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.

Use of short videos and case studies to enhance student confidence in biochemistry knowledge and application in a large lecture biochemistry course in first year veterinary curriculum.

Large lecture courses are an efficient way to convey material to many students but have potential limitations, most notably the tendency for them to promote passive learning opportunities rather than active pedagogies. The curriculum at Cummings School of Veterinary Medicine at Tufts University, like many veterinary schools, contains many large lecture courses in the pre-clinical curriculum. This objective of this study was to use two active pedagogical interventions in a first-year lecture course named Veterinary Biochemistry and Metabolism that drew connections between basic science and several veterinary diseases. The first intervention targeted increasing students' intrinsic motivation and their confidence with understanding biochemistry concepts using videos created via collaborations between students, staff, and clinical and basic science faculty. The second intervention targeted active and collaborative learning via the implementation of clinical case studies completed in groups to relate lecture content to clinical scenarios with the aim of further enhancing student confidence in their knowledge of the material. To assess the effectiveness of these two interventions, pre-and post-course surveys using Likert style questions were administered to evaluate student confidence in the targeted concepts. The post-survey included open-ended responses on students' perspectives on their most important takeaways from the activities and their suggestions for improvements. The data showed a positive impact of these interventions on student motivation and confidence in their knowledge. This study provides support that targeted interventions to increase active learning strategies increase student engagement and may improve learning efficacy in large lecture courses.

Gastrointestinal signs and a need for nutritional management may persist long term in dogs and cats undergoing resection of the ileocolic junction: 35 cases (2008-2020).

OBJECTIVE: To evaluate the effects of ileocecocolic junction (ICJ) resection on gastrointestinal signs, biochemical parameters, and nutritional variables in dogs and cats. ANIMALS: 20 dogs and 15 cats that underwent ICJ resection between January 2008 and June 2020. PROCEDURES: Medical records of dogs and cats that underwent ICJ resection were reviewed, and clinical signs, laboratory abnormalities, and nutritional information were obtained. Additional follow-up information was obtained by contacting primary care veterinarians or owners. A subset of dogs (n = 6) and cats (2) were evaluated in the hospital via clinical examination, clinicopathologic testing, nutritional testing, and abdominal ultrasound. RESULTS: Twenty dogs and 15 cats underwent resection of the ICJ for treatment of a variety of conditions. Ten of 20 dogs (50%) and 11/15 cats (73%) were reported by their owners to have a good long-term outcome based on the lack of long-term gastrointestinal signs or the ability to control gastrointestinal signs with diet and supplements alone. Despite owner-reported good outcomes, long-term diarrhea, weight loss, and muscle loss were common. Of the 6 dogs evaluated in the hospital, 3/6 (50%) had muscle loss, 2/6 (33%) had low taurine concentrations, and 1 dog each had low cobalamin, folate, 25-hydroxyvitamin D, and ionized calcium. Neither of the 2 cats evaluated in the hospital had nutritional abnormalities identified. CLINICAL RELEVANCE: Owners should be informed of the possibility of long-term gastrointestinal clinical signs and the potential need for long-term nutritional management after ICJ resection.

Pre-operative Hemostatic Status in Dogs Undergoing Splenectomy for Splenic Masses.

Portal system thrombosis is a rare but potentially fatal complication of splenectomy in dogs. The mechanism behind development of post-operative portal system thrombosis is unclear but may include alterations of portal blood flow following surgery, acquired hypercoagulability and endothelial dysfunction. The aim of the study was to evaluate hemostatic biomarkers in hemodynamically stable (heart rate <130 beats/min, blood lactate < 2.5 mMol/L) and non-anemic (hematocrit >35%) dogs prior to splenectomy for splenic masses. Our hypothesis was that this population of stable dogs would have pre-existing laboratory evidence of hypercoagulability unrelated to shock, bleeding, anemia, or other pre-operative comorbidities. Pre-operatively, abdominal ultrasonography was performed and blood was collected for platelet enumeration, prothrombin time (PT), activated partial thromboplastin time (aPTT), kaolin-activated thromboelastography (TEG), fibrinogen, von Willebrand factor activity (vWF:Ag), antithrombin and thrombin-antithrombin complex (TAT). Histopathological diagnosis and 30-day survival were recorded. None of the 15 enrolled dogs had pre-operative sonographic evidence of portal system thrombosis. Three of fifteen dogs were thrombocytopenic, three had thrombocytosis, three were hyperfibrinogenemic, one had low vWF:Ag, three had mild prolongations of PT and none had abnormal aPTT. Based on the TEG G value, 13/15 dogs were hypercoagulable (mean ± SD 13.5 ± 5.4 kd/s). Antithrombin deficiency was identified in 9/15 dogs (mean ± SD 68.7 ± 22.7%) with 5/9 having concurrently elevated TAT suggesting active thrombin generation. No dogs developed portal system thrombosis and all achieved 30-day survival. Pre-operative hypercoagulability was recognized commonly but its association with post-operative thrombosis remains undetermined.

Serum 25-hydroxyvitamin D and C-reactive protein and plasma von Willebrand concentrations in 23 dogs with chronic hepatopathies.

BACKGROUND: Serum concentrations of 25-hydroxyvitamin D (25(OH)VD) and C-reactive protein (CRP) and von Willebrand's factor (vWF) concentration correlate with histopathologic disease grade and stage in chronic inflammatory and fibrotic hepatopathies (CH) in humans. OBJECTIVES: To evaluate serum 25(OH)VD and serum CRP concentrations and plasma vWF concentration and determine if they correlate with histopathologic and biochemical variables in dog with CH. ANIMALS: Twenty-three client-owned dogs with a histopathologic diagnosis of CH were prospectively enrolled. METHODS: Blood samples were collected before liver biopsy. Correlations between biomarkers and clinical pathological and histopathologic variables were evaluated using Pearson's or Spearman's test. RESULTS: Serum 25(OH)VD concentration (median, 213 nmol/L; range, 42-527 nmol/L) was negatively correlated with serum aspartate aminotransferase activity (AST; rho = -0.59, P < .01), polymorphonuclear neutrophil count (PMN; r = -0.46, P < .05), and positively correlated with serum albumin concentration (r = 0.69, P < .001). Serum CRP concentration (median, 7.4 µg/L; range, 1-44.9 µg/L) was positively correlated with overall histopathologic necroinflammatory activity (r = 0.78, P < .001) and fibrosis score (rho = 0.49, P < .05). Plasma vWF concentration (median, 73.3%; range, 15-141%) was positively correlated with fibrosis score (r = 0.53, P < .05) and prothrombin time (rho = 0.67, P < .01), and negatively correlated with serum albumin concentration (r = -0.73, P < .001). CONCLUSION AND CLINICAL IMPORTANCE: In dogs with CH, serum 25(OH)VD concentration was negatively correlated with disease activity, whereas serum CRP concentration and plasma vWF concentration were positively correlated with histopathologic grade and stage. Our results provide preliminary evidence that these biomarkers may be useful to assess grade and stage of CH in dogs in the absence of liver biopsy.

Evaluation of coagulation parameters in dogs with gallbladder mucoceles.

BACKGROUND: Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Limited information is available on the coagulation status of dogs with GBM. HYPOTHESIS/OBJECTIVES: To determine patterns of coagulation alterations in dogs with GBM and correlate them with clinicopathologic abnormalities and ultrasonographic findings of disease severity. ANIMALS: Twenty-three dogs with GBM identified on ultrasound examination were prospectively enrolled. METHODS: At the time of GBM identification, blood and urine were collected for CBC, serum biochemical panel, urinalysis, prothrombin time, activated partial thromboplastin time (aPTT), factor VIII, protein C (PC), von Willebrand's factor (vWF), antithrombin activity, fibrinogen, D-dimers, and thromboelastrography (TEG). Gallbladder mucoceles were classified into ultrasound types 1 to 5. Medical records were reviewed for clinical presentation, underlying conditions and to determine if systemic inflammatory response syndrome (SIRS) was present. RESULTS: Based on TEG parameters, maximal amplitude, and G, 19/23 (83%) of dogs with GBM had evaluations consistent with hypercoagulability. On plasma-based coagulation testing, dogs with GBM had increased total PC activity (20/23, 87%), fibrinogen (9/23, 39%), platelet count (9/23, 39%), and D-dimers (6/15, 40%) as well as prolongations in aPTT (9/22, 41%) and low vWF activity (5/21, 24%). No correlation was found between TEG G value and any coagulation or clinical pathology variables, ultrasound stage of GBM or disease severity as assessed by the presence of SIRS. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with ultrasonographically identified GBM have changes in whole blood kaolin-activated TEG supporting a hypercoagulable state although traditional plasma-based coagulation testing suggests that a complex state of hemostasis exists.

Hepatocyte ploidy in cats with and without hepatocellular carcinoma.

BACKGROUND: Domestic cats rarely develop hepatocellular carcinoma. The reason for the low prevalence is unknown. Reductions in hepatocellular ploidy have been associated with hepatic carcinogenesis. Recent work in mice has shown that livers with more polyploid hepatocytes are protected against the development of hepatocellular carcinoma. Hepatocyte ploidy in the domestic cat has not been evaluated. We hypothesized that ploidy would be reduced in peri-tumoral and neoplastic hepatocytes compared to normal feline hepatocytes. Using integrated fluorescence microscopy, we quantified the spectra of ploidy in hepatocellular carcinoma and healthy control tissue from paraffin embedded tissue sections. RESULTS: Feline hepatocytes are predominantly mononuclear and the number of nuclei per hepatocyte did not differ significantly between groups. Normal cats have a greater number of tetraploid hepatocytes than cats with hepatocellular carcinoma. CONCLUSIONS: Total hepatocellular polyploidy in normal cat liver is consistent with values reported in humans, yet cellular ploidy (nuclei per cell) is greater in humans than in cats. Tetraploid cat hepatocytes are predominantly mononuclear.

Approach to the Diagnosis of Hepatocutaneous Syndrome in Dogs: A Retrospective Study and Literature Review.

Superficial necrolytic dermatitis (SND) is a rare and often fatal disease in dogs that has been associated with pancreatic neuroendocrine neoplasia (SND/EN) and hepatocutaneous syndrome (SND/HCS). Although various combinations of diagnostics have been used to differentiate these two causes of SND, there are currently no data on which combination would enable the most timely and noninvasive way to diagnose HCS. Medical records were reviewed retrospectively (2004-2018) for dogs with SND/HCS (n = 24) and SND/EN (n = 1). These data were compared with cases found by review of the literature of dogs with SND/HCS (n = 105) and SND/EN (n = 13). The most consistent findings with SND were dermatological lesions affecting paw pads or mucocutaneous junctions (143/143, 100%) and marked plasma hypoaminoacidemia (58/58, 100%). On ultrasound, a honeycomb liver was seen in 62/63 (98%) dogs with SND/HCS but none with SND/EN. Six out of 23 (26%) dogs in the retrospective study with SND/HCS had marked keratinocyte apoptosis, a finding that was associated with diabetes mellitus. This study suggests that in dogs with characteristic skin lesions, an amino acid profile permits a noninvasive diagnosis of SND. An abdominal ultrasound can then assist in the differentiation of SND/HCS and SND/EN.

Hemorrhage and complications associated with percutaneous ultrasound guided liver biopsy in dogs.

BACKGROUND: Liver biopsy is often necessary to obtain a diagnosis in dogs with hepatobiliary disease. Hemorrhage after biopsy is a concern. OBJECTIVE: To describe the extent of hemorrhage and incidence of complications after percutaneous ultrasound guided liver biopsy (PUGLB) in dogs and to examine risk factors for hemorrhage or complications. ANIMALS: One hundred two client owned dogs with suspected hepatobiliary disease that underwent PUGLB. METHODS: Medical records were retrospectively reviewed. Using human guidelines, major hemorrhage was defined as an absolute decrease in the PCV (ΔPCV) ≥ 6%. Complications were defined separately as clinically relevant physiologic compromise that necessitated intervention or death. The relationship between ΔPCV and the occurrence of complications and the initial PCV, coagulation variables, serum activity of liver-derived enzymes, serum bilirubin concentration, number of biopsies, biopsy needle gauge, radiologist experience, histological diagnosis, and ultrasound variables were compared. RESULTS: Before PUGLB, most aberrations in coagulation variables were mild. After biopsy a decrease in PCV occurred in 87/102 (85.3%) dogs. The mean ΔPCV was -7.2% ± 4.5%. Major hemorrhage occurred in 43/102 (42.2%) dogs and complications in 2/102 (1.9%). ΔPCV was significantly positively correlated with PCV before biopsy (r = .47, P = .004). There was no correlation between ΔPCV or complications with any of the variables examined. CONCLUSION AND CLINICAL IMPORTANCE: Percutaneous ultrasound guided liver biopsy in the population of dogs in the current study, with normal or mild abnormalities in coagulation, results in a high incidence of clinically silent, major hemorrhage (42.5%), but few complications (1.9%).

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.

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.

Mechanism of inhibition of taurolithocholate-induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate.

Taurolithocholate (TLC) produces cholestasis by inhibiting biliary solute secretion in part by retrieving MRP2 from the plasma membrane (PM). Tauroursodeoxycholate (TUDC) and cAMP reverse TLC-induced cholestasis by inhibiting TLC-induced retrieval of MRP2. However, cellular mechanisms for this reversal are incompletely understood. Recently, we reported that TLC decreases PM-MRP2 by activating PKCε followed by phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS). Thus, cAMP and TUDC may reverse TLC-induced cholestasis by inhibiting the TLC/PKCε/MARCKS phosphorylation pathway. We tested this hypothesis by determining whether TUDC and/or cAMP inhibit TLC-induced activation of PKCε and phosphorylation of MARCKS Studies were conducted in HuH-NTCP cell line and rat hepatocytes. Activation of PKCε was determined from the translocation of PKCε to PM using a biotinylation method. Phosphorylation of MARCKS was determined by immunoblotting with a phospho-MARCKS antibody. TLC, but not cAMP and TUDC, activated PKCε and increased MARCKS phosphorylation in HuH-NTCP as well in rat hepatocytes. Treatment with TUDC or cAMP inhibited TLC-induced activation of PKCε and increases in MARCKS phosphorylation in both cell types. Based on these results, we conclude that the reversal of TLC-induced cholestasis by cAMP and TUDC involves, at least in part, inhibition of TLC-mediated activation of the PKCε/MARCKS phosphorylation pathway.

Hemostatic Disorders Associated with Hepatobiliary Disease.

The liver plays a crucial role in all aspects of coagulation because most factors that regulate procoagulation, anticoagulation, and fibrinolysis are produced, cleared, and/or activated in the liver. Establishing the coagulation status of an individual patient with hepatobiliary disease can therefore be challenging. Although, classically, patients with hepatobiliary disease were thought of as potentially hypocoagulable, hypercoagulability also occurs. The article summarizes the breadth of coagulation abnormalities that have been reported in dogs and cats with hepatobiliary disease and provides strategies to respond to bleeding and thrombotic risk.

Gastroduodenal Ulceration in Small Animals: Part 2. Proton Pump Inhibitors and Histamine-2 Receptor Antagonists.

In the first part of this review, we discussed the pathophysiology and epidemiology of gastric acid secretion and the epidemiology of gastroduodenal ulceration in dogs and cats. In this section, we discuss the pharmacology and evidence-based clinical use of histamine-2 receptor antagonists and proton pump inhibitors.

Gastroduodenal Ulceration in Small Animals: Part 1. Pathophysiology and Epidemiology.

Gastroduodenal ulceration in small animals is a complex and important comorbidity that occurs when the physiological homeostasis of the gastrointestinal tract is disrupted secondary to administration of medications or the presence of local or systemic diseases. The aim of this article is to provide a comprehensive review of the veterinary literature regarding the pathophysiology, epidemiology, and risk factors associated with gastroduodenal ulceration in small animals. Pertinent concepts from the human literature will be integrated into the discussion. This article serves as an introduction to the second part of this series, which will review current evidence regarding the use of H2-receptor antagonists and proton pump inhibitors in small animals.

Adrenal function in cats with cholestatic liver disease.

Cats with cholestatic liver disease experience significant morbidity and mortality when they undergo invasive procedures under anesthesia. Although inadequate adrenal response might account for these outcomes, adrenal function in cats with cholestatic liver disease has not been documented, to our knowledge. The goal of our study was to describe adrenal function in these cats. Twenty-seven cats with a serum bilirubin >230 µmol/L (3 mg/dL) and serum alanine aminotransferase >2 times the upper limit of normal had pre- and 60-min post-adrenocorticotropic hormone (ACTH) cortisol analysis after administration of 5 µg/kg cosyntropin intravenously. The change in cortisol concentrations (delta cortisol) was calculated. Pre- and post-ACTH cortisol concentrations were compared to reference values. Pre-ACTH, post-ACTH, and delta cortisol values were compared between cats surviving to discharge or for 30 d postdischarge. Mean pre-ACTH cortisol levels (205 ± 113 nmol/L [7.4 ± 4.2 µg/dL]) and post-ACTH cortisol levels (440 ± 113 nmol/L [15.9 ± 4.1 g/dL]) in cholestatic cats were significantly greater than reference values in clinically normal cats. There was no association of pre- or post-ACTH cortisol with survival. Cats with a delta cortisol <179 nmol/L (6.5 µg/dL) were more likely to be non-survivors at 30 d post-discharge ( p = 0.037) than cats with delta cortisol >179 nmol/L (6.5 µg/dL). Results indicate that cats with cholestasis have high basal and ACTH-stimulated cortisol values. A delta cortisol <179 nmol/L (6.5 µg/dL) defines a population of cats that have decreased 30-d survival.

Retrospective evaluation of acute liver failure in dogs (1995-2012): 49 cases.

OBJECTIVE: To characterize the clinical presentation and outcome of dogs with acute liver failure (ALF). DESIGN: Retrospective case series from January 1995 to December 2012. SETTING: University teaching hospital. ANIMALS: Forty-nine dogs were diagnosed with ALF defined as the acute onset of clinical signs accompanied by serum hyperbilirubinemia and coagulopathy (prothrombin time >1.5 times the upper limit of the reference interval) with or without signs of hepatic encephalopathy. METHODS: Medical records were retrospectively analyzed for clinical presentation, history, physical examination findings, clinicopathologic data, diagnostic imaging findings, hepatic histopathology, treatment, and outcome. MAIN RESULTS: Presenting signs included anorexia (28/49, 57%), vomiting (25/49, 51%), neurologic abnormalities (17/49, 35%), and polydipsia/polyuria (10/49, 20%). Neurologic impairment compatible with hepatic encephalopathy occurred at some point during hospitalization in 28/49 (57%) of dogs. Common clinicopathologic abnormalities on presentation other than hyperbilirubinemia and increased serum liver enzyme activity included thrombocytopenia (25/49, 51%), hypoalbuminemia (23/49, 46%), leukocytosis (17/49, 34%), anemia (14/49, 29%), hypokalemia (13/49, 27%), and hypoglycemia (10/49, 20%). The causes of ALF included neoplasia (13/49, 27%), presumptive leptosporosis (4/49, 8%), and ischemia (1/49, 2%). The remaining cases were idiopathic although 15 of these dogs had exposure to possible hepatotoxins. Common lesions in the 35/49 (71%) dogs that had hepatic histopathology were necrosis (19/39, 48%), lipidosis (16/39, 41%), vacuolar change (7/49, 14%), and inflammation (4/49, 8%). Complications included ascites (20/49, 41%), bleeding tendencies (14/49, 29%), pancreatitis (12/49, 24%), and acute tubular necrosis (11/49, 22%). Seven (14%) dogs survived to discharge. Survivors had higher alanine aminotransferase activity, and were more likely to maintain normal albumin concentrations and not develop clinical bleeding or ascites during hospitalization. CONCLUSIONS: Canine ALF is associated with multiple etiologies and a high mortality rate. Strategies to increase survival are urgently required.