Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury.

BACKGROUND: Traumatic brain injury (TBI) elicits intense sympathetic nervous system (SNS) activation with profuse catecholamine secretion. The resultant hyperadrenergic state is linked to immunomodulation both within the brain and systemically. Dysregulated inflammation post-TBI exacerbates secondary brain injury and contributes to unfavorable patient outcomes including death. The aim of this study was to characterize the early dynamic profile of circulating inflammatory cytokines/chemokines in patients admitted for moderate-to-severe TBI, to examine interrelationships between these mediators and catecholamines, as well as clinical indices of injury severity and neurological outcome. METHODS: Blood was sampled from 166 isolated TBI patients (aged 45 ± 20.3 years; 74.7 % male) on admission, 6-, 12-, and 24-h post-injury and from healthy controls (N = 21). Plasma cytokine [interleukin (IL)-1ß, -2, -4, -5, -10, -12p70, -13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] and chemokine [IL-8, eotaxin, eotaxin-3, IFN-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1ß, thymus activation regulated chemokine (TARC)] concentrations were analyzed using high-sensitivity electrochemiluminescence multiplex immunoassays. Plasma catecholamines [epinephrine (Epi), norepinephrine (NE)] were measured by immunoassay. Neurological outcome at 6 months was assessed using the extended Glasgow outcome scale (GOSE) dichotomized as good (>4) or poor (≤4) outcomes. RESULTS: Patients showed altered levels of IL-10 and all chemokines assayed relative to controls. Significant differences in a number of markers were evident between moderate and severe TBI cohorts. Elevated IL-8, IL-10, and TNF-α, as well as alterations in 8 of 9 chemokines, were associated with poor outcome at 6 months. Notably, a positive association was found between Epi and IL-1ß, IL-10, Eotaxin, IL-8, and MCP-1. NE was positively associated with IL-1ß, IL-10, TNF-α, eotaxin, IL-8, IP-10, and MCP-1. CONCLUSIONS: Our results provide further evidence that exaggerated SNS activation acutely after isolated TBI in humans may contribute to harmful peripheral inflammatory cytokine/chemokine dysregulation. These findings are consistent with a potentially beneficial role for therapies aimed at modulating the inflammatory response and hyperadrenergic state acutely post-injury.

Diurnal Plasma Cortisol Measurements Utility in Differentiating Various Etiologies of Endogenous Cushing Syndrome.

Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4±0.6 vs. 2.3±1.5, p<0.001, respectively). An AM/PM cortisol ratio≥2.0 among patients with unsuppressed ACTH (>15 pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol≥1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia.

Diabetes Mellitus-Associated Functional Hypercortisolism Impairs Sexual Function in Male Late-Onset Hypogonadism.

Functional hypercortisolism is generated by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and has been proven to have a negative role in several complications. However, no study has evaluated the possible influence of diabetes mellitus-associated functional hypercortisolism on male hypogonadism and sexual function. We aimed to identify any association of hypothalamic-pituitary-adrenal axis dysregulation measures with testosterone and sexual function in men simultaneously affected by diabetes mellitus and late-onset hypogonadism. Fifteen diabetes mellitus and late-onset hypogonadism subjects suffering from functional hypercortisolism and fifteen diabetes mellitus and late-onset hypogonadism subjects who were free of functional hypercortisolism were retrospectively reviewed. Clinical, hormonal, and sexual parameters were considered. Hypercortisolemic subjects showed higher values of body mass index, waist, and glycated hemoglobin and lower ones of testosterone compared to normocortisolemic ones. All sexual parameters, except for orgasmic function, were significantly worse in hypercortisolemic than in normocortisolemic subjects. Hypercortisolemic patients showed higher values of cortisol after dexamethasone and urinary free cortisol as well as a lesser ACTH response after corticotropin releasing hormone test (ACTH area under curve) compared to normocortisolemic ones. No significant association was found at Poisson regression analysis between hormonal and sexual variables in normocortisolemic patients. In hypercortisolemic subjects, negative and significant associations of cortisol response after corticotropin releasing hormone (cortisol area under curve) with erectile function (ß: -0.0008; p: 0.015) and total international index of erectile function score (ß: -0.0006; p: 0.001) were evident. This study suggests for the first time the impairing influence of the dysregulated hypothalamic-pituitary-adrenal axis on sexual function in diabetes mellitus-associated late-onset hypogonadism.

Lack of association between clinical signs and laboratory parameters in dogs with hyperadrenocorticism before and during trilostane treatment.

INTRODUCTION: Trilostane therapy, the treatment of choice for pituitary- dependent hyperadrenocorticism (HAC) in dogs, is monitored by assessing resolution of clinical signs and measuring adrenocortical reserve capacity with an ACTH-stimulation test. The aim of this prospective study was to evaluate agreement between clinical signs reported by owners and cortisol or ACTH concentrations before and during trilostane therapy (starting dose 1-2 mg/kg once daily). A questionnaire on signs of HAC was used and a clinical score calculated as the sum of the 9 questions. Eighteen questionnaires at diagnosis and 97 during therapy were filled out by owners of 32 dogs. An ACTH-stimulation test was performed at each reevaluation. There were weak correlations between abdominal girth, appetite or weight gain and cortisol concentrations during therapy. However, the clinical score did not correlate with cortisol or cACTH values. In 50% of dogs, trilostane application had to be changed from once daily to twice daily during the study. Clinical signs reported by owners matched poorly with cortisol or cACTH concentrations at any time point. If low-dose trilostane is used, treatment frequency often has to be increased.

INTRODUCTION: Le traitement au trilostane, médicament de choix dans les cas d'hyperadrénocorticisme hypophyso-dépendant chez le chien, est évalué sur la base de la disparition des symptômes cliniques et des résultats des tests de stimulation à l'ACTH. Le but de la présente étude prospective était de comparer les symptômes cliniques (évalués par les propriétaires) avec les concentrations de cortisol et d'ACTH endogène avant et durant un traitement au trilostane (dose initiale 1­2 mg/kg, 1× par jour). On a utilisé un questionnaire composé de 9 questions relatives aux symptômes cliniques sur la base desquels on a calculé un score clinique total. Dix-huit questionnaires ont été remplis au moment du diagnostic et 97 durant le traitement par les propriétaires de 32 chiens. Un test de stimulation à l'ACTH a été réalisé lors de chaque contrôle. Il existait de faibles corrélations entre le périmètre abdominal, l'appétit et la prise de poids et les taux de cortisol durant le traitement. Le score clinique total n'était toutefois pas corrélé avec les concentrations de cortisol ou d'ACTH. Chez la moitié des chiens, la dose de trilostane a du être répartie en deux prises journalières. Les symptômes cliniques jugés par les propriétaires montraient une mauvaise corrélation avec les taux de cortisol et d'ACTH durant le traitement au trilostane. Si on dose ce médicament de façon faible, il y a souvent lieu d'augmenter la fréquence des prises.

Phosphocalcic metabolism and its potential association with biomarkers of kidney disease in dogs with spontaneous hyperadrenocorticism.

The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH)2Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH)2Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation.

Description of serum symmetric dimethylarginine concentration and of urinary SDS-AGE pattern in dogs with ACTH dependent hyperadrenocorticism.

Serum symmetric dimethylarginine (SDMA) and patterns of urinary protein separated by sodium dodecyl sulfate agarose gel electrophoresis (SDS-AGE) have not been investigated as biomarkers in dogs with ACTH-dependent hyperadrenocorticism (ADHAC). This exploratory prospective study aimed to evaluate SDMA, serum creatinine (sCR), and SDS-AGE in dogs with ADHAC with and without proteinuria (ADHAC-P and ADHAC-nP, respectively). Thirty-five pet dogs classified as ADHAC-P (n=16), ADHAC-nP (n=6) and healthy (n=13) were included. Renal biomarkers were evaluated in all dogs at diagnosis. Baseline concentration of SDMA was not significantly different between the three groups (P = 0.15) whereas sCr was significantly lower in dogs in ADHAC dogs compared to healthy dogs (88.0 µmol/L [70.4-132.6; 79.2-114.4]) whether they had proteinuria or not (P = 0.014 and 0.002, respectively). However, baseline concentrations of sCr and SDMA were not significantly different between dogs with ADHAC-P dogs (SDMA, 8 µg/dL [5-12; 7-9]; sCr, 57.2 µmol/L [35.2-212.2; 52.8-92.4]) and ADHAC-nP dogs (SDMA, 8.5 µg/dL [7-13; 8-10]; sCr, 70.4 µmol/L [61.6-79.2; 61.6-70.4]) (P = 0.35 and P = 0.41, respectively). Proteinuria in dogs with ADHAC-P was mainly of glomerular origin (SDS-AGE pattern: glomerular in 10/16 dogs; mixed glomerular/tubular in four dogs). In our study, SDMA was neither significantly different in dogs with ADHAC whether they were proteinuric or not, nor between ADHAC and healthy dogs. Urinary electrophoresis provides additional information to the UPC and further investigations are needed to determine whether it may help identify dogs with ADHAC-P requiring specific antiproteinuric treatment.

[Diagnostic efficacy of plasma ACTH-measurement by a chemiluminometric assay in canine hyperadrenocorticism]. / Klinische Anwendung einer chemiluminometrischen ACTH-Bestimmung beim caninen Hyperadrenokortizismus.

This retrospective study was performed to investigate the diagnostic efficacy of the chemiluminometric ACTH-measurement to differentiate between pituitary and adrenal dependent hyperadrenocorticism (HAC) in dogs. 49 dogs with pituitary HAC, 10 dogs with adrenal HAC and 1 dog with a combination of both pathologies were included. Dogs with HAC like symptoms, where HAC had been ruled out, served as controls (n = 18). All dogs with adrenal HAC, as well as 9 dogs with pituitary HAC had an ACTH concentration below the detection limit of 2.2 pmol/l (10 pg/dl) plasma. Using 2.2 pmol/l as a cut-off the sensitivity and specificity to diagnose pituitary HAC was 0.82 (95 % CI 0.686 - 0.914) and 1 (95 % CI 0.692 - 1), respectively. With the help of the chemiluminometric assay, a correct classification was possible in 85 % of patients with HAC. As an ACTH-concentration below the detection limit was found in dogs with adrenal as well as pituitary HAC, additional discriminatory tests are necessary in these cases.

A preliminary evaluation of the circulating leptin/adiponectin ratio in dogs with pituitary-dependent hyperadrenocorticism and concurrent diabetes mellitus.

Leptin and adiponectin are thought to modulate insulin sensitivity and pancreatic ß-cell function, but there is limited information regarding the adipokine status of hyperglycemic dogs with hyperadrenocorticism. This study aimed to determine whether alterations in the leptin/adiponectin ratio, insulin sensitivity, and/or pancreatic ß-cell function are associated with diabetes mellitus (DM) in dogs with pituitary-dependent hyperadrenocorticism (PDH). A total of 48 client-owned dogs were included in this prospective observational study: 20 dogs with PDH (10 normoglycemic and 10 with DM), 15 dogs with DM, and 13 healthy dogs. The serum concentrations of leptin, adiponectin, resistin, interleukin (IL)-1ß, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-α were measured, and homeostatic model assessment indices (HOMAs) were calculated and compared among the groups. Serum leptin was significantly higher in PDH dogs with and without DM than in healthy and DM dogs, and it was lower in DM dogs than in PDH dogs without DM. Serum adiponectin was significantly lower in PDH dogs with DM than in healthy and PDH dogs, and it was significantly lower in DM dogs than in healthy dogs. Serum IL-10 was significantly higher in PDH dogs with DM than in healthy and PDH dogs without DM. The leptin/adiponectin ratio was significantly higher in PDH dogs with DM than in normoglycemic PDH dogs. Serum IL-6 concentrations were significantly higher in DM dogs than in healthy dogs. Serum IL-1ß concentration was significantly higher in DM dogs than in healthy dogs and PDH dogs with DM and without DM. Serum TNF-α and IL-18 concentrations were not different among groups. The HOMAß-cell function was significantly lower in PDH dogs with DM than in normoglycemic PDH dogs, while HOMAinsulin sensitivity was significantly lower in PDH dogs with DM than in healthy dogs. These results suggest that adipokine dysregulation, a reduction in insulin sensitivity, and a further impairment in pancreatic ß-cell function might predispose PDH dogs to DM. Further longitudinal study will be necessary to confirm this result.

Metabolic profiling of serum from dogs with pituitary-dependent hyperadrenocorticism.

Hyperadrenocorticism (HAC) is one of the most common endocrine diseases in dogs characterized by excessive cortisol production caused by an adrenocorticotropic hormone (ACTH)-secreting tumor, namely pituitary-dependent HAC (PDH) or cortisol-secreting adrenal tumor. Metabolomics presents the ability to identify small molecule metabolites. Thus, the use of metabolomics techniques in canine PDH can provide information about the pathophysiology and metabolic changes in this disease. This study aimed to identify and compare differences in serum metabolites between dogs with PDH and healthy dogs. The metabolomic profile of 20 dogs diagnosed with PDH was compared with 20 healthy dogs using liquid chromatography/mass spectrometry (LC/MS), and metabolite discrimination was performed using partial least squares-discriminant analysis (PLS-DA), the variable important in projection (VIP) and fold changes (FC) group-wise comparisons. The hypergeometric test identified the significantly altered pathways. A total of 21 metabolites were found to be significantly different between the two groups. The major alterations were found in arachidonic and decanoic acid, and phospholipids related to phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI). These metabolites are related to insulin resistance and other complications (i.e. hypertension). Our results indicate that PDH produces changes in serum metabolites of dogs, and the knowledge of these changes can aid to better understanding of pathophysiological processes involved and contribute to potentially detect new biomarkers for this disease.

Serum 17alpha-hydroxyprogesterone concentrations during the reproductive cycle in healthy dogs and dogs with hyperadrenocorticism.

OBJECTIVE: To determine concentrations of 17alpha-hydroxyprogesterone (17OHP) in serum of healthy bitches during various stages of the reproductive cycle and in bitches with hyperadrenocorticism and to compare the dynamics of 17OHP with those of progesterone. DESIGN: Prospective evaluation study. ANIMALS: 15 healthy sexually intact bitches and 28 spayed bitches with hyperadrenocorticism. PROCEDURES: 11 healthy bitches were evaluated during estrus, nonpregnant diestrus, and anestrus (group 1); 4 other healthy bitches were evaluated during pregnancy and after ovariohysterectomy (group 2). Cycle stages were determined via physical examination, vaginal cytologic evaluation, and serum progesterone concentration. Bitches with hyperadrenocorticism were evaluated once at the time of diagnosis (group 3). Serum hormone concentrations were determined with immunoassays. RESULTS: In group 1, the serum 17OHP concentration was significantly higher in diestrus (median, 1.8 ng/mL) than in estrus (median, 1.1 ng/mL) and anestrus (median, 0.2 ng/mL) and higher in estrus than in anestrus. Changes in serum progesterone concentrations accounted for 22% (estrus) or 23% (diestrus) of the variation in serum 17OHP concentrations. In group 2, 17OHP and progesterone concentrations were significantly higher during pregnancy than after ovariohysterectomy. The serum 17OHP concentration in group 3 was significantly lower (median, 0.2 ng/mL) than in group 1 in estrus and diestrus and in group 2 during pregnancy (median, 0.7 ng/mL) but was not different from 17OHP concentrations in anestrus or after ovariohysterectomy (median, 0.2 ng/mL). CONCLUSIONS AND CLINICAL RELEVANCE: Serum 17OHP concentrations in healthy bitches increased during estrus, diestrus, and pregnancy and at those times were higher than in spayed bitches with hyperadrenocorticism.

Influence of dental restoration under general anaesthesia on the low-dose dexamethasone suppression test in dogs.

It was the aim of the study to assess the impact of a minor surgical intervention under general anaesthesia on results of a low-dose dexamethasone suppression test (LDDST) in dogs. Five clinically healthy dogs underwent a LDDST (standard protocol) prior and 1, 4, 7, 14 and 28 days after a dental restoration under general anaesthesia. All LDDSTs revealed negative results. On all test days after intervention some dogs had basal cortisol concentrations below the reference range. Accordingly, plasma cortisol concentrations 4 and 8 h after dexamethasone injection were noticeably lower than before surgery and often even below the lower detection limit of 2.0 ng/ml. The study results may indicate a suppressive effect of a minor surgery under general anaesthesia on cortisol measurements during LDDSTs. It may be speculated that this could possibly lead to false negative test results in the postsurgical period, although transfer of these results to clinical cases is subject to limitations.

Chromatographic analysis of lipid fractions in healthy dogs and dogs with obesity or hyperadrenocorticism.

Obesity and endogenous hyperadrenocorticism (HAC) are common clinical conditions in veterinary practice, and both conditions have clinical and laboratory similarities, such as weight gain and dyslipidemia. The objective of the present study was to characterize and compare the lipid profiles and plasma lipoprotein fractions in healthy dogs (n = 10), in obese dogs (n = 10), and in dogs with HAC (n = 6). All of the dogs were client owned. The lipoproteins were separated by fast protein liquid chromatography, and the plasma concentrations of total cholesterol and total triacylglycerol (TAG) were determined by enzymatic methods. When compared with the healthy and obese groups, dogs with HAC had a significant increase (P < 0.01) in the total concentrations of TAGs and cholesterol (CHOL), with higher distribution in the very low-density lipoprotein (VLDL)-CHOL fractions. In addition, the distributions of the high-density lipoprotein (HDL)-CHOL and HDL-TAG fractions were significantly lower (P < 0.01) in dogs with HAC than in healthy dogs. Considering the animals in this study, it was determined that the dogs with HAC differed significantly from the healthy and obese dogs regarding the metabolism of CHOL and TAG, as well as their VLDL and HDL fractions. Similar laboratory findings could allow veterinarians to distinguish obese dogs from those with HAC. In addition, dogs with HAC may be at higher risk for developing metabolic and atherosclerotic complications.

Hyperaldosteronism and hyperprogesteronism in a cat.

UNLABELLED: CLINICAL FINDINGS AND INVESTIGATIONS: A 14-year-old female neutered domestic shorthair cat was referred for investigation of progressive hair loss, muscle wasting and hind limb weakness. Diabetes mellitus had been diagnosed 8 months earlier and was well controlled. Abnormalities on serum biochemistry included persistent mild azotaemia, hypochloridaemia, hypokalaemia, metabolic alkalosis and elevated creatine kinase. Physical examination revealed a pot-bellied appearance, with muscle wasting, marked thinning and fragility of the skin, bilaterally symmetrical alopecia, a gallop rhythm and systolic hypertension (173 mmHg). A large, lobulated left adrenal mass was identified using abdominal ultrasound. CONFIRMATION OF DIAGNOSIS: Primary hyperaldosteronism was diagnosed based on an elevated plasma aldosterone concentration and normal plasma renin activity. Hyperprogesteronism was confirmed by adrenocorticotrophic hormone stimulation test. PRACTICAL RELEVANCE: This is only the second reported case of hyperaldosteronism and hyperprogesteronism in the cat. Clinicians should be alert to the possibility of concurrent hyperaldosteronism and hyperprogesteronism in cats with adrenal tumours showing clinical signs referable to both conditions. The putative mechanism is either increased secretion of aldosterone and progesterone from neoplastic cells of the zona glomerulosa and fasciculata/reticularis, respectively, or increased production of progesterone, as an intermediate in the synthesis of aldosterone, from neoplastic cells of the zona glomerulosa alone.

Elevations in sex hormones in dogs with sudden acquired retinal degeneration syndrome (SARDS).

Dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) commonly are presented with concurrent clinical, physical, and historical findings consistent with hyperadreno-corticism (HAC) at the time of vision loss. Thirteen dogs diagnosed with SARDS on the basis of complete ophthalmic examination and extinguished bright-flash electroretinogram were evaluated for steroid hormonal abnormalities. Signalment, case history, physical examination, and clinicopathological findings were recorded. Serum cortisol and sex-hormone concentrations were measured before and after adrenocorticotropic hormone (ACTH) stimulation. Clinical signs of HAC, systemic hypertension, and proteinuria were commonly found in dogs with SARDS. Elevations in one or more sex hormones were found in 11 (85%) of 13 dogs (95% confidence interval [CI] 65% to 100%); cortisol was elevated in nine (69%) of 13 dogs (95% CI 44% to 94%). A minority of dogs (three [23%] of 13; 95% CI 0.2% to 46%) exhibited only an increase in adrenal sex hormones. Only one dog had completely normal ACTH stimulation test results. Symptoms of HAC were associated with abnormal ACTH stimulation results. Routine ACTH stimulation testing to evaluate cortisol and sex hormones, blood pressure screening, and urinalysis are recommended in these animals.

Serum acute phase protein concentrations in dogs with hyperadrenocorticism with and without concurrent inflammatory conditions.

BACKGROUND: Acute phase proteins (APPs) are promising markers of inflammation in dogs, because they are more sensitive than WBC counts in detecting clinical and subclinical inflammation. Endogenous corticosteroids can mask an acute phase response and make it more difficult to identify underlying inflammatory disease. OBJECTIVE: The purpose of this study was to evaluate the acute phase protein response in dogs with spontaneous hyperadrenocorticism (HAC) with and without concurrent inflammatory conditions. METHODS: Serum concentrations of C-reactive protein (CRP), haptoglobin (Hp), fibrinogen, and albumin were measured in 44 healthy adult dogs and 39 dogs with HAC; the HAC group was further divided into dogs with and without concurrent infection/inflammation. A fourth group of dogs with severe sepsis and without HAC was compared with the dogs with HAC and severe sepsis. RESULTS: Dogs with uncomplicated HAC had significantly higher Hp and fibrinogen concentrations compared with healthy control dogs (P<.001). Dogs with HAC and severe inflammatory disease also had significantly higher CRP and lower albumin concentrations than control dogs and dogs with HAC without concurrent inflammation. Dogs with sepsis but without HAC had significantly higher CRP concentrations than dogs with HAC and sepsis. CONCLUSIONS: Dogs with HAC had increases in the moderate APPs (Hp and fibrinogen), and no significant changes in CRP and albumin compared with healthy dogs. Although concurrent HAC appeared to blunt the CRP response in dogs with sepsis, increased serum CRP concentration in dogs with HAC is likely indicative of severe concurrent inflammation.

[Hyperprogesteronism due to bilateral adrenal carcinomas in a cat with diabetes mellitus]. / Hyperprogesteronismus infolge bilateraler Nebennierenrindenkarzinome bei einer Katze mit Diabetes mellitus.

An 8 year old male castrated Russian Blue cat with polyuria, polydipsia, polyphagia, abdominal enlargement, unkempt and easily epilated hair coat and abdominal alopecia is described. As a first step diabetes mellitus was diagnosed. Further work-up by ultrasonography revealed severe bilateral enlargement of the adrenal glands. Hypercortisolism was suspected and therefore ACTH stimulation test and dexamethasone suppression test were performed. In all samples cortisol concentrations were below the detection limit of the assay used. Various precursor hormones were measured and high progesterone concentrations were found. Histologically, the adrenal masses were characterised as bilateral adrenal carcinomas of the adrenal cortex. The case report demonstrates that adrenal gland tumors are also capable to secrete sex hormones instead of cortisol. Clinical signs of hyperprogesteronism are identical to those of hypercortisolism.

Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.

Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

Adrenal hypersensitivity precedes chronic hypercorticism in streptozotocin-induced diabetes mice.

Previous studies have demonstrated that type 1 diabetes is characterized by hypercorticism and lack of periodicity in adrenal hormone secretion. In the present study, we tested the hypothesis that hypercorticism is initiated by an enhanced release of ACTH leading subsequently to adrenocortical growth and increased output of adrenocortical hormones. To test this hypothesis, we used the streptozotocin (STZ)-induced diabetes mouse model and measured hypothalamic-pituitary-adrenal axis activity at different time points. The results showed that the expected rise in blood glucose levels induced by STZ treatment preceded the surge in corticosterone secretion, which took place 1 d after diabetes onset. Surprisingly, circulating ACTH levels were not increased and even below control levels until 1 d after diabetes onset and remained low until d 11 during hypercorticism. In response to ACTH (but not vasopressin), cultures of adrenal gland cells from 11-d diabetic mice secreted higher amounts of corticosterone than control cells. Real-time quantitative PCR revealed increased expression of melanocortin 2 and melanocortin 5 receptors in the adrenal glands at 2 and 11 d of STZ-induced diabetes. AVP mRNA expression in the paraventricular nucleus of the hypothalamus was increased, whereas hippocampal MR mRNA was decreased in 11-d diabetic animals. GR and CRH mRNAs remained unchanged in hippocampus and paraventricular nucleus of diabetic mice at all time points studied. These results suggest that sensitization of the adrenal glands to ACTH rather than an increase in circulating ACTH level is the primary event leading to hypercorticism in the STZ-induced diabetes mouse model.

ACTH-independent hyperadrenocorticism due to food-dependent hypercortisolemia in a dog: a case report.

In addition to adrenocortical tumours, aberrant expression of functional hormone receptors in the adrenal cortex may cause adrenocorticotrophic hormone (ACTH)-independent hyperadrenocorticism. Here we report on a 6 year old Vizsla dog in which ACTH-independent hyperadrenocorticism was associated with meal-induced hypercortisolemia. Diagnosis was based on history, physical findings, biochemical changes, and elevation of the urinary corticoid/creatinine ratio (UCCR) on two consecutive days (11 and 8.3 x 10(-6), reference range <8.3 x 10(-6)). Basal plasma ACTH concentration was found by repeated measurements to be suppressed (<1 ng/L, reference range 5-85 ng/L) and administration of corticotrophin releasing hormone (CRH) resulted in a minor increase (to 6 ng/L), consistent with ACTH-independent hyperadrenocorticism. Ultrasonography and computed tomography revealed two uniformly enlarged adrenal glands. Magnetic resonance imaging of the pituitary area showed a non-enlarged, normally enhancing pituitary gland. Based on these results, expression of functional aberrant adrenocortical receptors was suspected and the possibility of food-dependent hyperadrenocorticism was explored. The UCCR on two separate occasions rose from 11 and 8 x 10(-6) before a meal to 25 and 23 x 10(-6) at 3 h after ingestion of a meal, respectively. There was a corresponding increase in plasma cortisol concentration (from 90 to 150 nmol/L), while plasma ACTH concentration remained low or undetectable. Consistent with the diagnostic criteria for food-dependent hyperadrenocorticism in humans, administration of octreotide completely prevented meal-induced hypercortisolemia. The dog was treated successfully with the cortisol-synthesis-inhibitor trilostane (2h before meal), and at 26 months after the final diagnosis the dog is still in good condition. The combination of (1) low plasma ACTH concentration in the absence of an adrenocortical tumour, (2) an increase of >100% in UCCR after ingestion of a meal, (3) prevention of the meal-induced increase in plasma cortisol concentration by octreotide, and (4) reversal of signs of hypercortisolism by administration of trilostane a few hours before the meal led to the diagnosis of food-dependent hyperadrenocorticism in this dog.

Pituitary-dependent hyperadrenocorticism in a cockatoo.

CASE DESCRIPTION: A 13-year-old female intact Moluccan cockatoo (Cacatua moluccensis) was evaluated because of coelomic distention, presumed to be secondary to an abdominal hernia. The patient also had a history of rapid weight gain and polyuria and polydipsia. CLINICAL FINDINGS: Ultrasonography was used to confirm the existence of a pseudohernia that appeared to contain the small intestines, pancreas, and reproductive tract. Results of plasma biochemical analysis revealed hyperglycemia, hypophosphatemia, and high nonfasting bile acid concentrations and aspartate aminotransferase activity. A CBC revealed a relative heterophilia with a concomitant lymphopenia and mild monocytosis. Histologic evaluation of a liver biopsy specimen indicated chronic hepatic lipidosis. Despite a strong clinical suspicion of hyperadrenocorticism, ACTH stimulation test results were equivocal. TREATMENT AND OUTCOME: The pseudohernia was strengthened with a prolene mesh. Despite ongoing medical and surgical care, the patient developed complications associated with the herniorrhaphy and was euthanatized. The clinical suspicion of hyperadrenocorticism was confirmed on the basis of histologic evaluation of the pituitary gland by use of special stains. CLINICAL RELEVANCE: To our knowledge, pituitary-dependent hyperadrenocorticism has not been previously confirmed in Psittaciformes. The condition should be considered in birds with clinical signs consistent with those observed in mammals. For the cockatoo of this report, ACTH stimulation test results were equivocal and additional diagnostic tests should be developed for avian patients.