Clinical features of muscle stiffness in 37 dogs with concurrent naturally occurring hypercortisolism.

BACKGROUND: Severe muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon. OBJECTIVES: To evaluate signalment, presentation, treatments, and long-term outcomes of dogs with concurrent HC and SMS. ANIMALS: Thirty-seven dogs. METHODS: Medical records of dogs with HC and concurrent SMS were recruited from 10 institutions. Clinical information, test results, therapeutic responses, and survival times were reviewed. RESULTS: All 37 dogs with HC and SMS had pituitary-dependent hypercortisolism (PDH); 36/37 weighed <20 kg. Signs and test results were typical of PDH aside from SMS, initially diagnosed in all 4 limbs in 9, pelvic limbs of 22, and thoracic limbs of 6 dogs. Hypercortisolism and SMS were diagnosed together in 3 dogs; HC 1-36 months before SMS in 23; SMS 1-12 months before HC in 11. Mitotane or trilostane, given to control HC in 36/37 dogs, improved or resolved HC signs in 28; SMS did not resolve, remaining static or worsening in 31/36 dogs, mildly improving in 5/19 dogs given additional therapies. Progression of SMS included additional limbs in 10 dogs and the masticatory muscles of 2. The median survival time from diagnosis of SMS was 965 days (range, 8-1188). CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent SMS and HC is uncommon, possibly affecting only dogs with PDH. Development of SMS might occur before or after diagnosis of HC. Apart from SMS, the clinical picture and survival time of these dogs seem indistinguishable from those of dogs with HC in general. However, while muscle weakness usually resolves with HC treatment SMS does not.

Comparison of methods to monitor dogs with hypercortisolism treated with trilostane.

BACKGROUND: The use of adrenocorticotropic hormone stimulation test as method to monitor efficacy of trilostane treatment of hypercortisolism (HC) in dogs has been questioned. OBJECTIVES: To evaluate and compare 12 methods with which to monitor efficacy of trilostane treatment in dogs with HC. ANIMALS: Forty-five client-owned dogs with HC treated with trilostane q12h. METHODS: Prospective cross-sectional observational study. The dogs were categorized as well-controlled, undercontrolled, and unwell through a clinical score obtained from an owner questionnaire. The ability to correctly identify trilostane-treatment control of dogs with HC with the following variables was evaluated: before trilostane serum cortisol (prepill), before-ACTH serum cortisol, post-ACTH serum cortisol, plasma endogenous ACTH concentrations, prepill/eACTH ratio, serum haptoglobin (Hp) concentration, serum alanine aminotransferase (ALT), gamma-glutamyl transferase (γGT) and alkaline phosphatase activity, urine specific gravity, and urinary cortisol : creatinine ratio. RESULTS: Ninety-four re-evaluations of 44 dogs were included; 5 re-evaluations of 5 unwell dogs were excluded. Haptoglobin was significantly associated with the clinical score (P < .001) and in the receiver operating characteristic analysis, Hp cutoff of 151 mg/dL correctly identified 90.0% of well-controlled dogs (specificity) and 65.6% of undercontrolled dogs (sensitivity). Alanine aminotransferase (P = .01) and γGT (P = .009) were significantly higher in undercontrolled dogs. Cutoff of ALT and γGT greater than or equal to 86 U/L and 5.8 U/L, respectively, were significantly associated with poor control of HC by trilostane. CONCLUSIONS AND CLINICAL IMPORTANCE: Of all the 12 variables, Hp, and to a lesser degree ALT and γGT, could be considered additional tools to the clinical picture to identify well-controlled and undercontrolled trilostane-treated dogs.

Supplementation of omega-3 and dietary factors can influence the cholesterolemia and triglyceridemia in hyperlipidemic Schnauzer dogs: A preliminary report.

Primary hyperlipidaemia in Schnauzer is characterized by increased plasma triglycerides (TG) and/or total cholesterol (TC) concentration and is associated with an increased risk of developing pancreatitis, insulin resistance and seizures. In humans, omega-3 fatty acids in addition to a low-fat diet can be used to reduce TG and TC. This study evaluated the therapeutic efficacy of omega-3 fatty acids associated to a diet management with two different fat content in Schnauzer with primary hyperlipidaemia. Eighteen dogs with primary hyperlipidaemia were divided into two groups: group 1, n = 10, 8 females, 2 males, age (mean ± standard deviation) of 7.13 ± 2.70 years and body weight (BW) (mean ± standard deviation) of 7.25 ± 1.22 kg were treated with fish oil (approximately 730 mg/day of omega-3) associated with a low-fat and low-calorie diet (approximately 24g of fat/1000 kcal) for 90 days (T90); and group 2, n = 8 dogs, 6 females, 2 males, with 7.0 ± 1.77 years old and average BW of 8.36 ± 1.51 kg, treated with fish oil (approximately 730 mg/day of omega-3) and maintenance diet with moderate amount of fat (approximately 33g of fat/1000 kcal) for 90 days. Plasma TG and TC concentrations and lipoprotein (LP) profile (VLDL, LDL, HDL) were evaluated before and after treatment. TG and TC serum concentrations, expressed in mg/dL (mean ± standard deviation), before and after treatment in group 1 were: TG = 391.30 ± 487.86 (T0) and 118.7 ± 135.21 (T90); TC = 308.2 ± 63.06 (T0) and 139 ± 36.91 (T90). As for group 2, TG = 391.63 ± 336.89 (T0) and 250.75 ± 211.56 (T90); TC = 257.25 ± 92.88 (T0) and 207.25 ± 63.79 (T90). A reduction (p<0.05) of TG and TC was observed in both groups. The distribution of TG and TC among LP was not different between the pre (T0) and post treatment (T90) periods. After 90 days of treatment, the administration of omega-3 fatty acids, associated with a low-fat or maintenance diet reduced triglyceridemia and cholesterolemia without altering LP profile. The current investigation shows that both therapies were effective in reducing plasma TC and TG concentrations without altering LP profile.

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles.

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

Avaliação terapêutica e posológica da levotiroxina sódica em cães com hipotiroidismo primário adquirido / L-levothyroxine therapeutic dosage evaluation in dogs with primary hypothyroidism

O hipotireoidismo primário adquirido é uma endocrinopatia frequentemente diagnosticada na espécie canina. A terapia consiste na suplementação oral com levotiroxina sódica (L-tiroxina), no entanto vários protocolos terapêuticos têm sido propostos pela literatura, com doses variando 11 a 44µg/kg uma a duas vezes ao dia, visto à grande variabilidade de absorção e meia-vida plasmática do fármaco. Foram estudados 30 cães com hipotiroidismo primário adquirido (13 machos e 17 fêmeas, idade média de 7,9±1,9 anos e peso médio de 19,1±12,6 kg) atendidos no Hospital Veterinário da Universidade Guarulhos (UnG) e no Serviço de Endocrinologia de duas clínicas particulares da cidade de São Paulo (2009-2011), com o objetivo de avaliar a posologia e a frequência de administração da L-tiroxina, mais frequentemente utilizada, capaz de garantir um controle terapêutico satisfatório, avaliado através dos sinais clínicos e do teste pós-tiroxina, além de correlacionar a dose de tiroxina empregada com o peso dos animais. A dose média de tiroxina utilizada em nossa casuística foi de 16,9±3,1µg/kg, sendo a frequência de administração a cada 12 horas em 50% dos casos. Para se investigar uma possível correlação entre o peso e a dosagem de tiroxina utilizada, uma vez que cães de pequeno porte apresentam maior taxa metabólica que cães de grande porte, os animais foram agrupados em grupo A, cães com peso <10 Kg (n=12/30; 7,7±2,1 kg) e grupo B, cães com peso >10 kg (n=18/30, 26,8±10,7 kg). A dose média de tiroxina empregada nos grupos A e B não apresentaram diferença estatística e foram, respectivamente, 16±3µg/kg e 17±3µg/kg. A frequência de administração foi 50% a cada 24 horas e 50% a cada 12 horas para ambos os grupos. Dessa forma, a dose de tiroxina não parece se correlacionar com o peso do animal, sendo imprevisível quem deverá receber dose e frequência máxima da medicação. O protocolo deve ser individualizado e o paciente devidamente monitorado.

The acquired primary hypothyroidism is a frequently diagnosed endocrinopathy in dogs. The therapy constitutes in oral supplementation with sodium levothyroxine (L-thyroxine), however various therapeutic protocols have been proposed in the literature, with doses ranging from11 to 44mg/kg once or twice a day, since L-thyroxine has a great variability of absorption and plasma half life. We studied 30 dogs with primary hypothyroidism (13 males and 17 females, mean age 7.9±1.9 years and mean weight of 19.1±12.6 kg), in order to evaluate the dose and frequency of administration of L-thyroxine used more often able to secure a satisfactory therapeutic control as measured by clinical signs and test post-pill, and to correlate the amount of thyroxine employed with the animals' weight. The mean dose of thyroxine used in our study was 16.9±3.1mg/kg, and the frequency of administration every 12 hours in 50% of cases. To investigate a possible correlation between weight and dose of thyroxine used, since small dogs have a higher metabolic rate than large dogs, the animals were grouped in Group A, dogs weighing <10 kg (n=12/30, 7.7±2.1 kg) and group B, dogs weighing> 10 kg (n=18/30, 26.8±10.7 kg). The mean dose of thyroxine used in groups A and B did not differ significantly and were respectively 16±3mg/kg and 17±3mg/kg. The frequency of administration was 50% every 24 hours and 50% every 12 hours for both groups. Thus, the dose of thyroxine does not seem to correlate with the weight of the animal being unpredictable who should receive the highest dose and frequency of the medication. The protocol should be individualized and the patient adequately monitored.

Estudos dos genes Tbx19 e Crhr1 em cães da raça poodle com hipercortisolismo ACTH-dependente / Study of Tbx19 and Crhr1 genes in poodle dogs with ACTH-dependent hypercortisolism

O hipercortisolismo ACTH-dependente (HAD), também chamado de doença de Cushing, é uma das endocrinopatias mais comumente diagnosticadas na espécie canina. A sintomatologia clínica ocorre, secundariamente, aos efeitos gliconeogênicos, catabólicos, antiinflamatórios e imunossupressores dos glicocorticóides sobre vários sistemas orgânicos. Há uma marcante predisposição da doença na raça poodle e casos familiais têm sido diagnosticados sugerindo uma causa genética. As alterações moleculares que levam ao desenvolvimento do HAD em cães permanecem indefinidas. Dentre os genes implicados no desenvolvimento dos corticotrofos e na regulação do eixo corticotrófico, destacam-se o Tbx19 e o Crhr1, respectivamente. O Tbx19 é um fator de transcrição obrigatório para a transcrição do gene da proopiomelanocortina (POMC) e para a diferenciação terminal dos corticotrofos. Como está presente, exclusivamente, em corticotrofos normais e adenomatosos, foi proposto seu envolvimento na secreção excessiva de ACTH na doença de Cushing. A presença de CRHR1 nos corticotrofinomas na espécie humana e canina levantou a hipótese da sua participação na tumorigênese hipofisária, promovendo uma estimulação celular prolongada, mesmo na ausência de hormônios hipotalâmicos. Um aumento da expressão do CRHR1 foi demonstrado nos tumores corticotróficos, apesar da secreção autônoma de ACTH e dos níveis portais suprimidos de CRH em pacientes humanos e caninos com doença de Cushing. Os objetivos do presente trabalho foram pesquisar a presença de mutações germinativas nas regiões codificadoras dos genes Tbx19 e Crhr1 em cães com HAD. Para tanto, estudamos 50 cães da raça poodle com hipercortisolismo ACTH-dependente (33 fêmeas e 17 machos), com idade média de 8,71 anos e 50 cães controle da mesma raça (32 fêmeas e 18 machos) com idade superior a 6 anos (média de 9,38 anos) e sem endocrinopatias...

The ACTH-dependent hypercortisolism (ADH), also called Cushing's disease, is one of the most commonly diagnosed endocrine diseases in dogs. The symptoms occur due to glucocorticoids excess leading to gluconeogenic, catabolic, anti-inflammatory and immunosuppressive effects in multiple organs and systems. There is a high incidence of Cushing's disease in Poodles and familial disease has been identified suggesting a genetic involvement. The molecular changes that lead to the development of ACTH-dependent hypercortisolism in dogs remain undefined. Among genes implicated in corticotroph development and in corticotropic axis regulation, we would like to point out Tbx19 and Crhr1, respectively. Tbx19 gene is a transcription factor required for transcription of the proopiomelanocortin gene and for terminal differentiation of the corticotroph. Inactivating mutations in that gene are associated with human isolated ACTH deficiency. Since Tbx19 is present exclusively in normal and adenomatous corticotroph cells, its involvement in the secretion of ACTH in Cushing's disease was proposed. The presence of CRHR1 in corticotrophinomas in humans and dogs raised the possibility of its involvement in pituitary tumorigenesis, promoting prolonged cell stimulation, even in the absence of hypothalamic hormones. An increased expression of the CRHR1 mRNA was demonstrated in human and canine ACTH-secreting pituitary adenomas, despite the autonomous ACTH secretion and the low portal levels of CRH. The aim of this study was to investigate Tbx19 and Crhr1 coding region mutations in Poodle dogs with ACTH-dependent hypercortisolism. We studied 50 Poodle dogs with ADH (33 females and 17 males) with a mean age of 8.71 years and 50 control dogs of the same breed (32 females and 18 males) older than 6 years (mean 9.38 years) and without endocrinopathies. Genomic DNA was extracted from peripheral blood, amplified by the polymerase chain reaction (PCR) using specific intronic primers...