Duncan C. Ferguson

Etiopathology of Feline Toxic Nodular Goiter

We have discussed the etiopathology of feline toxic nodular goiter in the context of human nodular goiter pathogenesis. We have reviewed thyroid heterogeneity, growth regulation, functional and growth autonomy, nodule and tumor formation, and the evolution of toxic nodular goiter in the human being. By addressing toxic nodular goiter of the cat, the history, morphologic findings, xenotransplantation and cell culture studies, evidence for and against circulating thyroid stimulators and epizootiological studies of the feline disease have been summarized. Due to its structure, the thyroid gland offers some unique possibilities to study the mechanisms that are responsible for cellular heterogeneity, the emergence of autonomous nodular growth and function, and, ultimately, the development of tumors. The demonstration of naturally occurring clones of cells with high intrinsic proliferation potential within the follicular epithelium of the thyroid has fostered promising new concepts on the genesis of nodular growth of benign and possibly malignant endocrine tumors. Hyperthyroid cat goiters contain single or multiple, autonomously (i.e., TSH-independently) functioning and growing nodules. Neither hyperfunction nor growth of these nodules depends on extrathyroidal circulating stimulators. The basic lesion appears to be an excessive intrinsic growth capacity of some thyroid cells. The factors enhancing the transformation of a normal thyroid into a nodular hyperfunctioning goiter over many years are still unknown. Immunological, environmental, and nutritional factors are the focus of ongoing studies, but an infectious agent can not yet be excluded.

The impact of obesity, sex, and diet on hepatic glucose production in cats

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using (2)H(2)O, [U-(13)C(3)]propionate, and [3,4-(13)C(2)]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had approximately 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Obesity and age are risk factors for feline diabetes. This study aimed to test the hypothesis that age, long-term obesity, and dietary composition would lead to peripheral and hepatorenal insulin resistance, indicated by higher endogenous glucose production (EGP) in the fasted and postprandial state, higher blood glucose and insulin, and higher leptin, free thyroxine, and lower adiponectin concentrations. Using triple tracer-(2)H(2)O, [U-(13)C(3)] propionate, and [3,4-(13)C(2)] glucose infusion, and indirect calorimetry-we investigated carbohydrate and fat metabolic pathways in overnight-fasted neutered cats (13 young lean, 12 old lean, and 12 old obese), each fed three different diets (high protein with and without polyunsaturated fatty acids, and high carbohydrate) in a crossover design. EGP was lowest in fasted and postprandial obese cats despite peripheral insulin resistance, indicated by hyperinsulinemia. Gluconeogenesis was the most important pathway for EGP in all groups, but glycogen contributed significantly. Insulin and leptin concentrations were higher in old than in young lean cats; adiponectin was lowest in obese cats but surprisingly highest in lean old cats. Diet had little effect on metabolic parameters. We conclude that hepatorenal insulin resistance does not develop in the fasted or postprandial state, even in long-term obese cats, allowing the maintenance of euglycemia through lowering EGP. Glycogen plays a major role in EGP, especially in lean fasted cats, and in the postprandial state. Aging may predispose to insulin resistance, which is a risk factor for diabetes in cats. Mechanisms underlying the high adiponectin of healthy old lean cats need to be further explored.

The feline thyroid gland: a model for endocrine disruption by polybrominated diphenyl ethers (PBDEs)?

The role of polybrominated diphenyl ethers (PBDE) was investigated in the occurrence of feline hyperthyroidism (FH) by evaluating 15 PBDE congeners in serum from 62 client-owned (21 euthyroid, 41 hyperthyroid) and 10 feral cats. Total serum PBDE concentrations in euthyroid cats were not significantly different from those of hyperthyroid cats. Total serum PBDE in feral cats were significantly lower than in either of the groups of client-owned cats. Total serum PBDE did not correlate with serum total T4 concentration. Ten samples of commercial canned cat food and 19 dust samples from homes of client-owned cats were analyzed. Total PBDE in canned cat food ranged from 0.42 to 3.1 ng/g, and total PBDE in dust from 510 to 95,000 ng/g. Total PBDE in dust from homes of euthyroid cats ranged from 510 to 4900 ng/g. In dust from homes of hyperthyroid cats, total PBDE concentrations were significantly higher, ranging from 1100 to 95,000 ng/g. Dust PBDE and serum total T4 concentration were also significantly correlated. Estimates of PBDE exposures calculated from canned cat food and dust data suggest that domestic cats are primarily exposed through ingestion of household dust. These findings indicate further study of the role of PBDE is needed in the development of FH, which might identify the cat as a model and sentinel for humans with toxic nodular goiter (TNG).

Effects of Developmental Exposure to Polychlorinated Biphenyls and/or Polybrominated Diphenyl Ethers on Cochlear Function

Developmental exposure to polychlorinated biphenyls (PCBs) causes hearing loss that may be due to reduced thyroxine during cochlear development. Polybrominated diphenyl ethers (PBDEs) are structurally similar to PCBs and reduce thyroxine. This study utilized an environmental PCB mixture and a commercial PBDE mixture, DE-71, that represents the PBDEs found in humans to assess the potential for additive effects of PCBs and PBDEs on cochlear function. Female Long-Evans rats were dosed with corn oil vehicle, PCBs (3 or 6 mg/kg), molar equivalent doses of PBDEs (5.7 or 11.4 mg/kg), 3 mg/kg PCBs + 5.7 mg/kg PBDEs, or 6 mg/kg PCBs + 11.4 mg/kg PBDEs throughout gestation and lactation. At weaning, pup blood was taken to assess thyroxine concentrations. One male and one female from each litter were maintained until adulthood for distortion product otoacoustic emission (DPOAE) measurements of cochlear function. DPOAE amplitudes were decreased and thresholds were elevated in the 6 mg/kg PCB group. Exposure to PBDEs did not cause DPOAE deficits. There was an interactive effect from combined exposure such that the individual low doses of PCBs and PBDEs did not result in DPOAE deficits, but the two combined produced a deficit similar to that in the high-dose PCB group. Serum thyroxine concentrations of all groups were reduced compared with controls, but PBDEs produced a less dramatic reduction than PCBs, which could explain the lack of DPOAE effects. Importantly, there was evidence that the co-exposure to subthreshold doses of PCBs and PBDEs can have an additive effect on cochlear function.

Effects of perinatal bisphenol A exposure during early development on radial arm maze behavior in adult male and female rats.

Previous work has shown that exposure to bisphenol A (BPA) can affect anxiety behavior. However, no studies have examined whether administration of this endocrine disruptor during the perinatal period has the potential to induce alterations in cognitive behavior in both adult males and females as assessed in an appetitive task. The goal of the current study was to determine whether exposure to different doses of BPA during early development alters performance on the 17-arm radial maze in adulthood in Long-Evans rats. Oral administration of corn oil (vehicle), 4 μg/kg, 40 μg/kg, or 400 μg/kg BPA to the dams occurred daily throughout pregnancy, and the pups received direct oral administration of BPA between postnatal days 1-9. Blood was collected from offspring at weaning age to determine levels of several hormones (thyroxine, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone). One male and one female from each litter were evaluated on the 17-arm radial maze, a working/reference memory task, in adulthood. Results indicated that after exposure to BPA at both 4 and 400 μg/kg/day, rats of both sexes had decreased levels of FSH at weaning. There were no significant effects of BPA on performance on the radial arm maze in males or females. In conclusion, exposure to BPA during early development had modest effects on circulating hormones but did not affect performance on a spatial learning and memory task.

Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity.

Objectives: Obese cats show many similarities to obese people, including insulin resistance and an increased diabetes risk. However, atherosclerosis and cardiovascular disease are not seen in cats. In people, they are associated with the development of an inflammatory response, which, we hypothesized, does not occur in cats.

Evaluation of long-term glucose homeostasis in lean and obese cats by use of continuous glucose monitoring

OBJECTIVEnTo evaluate intraday and interday variations in glucose concentrations in cats and to test the utility of a continuous glucose monitoring system (CGMS).nnnANIMALSn6 lean and 8 long-term (> 5 years) obese cats.nnnPROCEDURESnBlood glucose concentrations were measured during the course of 156 hours by use of a laboratory hexokinase-based reference method and a handheld glucometer. Interstitial glucose concentrations were evaluated with a CGMS.nnnRESULTSnPaired measures of glucose concentrations obtained with the CGMS typically were marginally higher than concentrations for the reference method and less biased than concentrations obtained with the glucometer. This was partially confirmed by the concordance correlation coefficients of the concentration for the CGMS or glucometer versus the concentration for the reference method, although the correlation coefficients were not significantly different. Mean ± SD area under the curve for the glucose concentration (AUCG) did not differ significantly between lean (14.0 ± 0.5 g/dL•h) and obese (15.2 + 0.5 g/dL•h) cats during the 156-hour period, but one of the obese cats had a much higher AUCG. Within-day glucose variability was small in both lean and obese cats.nnnCONCLUSIONS AND CLINICAL RELEVANCEnGlucose homeostasis was maintained, even in long-term obese cats, and intraday glucose fluctuations were small. One obese cat might have been classified as prediabetic on the basis of the AUCG, which was approximately 25% higher than that of the other obese and lean cats. The CGMS can be useful in the evaluation of long-term effects of drugs or diet on glucose homeostasis in cats.

2016 AAFP Guidelines for the Management of Feline Hyperthyroidism

Clinical context: Since 1979 and 1980 when the first reports of clinical feline hyperthyroidism (FHT) appeared in the literature, our understanding of the disease has evolved tremendously. Initially, FHT was a disease that only referral clinicians treated. Now it is a disease that primary clinicians routinely manage. Inclusion of the measurement of total thyroxine concentration in senior wellness panels, as well as in diagnostic work-ups for sick cats, now enables diagnosis of the condition long before the cat becomes the classic scrawny, unkempt, agitated patient with a bulge in its neck. However, earlier recognition of the problem has given rise to several related questions: how to recognize the health significance of the early presentations of the disease; how early to treat the disease; whether to treat FHT when comorbid conditions are present; and how to manage comorbid conditions such as chronic kidney disease and cardiac disease with treatment of FHT. The 2016 AAFP Guidelines for the Management of Feline Hyperthyroidism (hereafter referred to as the Guidelines) will shed light on these questions for the general practitioner and suggest when referral may benefit the cat. Scope: The Guidelines explain FHT as a primary disease process with compounding factors, and provide a concise explanation of what we know to be true about the etiology and pathogenesis of the disease. The Guidelines also: Distill the current research literature into simple recommendations for testing sequences that will avoid misdiagnosis and separate an FHT diagnosis into six clinical categories with associated management strategies. Emphasize the importance of treating all hyperthyroid cats, regardless of comorbidities, and outline the currently available treatments for the disease. Explain how to monitor the treated cat to help avoid exacerbating comorbid diseases. Dispel some of the myths surrounding certain aspects of FHT and replace them with an evidence-based narrative that veterinarians and their practice teams can apply to feline patients and communicate to their owners. Evidence base: To help ensure better case outcomes, the Guidelines reflect currently available, evidenced-based knowledge. If research is lacking, or if a consensus does not exist, the expert panel of authors has made recommendations based on their extensive, cumulative clinical experience.

Daily endogenous cortisol production and hydrocortisone pharmacokinetics in adult horses and neonatal foals.

OBJECTIVEnTo compare daily endogenous cortisol production rate and the pharmacokinetics of an i.v. bolus of hydrocortisone between neonatal foals and adult horses.nnnANIMALSn10 healthy full-term 2- to 4-day-old foals and 7 healthy adult horses.nnnPROCEDURESnBlood samples were collected from each horse every 15 to 20 minutes for 24 hours for determination of 24-hour mean cortisol concentration. Afterward, dexamethasone (0.08 mg/kg) was administered i.v. to suppress endogenous cortisol production. Twelve hours afterward, hydrocortisone sodium succinate (1.0 mg/kg) was administered as a rapid i.v. bolus and serial blood samples were collected to determine hydrocortisone pharmacokinetics. Cortisol concentrations, daily cortisol production rate, and hydrocortisone pharmacokinetics were determined, and results were compared between adult horses and foals.nnnRESULTSnThe mean ± SD 24-hour cortisol concentration was significantly lower in foals (20 ± 4 ng/mL) than in horses (26 ± 6 ng/mL), but the daily cortisol production rate was significantly greater in foals (6,710 ± 320 ng/kg/d) than in horses (2,140 ± 400 ng/kg/d). For hydrocortisone, foals had a significantly greater volume of distribution at steady state (1.92 ± 1.11 L/kg) and total body clearance (1.39 ± 0.108 L/kg/h) and significantly lower peak plasma concentration (1,051 ± 343 ng/mL) than did horses (0.58 ± 0.15 L/kg, 0.349 ± 0.065 L/kg/h, and 8,934 ± 3,843 ng/mL, respectively).nnnCONCLUSIONS AND CLINICAL RELEVANCEnImportant differences were detected in cortisol production and metabolism between neonatal foals and adult horses consistent with lower plasma protein binding of cortisol in foals. This decrease may contribute to cortisol insufficiency during prolonged critical illness in neonatal foals.