Tuesday, July 9, 2013

Top 10 Clinical Endocrinology Research Abstracts, Part 2

Following last week’s post, this is the next installment of my review of the "top 10 list" clinical endocrinology research abstracts presented at last month's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review 3 more of these "top 10" abstracts, followed by the remaining 4 abstracts in next week's post. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.


Lobetti R, Lindquist E, Frank J, et al. Adrenal gland ultrasonography in dogs with hypoadrenocorticism. J Vet Intern Med 2013:691. 

Hypoadrenocorticism can be a life-threatening disease if not treated immediately. Although a tentative diagnosis can be made on clinical signs and laboratory findings, a definitive diagnosis can only be made on an ACTH stimulation test. Unfortunately, typical clinical signs and laboratory findings are not evident in all cases and ACTH stimulation test results are usually not immediately available. As abdominal ultrasonography is widely used, it would be ideal as a diagnostic aid for hypoadrenocorticism. To date, there are only 2 studies that have shown small adrenal glands in dogs with hypoadrenocorticism on ultrasound. The purpose of this study was to identify a reliable set of adrenal ultrasonography parameters that could be used to identify dogs with hypoadrenocorticism. The records of 81 privately owned dogs that had abdominal ultrasonography done as well as an ACTH stimulation test were retrospectively evaluated. The dogs were divided into three groups: Group 1 consisted of 37 dogs with clinical signs and/or a sonogram appearance of their adrenal glands suspicious of hypoadrenocorticism and confirmed on an ACTH stimulation test. Group 2 consisted of 19 dogs with clinical signs and/or a sonogram appearance of their adrenal glands suspicious of hypoadrenocorticism but ruled out by a normal ACTH stimulation test. Group 3 consisted of 25 dogs that had no clinical signs or biochemical evidence of hypoadrenocorticism, normal sonogram appearance of their adrenal glands, and a normal ACTH stimulation test. Descriptive statistics were used to describe the data and one-way analysis of variance with Bonferroni and Tukey-Kramer comparisons used to test for statistical differences between the groups. The level of significance was set at p < 0.05. Results showed that the median right adrenal length in Group 1-3 was 1.75 cm, 1.8 cm, and 2.03 cm, respectively. Median left adrenal length in Group 1-3 was 1.77 cm, 2.08 cm, and 2.1 cm, respectively. There was no statistical difference between the right and left adrenal gland and within groups. Median right adrenal thickness in Group 1-3 was 0.34 cm, 0.37 cm, and 0.6 cm, respectively. Median left adrenal thickness in Group 1-3 was 0.31 cm, 0.4 cm, and 0.6 cm, respectively. In both right and left measurements, groups 1 and 2 were statistically different from group 3 but there was no statistical difference between groups 1 and 2. The study concluded that the ultrasound finding of small, flattened, isoechoic adrenal glands should be an alert for possible hypoadrenocorticism, prompting additional confirmatory function testing and/or therapeutic intervention.
  
 Comments—An abdominal ultrasound is often included as part of a diagnostic work-up for various disorders and clinical complaints. The ultrasound finding of bilaterally small adrenal glands, even if unexpected, should send an alert signal regarding the possibility of underlying adrenal insufficiency (1-3).

In general, dogs with hypoadrenocorticism have thinner adrenals than dogs with diseases that mimic the disorder or healthy dogs (2). Often, the left adrenal gland is easier to find than the right adrenal gland, and the left adrenal is less than 3.2 mm in diameter in dogs with confirmed hypoadrenocorticism (2). In this study, however, there was no statistical difference between the length or thickness of the either adrenal gland between the dogs with confirmed Addison's disease and sick dogs proven not to have hypoadrenocorticism.

The Bottom Line— Sonographic evidence of bilaterally small adrenal glands is a sensitive —but not specific —marker for hypoadrenocorticsm. Such findings should be followed-up with an ACTH response test, which remains the gold standard for the definitive diagnosis of hypoadrenocorticism.

References:
  1. Hoerauf A, Reusch C. Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Anim Hosp Assoc 1999;35:214-218. 
  2. Codreanu M, ┼×erdean C, Fernoag─â C, et al. Study concerning the importance of ultrasound examination in adrenal glands diseases in dog. Lucrari Stiintifice 2009;52:483-486. 
  3. Wenger M, Mueller C, Kook PH, et al. Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. Vet Rec 2010;167:207-210. 

Lourenco BN, Lunn KF. Abdominal ultrasound findings acromegalic cats. J Vet Intern Med 2013:689.

Acromegaly is increasingly recognized as a cause of insulin-resistance in diabetic feline patients. This study was designed to describe the sonographic changes in the abdominal organs of acromegalic cats. Cats were included if they presented to North Carolina State University or Colorado State University from January 2002 to October 2012 with poorly controlled diabetes mellitus, IGF-1 concentrations >100 nmol/L and had an abdominal ultrasound examination (AUS) performed with report available. A control group included age-matched cats that had an AUS performed for investigation of disease unlikely to affect liver, kidneys, pancreas or adrenal glands (e.g. lower urinary tract disease). Twenty five cats were included in each group. IGF-1 concentrations in the acromegaly group ranged from >148 to 638 mmol/l. Median left and right kidney length were significantly greater in the acromegaly group compared to controls (acromegaly—left: 47.0 mm; control-left: 38.1 mm; p < 0.0001; acromegaly—right: 47.0 mm; control-right: 42.2 mm; p = 0.0003). Hepatomegaly and bilateral adrenomegaly were reported in 63% and 53% of acromegalic cats respectively, and in none of the controls. Median left and right adrenal width were significantly greater in the acromegaly group compared to controls (acromegaly—left: 5.4 mm; control-left: 3.5 mm; p < 0.0001; acromegaly—right: 5.4 mm; control-right: 3.6 mm; p < 0.0001). Median pancreatic thickness was significantly greater in acromegalic patients compared to controls (13.5 mm vs. 6.1 mm; p = 0.0003). Pancreatic changes were described in 79% of the acromegalic cats and 9% of the controls. These findings indicate that compared to non-acromegalic cats, acromegalic patients have larger kidneys, liver, adrenals and pancreas.

Comments— It is well-known that growth hormone (GH) excess in the adult animal causes soft tissue (including the viscera) to grow.  Therefore, it is not unexpected that the sonographic appearance of the kidneys, liver, pancreas, and adrenal glands are enlarged in cats with acromegaly (1-6).

The Bottom Line— Acromegaly and hyperadrenocorticism are always on the rule-out list for any diabetic cat with insulin-resistance (2,5,6). In addition, both of these disorders share sonographic similarities such as liver and adrenal gland enlargement, which sometimes creates diagnostic confusion. However, it is important to keep in mind that sonographic evidence of bilateral adrenal enlargement is a sensitive, but not specific, marker for hyperadrenocorticism.

Clues that would point toward a diagnosis of hyperadrenocorticism instead of acromegaly in cats include weight loss, lack of or only mild-to-moderate insulin-resistance, muscle wasting, dermatologic signs, a generalized poor body condition, and a normal serum IGF-1 level (6). In contrast, cats with acromegaly frequently show weight gain, severe insulin-resistance, lack of muscle wasting or dermatologic signs, a good body condition, and an elevated IGF-1 level (1-6).

References:
  1. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990;4:192-201. 
  2. Berg RI, Nelson RW, Feldman EC, et al. Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 2007;21:892-898. 
  3. Niessen SJ, Petrie G, Gaudiano F, et al. Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med 2007;21:899-905. 
  4. Peterson ME. Acromegaly in cats: are we only diagnosing the tip of the iceberg? J Vet Intern Med 2007;21:889-891. 
  5. Niessen SJ. Feline acromegaly: an essential differential diagnosis for the difficult diabetic. J Feline Med Surg 2010;12:15-23. 
  6. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 

Reeve-Johnson MK, Rand JS, Vankan D, et al. Diagnosis of prediabetes in cats: cutpoints for impaired fasting glucose and impaired glucose tolerance in cats 8 years and older using ear or paw samples and a portable glucose meter calibrated for cats. J Vet Intern Med 2013:693.

Humans with fasting glucose above normal, but below diabetic, are classed as having impaired fasting glucose. Impaired glucose tolerance is diagnosed based on increased glucose concentration at 2 h after oral or iv glucose administration in a standardized test. Humans with impaired fasting glucose or impaired glucose tolerance below levels considered diabetic, are classed as prediabetic, and at high risk of developing type 2 diabetes. Human prediabetics outnumber diabetics 3-4:1. We have previously reported the upper cutpoint for casual blood glucose in cats, but tests for pre-diabetes and subclinical diabetes in cats are not well characterized, and therefore, cats are not typically diagnosed until clinical diabetes is evident. The aims were to establish cutpoints for healthy neutered cats > 8 years of age for fasting and 2 h glucose using a standardized test protocol with paw or ear samples and a portable glucose meter calibrated for feline blood. All cats were client-owned and healthy on the basis of client history, physical examination and a routine blood profile. Of the 82 cats tested (aged 8-18 years), 21 were Burmese and 61 non-Burmese (22 lean-BCS 3-5/9), 20 overweight-BCS 6-7/9; and 19 obese-BCS 8-9/9). Following >18 h fast, a catheter was inserted into the cephalic vein. After 3 h, fasting glucose was measured from the ear or paw using the Abbott AlphaTRAK. Glucose (0.5 g/kg bwt) was administered i.v. over 30s and glucose measured at 2 min and 2 h. Reference intervals were determined after Box-Cox transformation and exclusion of outliers. The cutpoints were defined as the upper limits of the 95% reference intervals. Based on a priori knowledge that overweight and obese cats have abnormal glucose tolerance, cats of BCS 7-9/9 were excluded from the fasting and 2 h reference interval calculations. Reference intervals for Burmese were pooled with non-Burmese because the percentage differences of the medians and interquartile ranges for the sub-groups were 50% and 100%, respectively. Based on the 95% reference interval, the fasting glucose cut-point for cats with BCS 6/9 (n = 44) was 6.3 mmol/L (113 mg/ dL); the associated 90% confidence interval was 6.1-6.5 mmol/L (110-117 mg/dL). 2/82 cats were classed as having impaired fasting glucose (BCS 5 and 7/9). The cutpoint for 2 h glucose established using cats with BCS 6/9 was 10.0 mmol/L (180 mg/dL) (90% confidence interval 9.1-10.8 mmol/L (164-194 mg/dL). Six of 82 cats were classed as having impaired glucose tolerance (4 with BCS 8 or 9/9 including 1 Burmese, 2 with BCS 7/9). We recommend that 6.3 mmol/l (113 mg/dL) be used as the cutpoint between normal and impaired fasting glucose, and that 10.0 mmol/L (180 mg/dL) be used as the 2-h glucose cutpoint between normal and impaired glucose tolerance in a simplified intravenous glucose tolerance test using a glucose dose of 0.5 g/kg with blood glucose measured from ear or pad samples using a portable glucose meter calibrated for feline blood. 

Comments—Humans with mild fasting hyperglycemia and/or slightly impaired glucose tolerance are classified as prediabetic and are at higher risk for type 2 diabetes mellitus (1). Interestingly, approximately 50% of human patients with diabetes go undiagnosed, and it is estimated that prediabetes is 4 times more common than is overt diabetes (1).

Until recently, little attention has been paid to the definition of prediabetes in cats, especially as it relates to blood glucose concentrations. In clinical practice, cats are not typically diagnosed until overt clinical diabetes (often severe and advanced) is evident. However, because most cats suffering from diabetes have a form similar to type 2 diabetes in people, it is likely that most cats will also go through a subclinical or prediabetic phase that goes undiagnosed (2). Obviously, better guidelines for early diagnosis of this common feline disorder is needed.

This group of investigators, lead by Jacquie Rand, have previously reported an upper cutoff value (174 mg/dl) for random blood glucose sampling that helps define the onset of pre-diabetes in cats (3). A random or casual blood glucose refers to measuring blood glucose whenever the cat arrives for an examination, so this may or may not be a fasted sample.

In this abstract, these investigators report that determination of a blood glucose concentration, measured after a prolonged fast, followed by glucose tolerance testing can act as more specific diagnostic tests for prediabetes and subclinical diabetes in cats.

The Bottom Line— Although measuring a fasted blood glucose value, followed by an IV glucose tolerance test, appear to be the best diagnostic tests for prediabetes,  performing these tests are not simple, and they are not going to be very useful in a busy clinical practice. The proper implementation of these tests involves prolonged fasting, hospitalization for several hours, intravenous catheter placement, and IV administration of 50% glucose (4).

In most clinical situations, a random blood glucose remains most practical test we have for diagnosing  early diabetes or prediabetes in cats. The finding of a random blood glucose concentration >180 mg/dl should never be ignored, even if the cat is showing no overt clinical signs.

In people, the treatment of prediabetes involves intensive lifestyle management such as weight loss or weight control, exercise, special diets, management of hypertension and dyslipidemias, and the occasional use of glucose-lowering agents such as metformin and acarbose (5,6). In the cat with suspected prediabetes, the most sensible and useful strategy to combat the risk of overt diabetes is to initiate a low-carbohydrate diet (7); if overweight or obese, this should be combined with a weight loss program.

However, in the future, if specific drugs designated for the treatment of prediabetes are developed and become available for use in cats, the rules regulating the use of these drugs may be based on strict guidelines for diagnosing prediabetes (i.e., fasting blood glucose and glucose tolerance testing).

References:
  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35 (Supp 1): S64-71.
  2. Rand JS, Fleeman LM, Farrow HA, et al. Canine and feline diabetes mellitus: nature or nurture? J Nutr 2004:134 (Supp 8):2072S-80S
  3. Reeves-Johnson M, Rand J, Anderson S, et al. Determination of reference values for blood glucose concentration in clinically-healthy, aged cats measured with a portable glucose meter from an ear or paw sample. J Vet Intern Med 2012;36:755
  4. Appleton DJ, Rand JS, Priest J, et al. Determination of reference values for glucose tolerance, insulin tolerance, and insulin sensitivity tests in clinically normal cats. Am J Vet Res 2001;62:630-636. 
  5. Bloomgarden ZT. Approaches to treatment of pre-diabetes and obesity and promising new approaches to type 2 diabetes. Diabetes Care 2008;31:1461-1466.
  6.  Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17 Suppl 2:1-53. 
    1. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North America Small Animal Practice 2013:43:233-243.

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