Feline cholangitis/cholangiohepatitis complex.

Cholangitis/cholangiohepatitis complex in cats is commonly encountered in clinical practice worldwide. Diagnosis and management of cats with this complex is difficult because of the ambiguity of clinical signs, diagnostic test results and commonality of comorbid disorders. These impediments can delay disease identification and treatment, which can increase morbidity and mortality. ​In this narrative review, we aimed to provide a thorough review of the unique physioanatomic features of the biliary system as well as clinically relevant updates on cholangitis/cholangiohepatitis complex in cats.

Canine intrahepatic biliary disease.

The intrahepatic biliary tract is comprised of a complex network of conduits that are essential in the transportation and formation of bile with components needed for fat digestion and absorption as well as the elimination of catabolised compounds. Derangements in this system can have dangerous sequela that affects morbidity and mortality. This review aimed to summarise clinically relevant updates on intrahepatic biliary disorders in dogs including human corollaries.

Canine extrahepatic biliary disease.

Extrahepatic biliary disease in dogs is commonly encountered in clinical practice worldwide. Diseases in this segment of the biliary tract are diverse and can manifest with mild clinical signs or can be life-threatening. In the last decade there have been advances in diagnostic tests, imaging modalities and therapeutic interventions as well as the identification of novel prognostic variables that could improve outcomes in dogs with extrahepatic biliary disease. Therefore, the objective of this review was to summarise clinically relevant updates of extrahepatic biliary disease in dogs.

Canine hepatobiliary anatomy, physiology and congenital disorders.

The biliary system is an integral component of normal physiologic homeostasis and essential for survival. It acts as a conduit for the removal of detoxified and catabolised compounds as well as aids in fat digestion and absorption. Derangements in this system can have dangerous sequela that are associated with varying degrees of morbidity and mortality. Moreover, abnormalities in development of the biliary system can have varied and unpredictable changes on function and long-term outcome. The aims of this article were to review canine hepatobiliary anatomy, physiology and cholestasis as well as summarise congenital biliary disorders including human corollaries.

Serum 25-hydroxyvitamin D concentrations and mortality in dogs with blastomycosis.

Blastomycosis is a prominent fungal disease in the United States. Vitamin D status has been found to be altered in critical illness and various infectious diseases. The objectives of this study were to compare serum 25-hydroxyvitamin D (25[OH]D) concentrations in dogs with blastomycosis and healthy controls, to assess the change in serum 25(OH)D concentrations in dogs with blastomycosis after 30 days of treatment, and to determine if baseline serum 25(OH)D concentrations in dogs with blastomycosis were associated with in-hospital, 30-day, or end-of-study mortality. In this prospective cohort study, 19 dogs newly diagnosed with blastomycosis had serum 25(OH)D concentrations measured with a commercially available validated radioimmunoassay at the time of diagnosis and 30 days after start of treatment. These values were compared to 24 healthy control dogs. Serum 25(OH)D concentrations at the time of diagnosis were lower in dogs with blastomycosis (median, 203 nmol/L; range, 31-590 nmol/L) than in clinically healthy control dogs (259.5 nmol/L, 97-829 nmol/L; P = 0.01). Despite clinical improvement, there was no significant change in serum 25(OH)D concentrations from baseline to 30-day follow-up. Dogs with baseline serum 25(OH)D concentrations <180.5nmol/L had a greater odds of death during hospitalization (odds ratio [OR], 15.0; 95% confidence interval [CI], 1.4-191.3; P = 0.04) and at 30 days follow-up (OR, 30.0; 95% CI, 2.5-366.7; P = 0.006). These findings highlight the need for further studies evaluating the prognostic value of vitamin D status in dogs with blastomycosis at diagnosis and throughout treatment and remission.

Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs.

Genotype-phenotype correlations of humans and dogs with hereditary methemoglobinemia are not yet well characterized. We determined total hemoglobin and methemoglobin (MetHb) concentrations, cytochrome b5 reductase (CYB5R) enzyme activities, genotypes, and clinical signs in 30 dogs with persistent cyanosis without cardiopulmonary disease. Erythrocytic CYB5R enzyme activities were low in all dogs assayed. Owner-reported quality of life ranged from subclinical to occasional exertional syncope. Two previously reported and two novel CYB5R3 missense variants were identified among the methemoglobinemic cohort and were predicted to impair enzyme function. Two variants were recurrent: a homozygous Ile194Leu substitution was found in Pomeranians and other small dogs, and a homozygous Arg219Pro change occurred predominately in pit bull terriers. The other two variants were Thr202Ala and Gly76Ser substitutions in single dogs. Of the two common CYB5R3 genotypes, Arg219Pro was associated with a more severe metabolic phenotype. We conclude that CYB5R3 deficiency is the predominate cause of canine hereditary methemoglobinemia. Although this finding is unlikely to alter the clinical approach to hereditary methemoglobinemia in dogs, it demonstrates the possibility of how genotype-phenotype cohort analysis might facilitate precision medicine in the future in veterinary medicine.

Diagnostic contribution of individual components of adrenal function tests to diagnose canine hyperadrenocorticism.

There is limited information regarding the value of constitutive components of the ACTH stimulation test (ACTHST) and low-dose dexamethasone suppression test (LDDST) including serum baseline cortisol (BC), difference between post-ACTH stimulation cortisol (PC) and BC (ΔACTHC), cortisol concentration 4h after dexamethasone administration (4HC), difference between 4HC and BC (Δ4C), and the difference between cortisol concentration 8h after dexamethasone administration and 4HC (Δ8C). Therefore, the objective of this study was to determine if these components can predict hyperadrenocorticism, pituitary-dependent hyperadrenocorticism (PDH), or functional adrenocortical tumor (FAT) in dogs. Cortisol concentrations were normalized, as fold change (FC), to the PC reference interval upper limit. A total of 1267 dogs were included, with hyperadrenocorticism diagnosed in 537 (PDH, n=356; FAT, n=28; undetermined, n=153) and excluded in 730. The area under the receiver operating curves for BC, ΔACTHC, 4HC, Δ4C, and Δ8C to predict hyperadrenocorticism were 0.76 (95% confidence interval (CI), 0.73-0.79), 0.91 (95% CI, 0.89-0.93), 0.83 (95% CI, 0.80-0.87), 0.55 (95% CI, 0.50-0.60), and 0.67 (95% CI, 0.62-0.72), respectively. A diagnostic limit of ≥0.78 FC for ΔACTHC had excellent sensitivity (1.00; 95% CI, 0.74-1.00), but poor specificity (0.67; 95% CI, 0.64-0.71), to predict FAT in dogs with a positive ACTHST. A diagnostic limit of ≥-0.26 FC for Δ4C had excellent sensitivity (1.00; 95% CI, 0.79-1.00), but poor specificity (0.21; 95% CI, 0.18-0.26), to predict FAT in dogs with a positive LDDST. In hyperadrenocorticoid dogs that have positive ACTHST or LDDST results, ΔACTHC or Δ4C, respectively, could be used to exclude FAT.

Immune function and serum vitamin D in shelter dogs: A case-control study.

This study sought to establish a baseline understanding of immune function and its association with serum vitamin D in shelter dogs. Ten apparently healthy shelter dogs housed in the Arizona Humane Society for ≥7 days and 10 apparently healthy, age, breed, and sex-matched control dogs were included. Serum 25-hydroxyvitamin D (25[OH]D), the major circulating vitamin D metabolite, was measured using high performance liquid chromatography. Whole blood samples were stimulated with lipopolysaccharide (LPS), lipoteichoic acid, or phosphate buffer solution, and tumor necrosis factor (TNF)-ɑ, interleukin (IL)-6, and IL-10 were measured using a canine-specific multiplex bead-based assay. Phagocytosis of opsonized-Escherichia coli and E. coli-induced oxidative burst were evaluated with flow cytometry. Shelter dogs had decreased percentages of granulocytes and monocytes (GM) that had phagocytized opsonized-E coli (P = 0.019) and performed E. coli-induced oxidative burst (P = 0.011). There were no significant differences in TNF-α, IL-6, IL-10, or 25(OH)D concentrations between shelter and control dogs. Serum 25(OH)D concentrations had a weak positive association with the intensity of GM E. coli-induced oxidative burst (r2 = 0.23, P = 0.03). There was a moderate inverse association between serum 25(OH)D concentration and LPS-stimulated TNF-ɑ production in shelter dogs (r2 = 0.40, P = 0.04). These results demonstrate immune dysregulation in vitro in shelter dogs housed for ≥7 days when compared to age, breed, and sex-matched control dogs. While serum 25(OH)D concentrations did not differ between shelter and control dogs, significant associations between 25(OH)D concentration and immune function parameters in vitro were identified.

Pulmonary hypertension secondary to respiratory disease and/or hypoxia in dogs: Clinical features, diagnostic testing and survival.

Pulmonary hypertension (PH) is associated with substantial morbidity and if untreated, mortality. The human classification of PH is based on pathological, hemodynamic characteristics, and therapeutic approaches. Despite being a leading cause of PH, little is known about dogs with respiratory disease and/or hypoxia (RD/H)-associated PH. Therefore, our objectives were to retrospectively describe clinical features, diagnostic evaluations, final diagnoses and identify prognostic variables in dogs with RD/H and PH. In 47 dogs identified with RD/H and PH, chronic airway obstructive disorders, bronchiectasis, bronchiolar disease, emphysema, pulmonary fibrosis, neoplasia and other parenchymal disorders were identified using thoracic radiography, computed tomography, fluoroscopy, tracheobronchoscopy, bronchoalveolar lavage, and histopathology. PH was diagnosed using transthoracic echocardiography. Overall median survival was 276.0 days (SE, 95% CI; 216, 0-699 days). Dogs with an estimated systolic pulmonary arterial pressure (sPAP) ≥47mmHg (n=21; 9 days; 95% CI, 0-85 days) had significantly shorter survival times than those <47mmHg (n=16; P=0.001). Estimated sPAP at a cutoff of ≥47mmHg was a fair predictor of non-survival with sensitivity of 0.78 (95% CI, 0.52-0.94) and specificity of 0.63 (95% CI, 0.38-0.84). Phosphodiesterase-5 (PDE5) inhibitor administration was the sole independent predictor of survival in a multivariable analysis (hazard ratio: 4.0, P=0.02). Canine PH is present in a diverse spectrum of respiratory diseases, most commonly obstructive disorders. Similar to people, severity of PH is prognostic in dogs with RD/H and PDE5 inhibition could be a viable therapy to improve outcome.

Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.

Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study.

INTRODUCTION: Canine pulmonary hypertension (PH) is associated with high morbidity and mortality. Tadalafil, a phosphodiesterase-5 inhibitor used commonly in humans with PH, has not been evaluated in a clinical trial in dogs with naturally occurring PH. Our objectives were to compare the efficacy of tadalafil and sildenafil on PH assessed by peak tricuspid regurgitant flow velocity, estimated systolic pulmonary arterial pressure gradient, voluntary activity, quality of life, and safety profiles in dogs with moderate to severe PH. ANIMALS: Twenty-three dogs with echocardiographic evidence of moderate to severe PH were enrolled. METHODS: A prospective short-term, randomized, double-blinded pilot study was carried out. Dogs with PH were randomly allocated to receive sildenafil or tadalafil for 2 weeks and assessed via echocardiography, activity monitors, and owner-reported outcomes. RESULTS: Collectively, phosphodiesterase-5 inhibition significantly decreased (improved) quality of life scores (p = 0.003) and visual analog score (p = 0.024) without significant between-treatment difference of these variables. Phosphodiesterase-5 inhibition did not significantly affect peak tricuspid regurgitant flow velocity (p = 0.056) or voluntary activity (p = 0.27). A total of 33% (7/21) of dogs experienced at least one adverse event during the study (tadalafil, n = 5; sildenafil, n = 2) with no significant difference between treatment type and incidence of adverse events (p = 0.36). DISCUSSION: In this pilot study, phosphodiesterase-5 inhibition led to apparent improvement in quality of life scores without documenting superiority of tadalafil over sildenafil. CONCLUSION: Tadalafil at a dose of 2 mg/kg once daily appears to be a viable alternative to sildenafil in dogs with moderate to severe PH.

A homozygous ADAMTS2 nonsense mutation in a Doberman Pinscher dog with Ehlers Danlos syndrome and extreme skin fragility.

An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species.

Effect of calcitriol on in vitro whole blood cytokine production in critically ill dogs.

Hypovitaminosis D has been identified as a predictor of mortality in human beings, dogs, cats and foals. However, the immunomodulatory effects of vitamin D in critically ill dogs has not been evaluated. The aim of this study was to evaluate the effect of calcitriol on cytokine production from whole blood collected from critically ill dogs in vitro. Twelve critically ill dogs admitted to a veterinary intensive care unit (ICU) were enrolled in a prospective cohort study. Whole blood from these dogs was incubated with calcitriol (2×10-7M) or ethanol (control) for 24h. Subsequent to this incubation, lipopolysaccharide (LPS)-stimulated whole blood production of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were measured using a canine-specific multiplex assay. Calcitriol significantly increased LPS-stimulated whole blood production of IL-10 and decreased TNF-α production without significantly altering IL-6 production. There was no significant difference in whole blood cytokine production capacity between survivors and non-survivors at the time of discharge from the ICU or 30days after discharge. These data suggests that calcitriol induces an anti-inflammatory phenotype in vitro in whole blood from critically ill dogs.

Gallbladder Mucocele: Variables Associated with Outcome and the Utility of Ultrasonography to Identify Gallbladder Rupture in 219 Dogs (2007-2016).

BACKGROUND: Gallbladder mucocele (GBM) is an increasingly recognized extrahepatic biliary disease in dogs. OBJECTIVES: To investigate cases of GBM and identify variables associated with survival and the sensitivity and specificity of ultrasonography to identify gallbladder rupture. ANIMALS: Two hundred and nineteen client-owned dogs with GBM. METHODS: Multicenter, retrospective study of dogs with GBM, presented from January 2007 to November 2016 to 6 academic veterinary hospitals in the United States. Interrogation of hospital databases identified all cases with the inclusion criteria of a gross and histopathologic diagnosis of GBM after cholecystectomy and intraoperative bacteriologic cultures of at least 1 of the following: gallbladder wall, gallbladder contents, or abdominal effusion. RESULTS: Two hundred and nineteen dogs fulfilled the inclusion criteria. Dogs with GBM and gallbladder rupture with bile peritonitis at the time of surgery were 2.7 times more likely to die than dogs without gallbladder rupture and bile peritonitis (P = 0.001; 95% confidence interval [CI], 1.50-4.68; n = 41). No significant associations were identified between survival and positive bacteriologic cultures, antibiotic administration, or time (days) from ultrasonographic identification of GBM to the time of surgery. The sensitivity, specificity, positive, and negative likelihood ratios for ultrasonographic identification of gallbladder rupture were 56.1% (95% CI, 39.9-71.2), 91.7% (95% CI, 85.3-95.6), 6.74, and 0.44, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Dogs in our study with GBM and intraoperative evidence of gallbladder rupture and bile peritonitis had a significantly higher risk of death. Additionally, abdominal ultrasonography had low sensitivity for identification of gallbladder rupture.

Long-term Treatment with Methylene Blue in a Dog with Hereditary Methemoglobinemia Caused by Cytochrome b5 Reductase Deficiency.

A juvenile male mixed breed dog was presented for lethargy, exercise intolerance, and aggression when touched on the head. Cyanosis, tachycardia, and tachypnea were observed and persisted during oxygen supplementation. Arterial blood gas analysis by co-oximetry identified an increased methemoglobin concentration (27%; normal, <2%) with normal arterial oxygen tension. The methemoglobinemia and associated clinical signs resolved after administration of methylene blue (1 mg/kg) IV, and the dog was discharged. The affected dog's whole-genome sequence contained 2 potentially causal heterozygous CYB5R3 missense mutations suggesting that cytochrome b5 reductase deficiency was responsible for the methemoglobinemia. This hypothesis was confirmed by enzyme analysis that identified cytochrome b5 reductase activity in the affected dog's erythrocytes to only approximately 6% of that in a control sample. Clinical signs recurred 11 days after discharge but normalized and the methemoglobin concentration decreased with methylene blue administration PO (1.5 mg/kg, initially daily and then every other day).

Desoxycorticosterone Pivalate Duration of Action and Individualized Dosing Intervals in Dogs with Primary Hypoadrenocorticism.

BACKGROUND: Clinicians alter dosing for desoxycorticosterone pivalate (DOCP) to mitigate costs, but this practice has not been critically evaluated in a prospective clinical trial. HYPOTHESIS/OBJECTIVES: The duration of action of DOCP is longer than 30 days in dogs with primary hypoadrenocorticism (PH). ANIMALS: A total of 53 client-owned dogs with PH. Twenty-four dogs with newly diagnosed PH (Group 1) and 29 dogs with treated PH (Group 2). METHODS: Prospective, multicenter, clinical trial. For phase I, DOCP was administered and plasma sodium and potassium concentrations were measured until the dog developed hyponatremia or hyperkalemia at a planned evaluation, or displayed clinical signs with plasma electrolyte concentrations outside of the reference interval independent of a planned evaluation, thus defining DOCP duration of action. Plasma electrolyte concentrations then were assessed at the end of the individualized dosing interval (IDI; i.e., DOCP duration of action minus 7 days, phase II and at least 3 months after concluding phase II, phase III). RESULTS: The duration of action of DOCP in dogs in phase I with naïve PH (n = 24) ranged from 32 to 94 days (median, 62 days; 95% confidence interval [CI], 57, 65) and previously treated PH (n = 29) from 41 to 124 days (median, 67 days; CI, 56, 72). Overall, the final DOCP dosing interval for all dogs that completed phase II (n = 36) ranged from 38 days to 90 days (median, 58 days; CI, 53, 61). No dog that completed phase III (n = 15) required reduction in the IDI. The DOCP duration of action, independent of group, was not significantly associated with several baseline variables. The median drug cost reduction using IDI was approximately 57.5% per year. CONCLUSION AND CLINICAL IMPORTANCE: The duration of action of DOCP in dogs with PH is >30 days, and plasma sodium and potassium concentrations can be maintained with an IDI >30 days long term.

Vasoproliferative process resembling pulmonary capillary hemangiomatosis in a cat.

BACKGROUND: Pulmonary capillary hemangiomatosis is a rare, vascular obstructive disorder that uniformly causes pulmonary arterial hypertension. Clinically, pulmonary capillary hemangiomatosis is indistinguishable from primary pulmonary arterial hypertension and histology is required for definitive diagnosis. The distinctive histologic feature of pulmonary capillary hemangiomatosis is non-malignant extensive proliferation of capillaries in the alveolar septae. Vasodilator treatment of humans with primary arterial hypertension due to pulmonary capillary hemangiomatosis can result in fatal acute pulmonary edema. Computed tomography is thus critical to discern pulmonary capillary hemangiomatosis from other causes of pulmonary arterial hypertension prior to vasodilator therapy. This is the first report of a vasoproliferative process resembling pulmonary capillary hemangiomatosis in the feline species. CASE PRESENTATION: A 15-year-old, male castrated, domestic shorthair cat presented for persistent labored breathing presumptively due to congestive heart failure despite treatment with diuretics for 7 days. Echocardiography showed evidence of hypertrophic cardiomyopathy with severe pulmonary hypertension; however, a normal sized left atrium was not consistent with congestive heart failure. Thoracic computed tomography was performed and showed evidence of diffuse ill-defined nodular ground glass opacities, enlarged pulmonary arteries, and filling defects consistent with pulmonary thromboembolism. The cat acutely decompensated after a single dose of sildenafil and was euthanized. Histopathology of the lungs showed severe multifocal alveolar capillary proliferation with respiratory bronchiolar infiltration, marked type II pneumocyte hyperplasia and multifocal pulmonary arterial thrombosis. CONCLUSION: This is the first description in a cat of a vasoproliferative disorder resembling pulmonary capillary hemangiomatosis complicated by multifocal pulmonary arterial thrombosis. Inspiratory and expiratory ventilator-driven breath holds with angiography revealed lesions predominantly characterized by ground glass opacification and vascular filling defects with absence of air trapping. The results from this report suggest that, as in humans, the cat can develop a pulmonary capillary hemangiomatosis-like disease in which vasodilator therapy to address pulmonary hypertension may lead to fatal pulmonary edema.