD (eosinophilic bronchitis or eosinophilic bronchopneumonia) were reviewed. Subgroups were made based on chronicity of clinical signs and findings of thoracic imaging: NCI (no changes in thoracic imaging), BRON (bronchial/peribronchial pattern), INT (bronchointerstitial/interstitial/alveolar). RESULTS: Seventy cases were included. There were more young to adult, crossbreed and female dogs. Compared with the other two groups NCI dogs showed lower bronchoalveolar lavage fluid eosinophilic pleocytosis and absence of circulating eosinophilia, bronchiectasis or death due to respiratory disease. All dogs responded clinically to corticosteroids. Median treatment duration was four months. Remission (no clinical signs after treatment discontinuation for >one month) and long-term remission (>six months) was achieved in 60 per cent, and 51 per cent of patients, respectively. Relapse occurred in 26 per cent of cases after remission but was rare (3 per cent) after long-term remission. The one-year, two-year and four-year survival to death due to respiratory disease was 98 per cent, 97 per cent and 91 per cent, respectively. CONCLUSION: Prognosis and initial clinical response for ELD was generally good although achievement of long-term remission was only seen in 51 per cent of dogs. Different outcomes based on chronicity of signs, corticosteroid dose, thoracic imaging abnormalities and other clinical variables were not appreciated.

Is It Being Overdiagnosed? Feline Pancreatitis.

In recent years, increased awareness of feline pancreatitis by the veterinary profession and improved diagnostic modalities have led to an increased frequency of diagnosis of pancreatitis in this species. Consequently, pancreatic diseases, especially chronic pancreatitis, are considered highly prevalent, even in populations of apparently healthy individuals. This prevalence has led to the suspicion that the condition may be overdiagnosed. This article summarizes the difficulties of diagnosis of acute and chronic pancreatitis, assesses the reasons why this is a challenging disease to recognize, and considers whether these difficulties could result in either overdiagnosis or underdiagnosis.

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.

Body weight at 10 years of age and change in body composition between 8 and 10 years of age were related to survival in a longitudinal study of 39 Labrador retriever dogs.

BACKGROUND: Overweight and obesity have been adversely associated with longevity in dogs but there is scarce knowledge on the relation between body composition and lifespan. We aimed to investigate the effects of body composition, and within-dog changes over time, on survival in adult Labradors using a prospective cohort study design. The dogs had a median age of 6.5 years at study start and were kept in similar housing and management conditions throughout. The effects of the various predictors, including the effect of individual monthly-recorded change in body weight as a time varying covariate, were evaluated using survival analysis. RESULTS: All dogs were followed to end-of-life; median age at end-of-life was 14.0 years. Body composition was measured annually with dual-energy x-ray absorptiometer (DEXA) scans between 6.2 and 17.0  years. All 39 dogs had DEXA recorded at 8, 9 and 10 years of age. During the study the mean (± SD) percent of fat (PF) and lean mass (PL) was 32.8 (± 5.6) and 64.2 (± 5.5) %, respectively, with a mean lean:fat ratio (LFR) of 2.1 (± 0.6); body weight (BW) varied from 17.5 to 44.0 kg with a mean BW change of 9.9 kg (± 3.0). There was increased hazard of dying for every kg increase in BW at 10 years of age; for each additional kg of BW at 10 years, dogs had a 19% higher hazard (HR = 1.19, P = 0.004). For the change in both lean mass (LM) and LFR variables, it was protective to have a higher lean and/or lower fat mass (FM) at 10 years of age compared to 8 years of age, although the HR for change in LM was very close to 1.0. For age at study start, older dogs had an increased hazard. There was no observed effect for the potential confounders sex, coat colour and height at shoulders, or of the time-varying covariate. CONCLUSIONS: These results suggest that even rather late-life control efforts on body weight and the relationship between lean and fat mass may influence survival in dogs. Such "windows of opportunity" can be used to develop healthcare strategies that would help promote an increased healthspan in dogs.

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.

Hepatic leptospiral infections in dogs without obvious renal involvement.

BACKGROUND: Reports of chronic hepatitis in dogs caused by Leptospira spp. are confined to small case series. Fluorescence in situ hybridization (FISH) allows the identification of spirochetes in liver samples. Consequently, this technique may help elucidate the role of Leptospira spp. in cases of chronic hepatitis. OBJECTIVES: To describe cases of hepatic leptospirosis in dogs diagnosed by FISH and subsequent polymerase chain reaction (PCR) speciation, with the absence of clinically relevant renal involvement. ANIMALS: Ten client-owned dogs. METHODS: Retrospective case series from the University of Cambridge presented between 2013 and 2016 or cases consulted by telephone advice during this time period. Cases were selected based on histopathologically confirmed granulomatous hepatitis and leptospiral organisms identified by FISH and PCR speciation (Leptospira interrogans/kirschneri). RESULTS: All cases had increased liver enzyme activities, and FISH in combination with PCR speciation-confirmed infection with L. interrogans/kirschneri. Four dogs underwent repeat liver biopsy, FISH and PCR speciation 4-15 months after initial presentation and doxycycline treatment with 1 dog undergoing repeat sampling at necropsy. Three dogs that underwent repeat biopsy remained positive for L. interrogans/kirschneri infection. Six dogs were alive at the time of manuscript preparation and 4 dogs were euthanized as a result of progressive liver disease. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of hepatic leptospiral organisms may be associated with chronic granulomatous hepatitis without clinical evidence of renal involvement. Further studies are necessary to elucidate the etiological role of these organisms in the disease.

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis.

BACKGROUND: Chronic hepatitis (CH) occurs commonly in dogs but is associated with a variable and largely unpredictable prognosis. p21, a cell-cycle inhibitor and marker of cellular senescence, is upregulated in human liver disease and is a better prognostic marker than histological or clinical scoring systems. OBJECTIVE: To quantify hepatocyte p21 immunopositivity in histopathology samples from dogs with CH and determine its association with outcome. ANIMALS: Twenty-six client-owned dogs with histologically confirmed CH, and 15 dogs with normal liver histology. METHODS: Medical records and liver histopathology samples were retrospectively reviewed to identify cases of CH. Immunohistochemistry for p21 was performed on all samples and hepatocyte immunopositivity was visually quantified. Relationships between p21 and dog age and dog survival time were statistically evaluated. RESULTS: Hepatocyte p21 immunopositivity in dogs with CH was high (median percentage of positive hepatocytes: 90%, range: 20%-98%) and exceeded 70% in 23/26 cases with no association with age. In control dogs, p21 immunopositivity was low (≤15% positive hepatocytes in 12/15 cases) and was positively correlated with age (rs = 0.63; P = .011). Dogs with p21 immunopositivity exceeding 91.8% (upper tercile) had significantly shorter survival compared to dogs with less than 88.9% immunopositivity (lowest tercile; 218 versus 874 days, P = .006). Increasing hepatocyte p21 immunopositivity was significantly negatively associated with survival time (HR 4.12; 95% CI 1.34-12.63; P = .013). CONCLUSIONS AND CLINICAL IMPORTANCE: Marked p21 immunopositivity in dogs with CH might be indicative of widespread hepatocellular senescence. A significant association with survival time also suggests a potential value for p21 quantification in determining prognosis.

Validation of a commercial 1,2-o-dilauryl-rac-glycero glutaric acid-(6'-methylresorufin) ester lipase assay for diagnosis of canine pancreatitis.

The objectives of this study were fourfold: technical validation of a commercial canine 1,2-o-dilauryl-rac-glycero glutaric acid-(6'-methylresorufin) ester (DGGR) lipase assay, to calculate a reference interval for DGGR lipase by the indirect a posteriori method, to establish biological validity of the assay, and to assess agreement between DGGR lipase and specific canine pancreatic lipase (Spec cPL) assays. Dogs with histologically confirmed acute pancreatitis (n=3), chronic pancreatitis (n=8) and normal pancreatic tissue (n=7) with stored (-80°C) serum samples were identified. Relevant controls were selected. Precision, reproducibility and linearity of DGGR lipase, and the effect of sample haemolysis and freezing, were assessed. Sensitivity and specificity of DGGR lipase and Spec cPL were determined. Agreement between these two parameters was calculated using Cohen's kappa coefficient (κ). The DGGR lipase assay demonstrated excellent precision, reproducibility and linearity. Sample haemolysis and storage at -80°C for 12 months did not influence the assay. DGGR lipase (>245IU/l) and Spec cPL (>400µg/l) both showed poor sensitivity but excellent specificity for acute pancreatitis, and poor to moderate sensitivity but excellent specificity for chronic pancreatitis. Substantial agreement (κ=0.679) was found between DGGR lipase and Spec cPL. The validated DGGR lipase assay had similar sensitivity and specificity for the diagnosis of acute and chronic pancreatitis to Spec cPL. DGGR lipase is a reliable alternative to Spec cPL for the diagnosis of pancreatitis.

Canine Breed-Specific Hepatopathies.

Canine hepatopathies, both congenital and acquired, arise from an interaction between genes and environment. Many show increased breed prevalences. This article reviews the current understanding on breed predispositions for congenital portosystemic shunts; microvascular dysplasia and portal vein hypoplasia; ductal plate abnormalities (congenital hepatic fibrosis and Caroli disease); chronic hepatitis (both copper associated and idiopathic); vacuolar hepatopathies; and gallbladder mucocele. Although all these diseases can occur in many breeds and crossbreeds, understanding breed predispositions helps recognition and will guide future research to improve understanding of causes and treatments.