Q & A: Hypoglycemia in a Dog with Hepatocellular Carcinoma

My patient is a 10-year-old, male, Husky that presented with hypoglycemic seizures and a large intra-abdominal tumor a year ago. Physical examination at that time showed cachexia and a palpable mass in the cranial aspect of the abdomen. The major laboratory abnormalities included hypoglycemia (32 mg/dl) and high enzyme activities for both alanine aminotransferase (ALT) and alkaline phosphate (AP). Fasting and postprandial serum bile acid concentrations were high. Insulinoma was considered but the serum concentrations of both insulin and insulin-like growth factor I (IGF-1) were found to bee low at that time.

Abdominal radiographs and abdominal ultrasonography confirmed that the intraabdominal mass was of liver origin. At surgery, the liver tumor appeared isolated to the left liver lobe and was removed. Biopsy confirmed hepatocellular carcinoma. Postoperatively, the hypoglycemia resolved and the dog did well.

Recently, the dog has presented again for generalized hypoglycemic seizures; my workup shows that the tumor now has diffusely infiltrated all the remaining liver lobes. The laboratory workup again shows severe hypoglycemia (35 mg/dl) and high ALT and AP activities. The serum concentrations of total bilirubin, total protein, albumin, and urea nitrogen all remain within reference range limits.

My questions are the following:

1. Can I assume that the hypoglycemia is secondary to the hepatic tumor secreting insulin or another insulin-like factor? I originally measured both serum insulin and IGF-1 but both concentrations were normal.
2. Or should I assume that the hypoglycemia is from the liver failing? If that is the case, I thought it odd to not have a concurrent hypoalbuminemia or a high total bilirubin concentration.

I'd appreciate your input on this case.

My Response:

If the etiology of this dog's hypoglycemia was purely from liver failure, then yes, it would be odd to see severe hypoglycemia from liver failure without also seeing a low serum albumin and urea nitrogen. Like you indicated, canine hepatocellular carcinomas can also produce hypoglycemia via paraneoplastic means — these tumors can make an insulin-like substance that causes the blood glucose to fall (1,2). Since it's not insulin being secreted, the serum insulin levels will be low concurrent with the hypoglycemia. The insulin concentrations would never be high, as would be expected with an insulinoma.

Hypoglycemia can be caused by non-insulinoma tumors in the retroperitoneum, thorax, or abdomen. Intra-abdominal tumors that may cause hypoglycemia include hepatocellular carcinoma (the most common primary liver tumor in the dog), hepatoma, leiomyoma, leiomyosarcoma, melanoma, and hemangiosarcoma (1-4). Large mammary gland tumors have also been associated with hypoglycemia in dogs (5).

Large non-islet cell tumors in the abdomen have been previously been associated with hypoglycemia. There may be more than one cause, but the most common is believed to be tumor production of insulin-like growth factors, especially IGF-2 (1,2,4). The tumor may produce excessive IGF-2 or impair IGF-2 binding to serum proteins. Other contributing factors may be rapid glucose utilization by the tumor or deficiency of insulin antagonists. A consistent finding is suppressed serum concentrations of insulin (and IGF-1), like you found in this case.

Sucessful removal of a hepatocellular carcinoma (or other non-non-islet cell tumors) associated with hypoglycemia should correct the hypoglycemia, like it originally did in this dog (1). Due to the widespread tumor infiltration through the liver, this dog's long-term prognosis is guarded at this time. However, use of frequent feedings and treatment with glucocorticoids may help control signs of hypoglycemia, at least temporarily.

References:

1. Sakai M, Asano K, Nakata M, et al. Diabetes mellitus after resection of hepatocellular carcinoma with hypoglycemia in a dog. The Journal of Veterinary Medical Science 2006;68:765-767.
2. Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992-2002). Journal of the American Veterinary Medical Association 2004;225:1225-1230.
3. Zini E, Glaus TM, Minuto F, et al. Paraneoplastic hypoglycemia due to an insulin-like growth factor type-II secreting hepatocellular carcinoma in a dog. Journal of Veterinary Internal Medicine 2007;21:193-195.
4. Leifer CE, Peterson ME, Matus RE, et al: Hypoglycemia associated with nonislet cell tumor in 13 dogs. Journal of the American Veterinary Medical Association 1985; 186:53-5.
5. Rossi G, Errico G, Perez P, et al. Paraneoplastic hypoglycemia in a diabetic dog with an insulin growth factor-2-producing mammary carcinoma. Veterinary Clinical Pathology 2010;39:480-484.

Q & A: Hypoglycemia in a 7-Year-Old Laborador Retreiver

I'm writing about a 7-year-old lab that present today for signs associated with hypoglycemia.He has been progressive lethargic for the last week. The owner noted staggering and weakness and brought him into our clinic for evaluation yesterday.

On examination, the dog was quiet but clinically normal. His blood glucose concentration, however, was low at 26 mg/dl (reference range, 70-125 mg/dl). All other serum chemistry results (including serum sodium and potassium were normal. Radiographs of the chest and abdomen were unremarkable. The owner has been quizzed at length about possible xylitol ingestion, but there is no history of possible ingestion.

We hospitalized the dog for observation and started a 5% dextrose drip overnight. This morning, the blood glucose was still quite low (only 47 mg/dl) after being off dextrose for about an hour. I continued the glucose drip (raised it to a 10% drip), and the blood glucose concentrations ranged from 41 to 70 mg/dl throughout the day. He is eating well and alert on the IV glucose supplementation.

My rule outs are the following intoxications or medical disorders:

• Xylitol ingestion 
• Atypical Addison's (the serum electrolytes and Na:K ratio were normal)
• Insulinoma (insulin-secreting pancreatic islet cell tumor)
• Portosystemic shunt

I have submitted an serum insulin level at the time when the dog's blood glucose was very low (42 mg/dl) and the results are still pending. I've also submitted a baseline cortisol concentration to help rule out Addison's disease. I have not measured his serum bile acids because I did not want to fast him just yet.

Any other thoughts, suggestions for diagnostics? Anything I am missing?

My Response:

You have the correct list of differential diagnoses and are working your way through the list properly. I'd agree with not fasting the dog — I'd just do a random bile acid measurement to first see it that's abnormal.

If this dog has an insulinoma, we have to remember that IV administration of dextrose may stimulate secretion by the pancreatic tumor. Insulin release post-hyperglycemia often results in rebound hypoglycemia, which necessitates additional dextrose administration and leads the clinician into a cyclical hyperglycemia/hypoglycemia "chase" which can be difficult to terminate.

In this cases, it an be really helpful to just use glucagon instead. Glucagon for injection (1 mg vial) is reconstituted according to the manufacturer's instructions with supplied diluent, then added to 1000 ml of 0.9% NaCl. The 1000 ng/ml solution is administered intravenously as a constant rate infusion (CRI) with the use of a syringe infusion pump. The glucagon CRI is initially given as a bolus of 50 ng/kg, then administered at a rate of 10 to 15 ng/kg/min. The dose may need to be increased up to 40 ng/kg/min as needed to maintain euglycemia.

Additional Followup:

I've put the dog on a glucagon constant rate infusion and it's been working great to maintain the blood glucose concentration in the normal range in the hospital!

The dog's resting serum cortisol concentration was normal at 3.2 μg/dl, so Addison's disease appears highly unlikely. My serum insulin and bile acid results still pending.

The owner has been internet investigating and he told me that his dog has eaten a birch limb/stick last week. I read that xylitol is derived from hardwoods such as birch — Is there any way the xylan from the birch could be metabolized to xylitol in the dog?

My Response:

You're right, the normal serum cortisol (>2.0 μg/dl) rules out Addison's disease.

As far as xylitol toxicity is concerned, I did some research myself and found that birch wood itself doesn't contain xylitol so that's unlikely to be the cause of the hypoglycemia. And this would be especially true since it was consumed a week ago, and you wouldn't expect continued hypoglycemia if the problem was due to xylitol toxicity.

Outcome:

Abdominal ultrasound showing
multiple hypoechoic masses in liver

The dog's serum insulin concentration, collected at the time of severe hypoglycemia, was extremely high (402 pmol/L; reference range, 60-230 pmol/L). The bile acids values were normal. An abdominal ultrasound revealed a pancreatic mass with several hypoechoic areas in liver, consistent with pancreatic neoplasia with metastasis to the liver. A trial of diazoxide was performed at home, but hypoglycemia persisted.

Based on the poor prognosis and lack of response to diazoxide, the owners elected euthanasia. Multiple pancreatic and hepatic nodules were identified at necropsy; histopathology confirmed beta cell islet cell neoplasia with metastasis to the liver.

Final Diagnosis: Insulinoma (insulin-secreting carcinoma of pancreas), producing hypoglycemia.

References:

1. Dunayer EK. Hypoglycemia following canine ingestion of xylitol-containing gum. Veterinary and Human Toxicology 2004;46:87-88.
2. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. Journal of the American Veterinary Medical Association 1986;188:60-64.
3. Smith SA. Miscellaneous Endocrine Disorders. In Morgan RH, Bright, R, and Swartout MS (eds). Handbook of Small Animal Practice, Fourth Edition. W. B. Saunders, Philadelphia, PA. 2003:731-751.
4. Fischer JR, Smith SA, Harkin, KR. Glucagon constant rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. Journal of the American Animal Hospital Association 2000; 36:27-32.
5. Lennon EM, Boyle TE, Hutchins RG, et al: Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). 
   Journal of the American Veterinary Medical Association 2007;231:413-16.

Top Endocrine Publications of 2010: Canine and Feline Islet Cell Tumors of the Pancreas

In my second compilation of the canine and feline endocrine publications of 2010, I’m sticking with disorders of the pancreas. But now let’s now move on to islet cell tumors (eg, insulinoma) and other causes of hypoglycemia.

Listed below are 6 research papers written in 2010 that review new aspects in the diagnosis or therapy of insulin-secreting tumors of the pancreas (1, 3), pancreatic polypeptide-secreting islet cell tumor (2), glucagon-secreting islet cell tumor or glucagonoma (4), and paraneoplastic hypoglycemia (6).

2010 Papers on Canine and Feline Islet Cell Tumors of the Pancreas and Other Causes for Hypoglycemia:

1. Buishand FO, Kik M, Kirpensteijn J. Evaluation of clinico-pathological criteria and the Ki67 index as prognostic indicators in canine insulinoma. Veterinary Journal 2010;185:62-67.
2. Cruz Cardona JA, Wamsley HL, Farina LL, et al. Metastatic pancreatic polypeptide-secreting islet cell tumor in a dog. Veterinary Clinical Pathology 2010;39:371-376.
3. Moretti S, Tschuor F, Osto M, et al. Evaluation of a novel real-time continuous glucose-monitoring system for use in cats. Journal of Veterinary Internal Medicine 2010;24:120-126.
4. Oberkirchner U, Linder KE, Zadrozny L, et al. Successful treatment of canine necrolytic migratory erythema (superficial necrolytic dermatitis) due to metastatic glucagonoma with octreotide. Veterinary Dermatology 2010;21:510-516.
5. Rivera N, Ramnanan CJ, An Z, et al. Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. The Journal of Clinical Investigation 2010;120:4425-4435.
6. Rossi G, Errico G, Perez P, et al. Paraneoplastic hypoglycemia in a diabetic dog with an insulin growth factor-2-producing mammary carcinoma. Veterinary Clinical Pathology 2010;39:480-484.

Q & A: Adjusting the Dose of Detemir Insulin in Dogs

I have recently switched one of my canine diabetic patients from NPH insulin to detemir. This is the first time I have used this insulin and I am looking for some help.

Rex is a 10-yr-old, male Schnauzer mix. We started him on 3 units of detemir twice daily and he is currently on 3.5 units twice daily.

We admitted Rex for a glucose curve today. His results were as follows:

• 8:00 am- 482 mg/dl (fasted and no insulin since 8 pm dose)
• 8:15 am- 3.5 units of detemir given and dog fed
• 9:15 am - 445 mg/dl
• 10:20 am- 301 mg/dl
• 12:30 pm- 147 mg/dl
• 1:25 pm- 97 mg/dl
• 2:30 pm- 80 mg/dl
• 3:30 pm- 72 mg/dl
• 4:40 pm- 82 mg/dl
• 5:10 pm- 108 mg/dl

I like the low glucose values in the middle of the day but am concerned about the severe morning hyperglycemia.

Any recommendations? Thank you for any help.

My Response:

How much does this dog weigh? The dose of detemir (Levemir insulin) we start at is generally around 0.1 mg/kg twice daily, so 7 U per day seems rather high (unless it's a big Schnauzer)

That all said, this curve doesn't look so bad. Like you, I'm not bothered by the afternoon glucoses. They still are normal and not low. Are the owners feeding the same food morning and night? Did the dog eat normally on the day of the glucose curve when hospitalized? If not, that could explain why the insulin worked so well that day; could it be that at home, the glucoses remain higher?

It seems unlikely that the blood sugar would go from 108 mg/dl at 5:10 PM to levels in the 400s 3 hours later when it's time for the shot again. Are the owners giving the insulin and then waiting before feeding?

If the dog is eating well, I like to give the insulin about 30 minutes before eating to ensure some insulin has been absorbed before feeding. We could consider that in this patient if not already being done.

Finally, is this dog feeling well? How if the thirst, appetite and attitude? We must always remember to look at the dog and talk to the owner. We can never just depend on blood glucose curves to make insulin dose adjustments,

Follow-up Information and Additional Questions:

Rex weighs 39 pounds (17.7 kg). The owners report that he is feeling great at home, has gained a little weight recently (1 pound over last 2 months). He is indeed feeling better, playing, and acting normal.

He didn't eat well while here for the curve so I would assume those middle-of-the-day glucose values would be higher at home. I can question the owners better about the timing of the feeding at home. I didn’t realize that could even be a factor!

Do you have owners feed the animal at home before coming in for the curve? Would the next step be to redo the glucose curve on a day when he has eaten that morning?

Would increasing the dose up to 4 units BID before the next curve be advisable?

My Response:

A common problem with the glucose curves is that dogs (or cats) don't eat well in the hospital, and results of a glucose curve really don’t mean much when they haven't eaten. I know it's nice to have a pretreatment glucose, but that's not as important to what else is going on throughout the day.

Given that the dog is doing well at home (which is much more important than ANY blood glucose curve!), I would not raise the dose just yet.

I would recommend repeat the glucose curve following this protocol: I would have them give the insulin injection, wait 15-30 minutes, fed exactly the food and amount that they normally do at home, and then bring the dog in to start the glucose curve shortly thereafter. If the glucose readings drop into the low-normal range as they did before, it would be helpful if you could go longer than 8 hours with your glucose monitoring.

1. Owner gives the insulin injection
2. Wait 30 minutes before feeding
3. Feed exactly the normal diet in the exact amount normally feed every other day
4. Then bring the dog to your hospital to start the glucose curve shortly thereafter
5. Measure blood glucose concentrations every 2 hours for at least 8 hours, but 12 hours is better if possible.

Finally, another way to get around some of these problems is to have the owners do home glucose monitoring. With a bit of training, most dog and cat owners can be trained how to do the measurements at home. This is particularly helpful in cats, where they almost all develop ‘stress’ hyperglycemia in the hospital.

Q & A: Transitioning Diabetic Cat Off Insulin to Oral Hypoglycemics

I have a 14-year-old female spayed DSH feline weighing 5.4 kg, who was diagnosed with diabetes one year ago. To date, she has been receiving 4 IU of PZI (ProZinc) twice daily, and the owners have been very good about keeping her on a diet of high protein/low carbohydrate canned food only.

The owners would like to try switching from the insulin to an oral hypoglycemic agent (glipizide or glyburide). They travel a lot and have difficulty finding someone to look after her, and even having to board her at the clinic is a problem because she is very fractious and difficult to catch and give injections too. The owners themselves can manage just fine with the insulin injections, but no one else can.

Recently, I did some blood work on her and she is doing great. She is no longer polydipsic or polyuric, her serum glucose was normal at 122 mg/dl, and her serum fructosamine was 275 μmol/l (reference range 150-350 μmol/l).

My questions are the following:

• How do I properly transition her to the glipizide or glyburide if we decide to go that route?
• Does this cat even need to continue with insulin or oral glucose products, or can I control her on diet therapy alone at this point?
• Could this cat be going into diabetes remission?

My Response:

The lack of clinical signs and normal fructosamine certainly indicates good diabetes control, and it is possible that the cat is going into remission. Clinical remission is actually not infreqent in cats with well-controlled diabetes mellitus (1).

However, remission, when it does occur, generally develops earlier than a year (generally within the first 3 months of starting insulin therapy) so it's less likely that a cat treated with insulin for a year would be in remission. In addition, when most cats are going into remission, they're generally not normal on 4 units BID — that would be an overdose in most cats in remission. The more typical scenario in a cat going into remission is that their glucose values are dropping too low even on 1 unit BID.

That all said, diabetic remission is possible at any time and it's still possible that your cat is going into remission.

Ideally, the first step in judging remission would be for you would do a complete glucose curve to see if the blood glucose concentrations remain normal through out the day. The finding of a single "normal" blood sugar really doesn't tell you very much at all.

I understand that hospitalizing this fractious cat for a glucose curve would probably not be a pleasant experience for either you or the cat; more importantly, the "stress" would likely make the results meaningless anyway. Can the owners do home glucose monitoring? If so, that would be extremely helpful. Can they, at the very least, measure urine glucose at home?

In the end, how you decide whether the diabetes is going into remission or not is to slowly taper down the insulin dosage by 0.5 U decrements (e.g., start by decreasing from 4 U, BID to 3.5 U, BID). If the blood and/or urine glucose concentration remain normal after a week, then the insulin taper can continue until the insulin can hopefully be discontinued.

The chance of an oral hypoglycemic agent (glibizide or glyburide) working is very small. I personally think it's easier to give insulin to a fractious cat than to give a pill, especially in the hospital or in a kennel.

Remember, oral hypoglycemic agents act by stimulating insulin secretion from the pancreatic islet cells (2). In a cat with borderline diabetes that is going into remission, changing from insulin therapy to one of these drugs may actually be the worst thing to do.

Use of these oral hypoglycemic drugs, by overstimulating any remaining insulin secretion, my actually lead to the final "burn out" of insulin secretion and result in permanent diabetes (2).

Reference:

1. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2010;24:1314-132
2. Hoenig M, Hall G, Ferguson D, et al. A feline model of experimentally induced islet amyloidosis. American Journal of Pathology 2000; 157:2143-50

Top Endocrine Publications of 2010: Canine and Feline Diabetes Mellitus

I know that many of you are very busy and may have trouble keeping up with the latest research studies and publications on issues concerning companion animal endocrinology. Therefore, I’ve compiled a fairly extensive list of some of the best clinical endocrine papers written last year (in 2010), and I’ll be sharing these with you over the next few weeks.

We are going to start off with papers that deal with the theme of Diabetes mellitus and its diagnosis and treatment in dogs and cats.

Listed below are 29 research papers written in 2010 that deal with a variety of diabetic topics and issues.

These range from the use of continuous glucose monitoring systems (1, 15, 22) to home glucose monitoring (5, 28); from insulin autoantibodies (4, 18) to insulin resistance (11, 25, 26);  from new insulin analogues (8, 10, 24) to diabetic cataracts (12, 21); and from the causes of secondary diabetes (2, 6, 13, 14, 16) to diabetic remission (29).

2010 Papers on Canine and Feline Diabetes Mellitus:

1. Affenzeller N, Benesch T, Thalhammer JG, et al. A pilot study to evaluate a novel subcutaneous continuous glucose monitoring system in healthy Beagle dogs. Veterinary Journal 2010;184:105-110.
2. Blois SL, Dickie EL, Kruth SA, et al. Multiple endocrine diseases in cats: 15 cases (1997-2008). Journal of Feline Medicine and Surgery 2010;12:637-642.
3. Claus MA, Silverstein DC, Shofer FS, et al. Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999-2007). Journal of Veterinary Emergency and Critical Care 2010;20:509-517.
4. Davison LJ, Herrtage ME, Catchpole B. Autoantibodies to recombinant canine proinsulin in canine diabetic patients. Research in Veterinary Science 2010.
5. Dobromylskyj MJ, Sparkes AH. Assessing portable blood glucose meters for clinical use in cats in the United Kingdom. The Veterinary Record 2010;167:438-442.
6. Fall T, Hedhammar A, Wallberg A, et al. Diabetes mellitus in elkhounds is associated with diestrus and pregnancy. Journal of Veterinary Internal Medicine 2010;24:1322-1328.
7. Furrer D, Kaufmann K, Reusch CE, et al. Amylin reduces plasma glucagon concentration in cats. Veterinary Journal 2010;184:236-240.
8. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. The Veterinary Clinics of North America Small Animal Practice 2010;40:297-307.
9. Gilor C, Graves TK, Lascelles BD, et al. The effects of body weight, body condition score, sex, and age on serum fructosamine concentrations in clinically healthy cats. Veterinary Clinical Pathology 2010;39:322-328.
10. Gilor C, Ridge TK, Attermeier KJ, et al. Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. Journal of Veterinary Internal Medicine 2010;24:870-874.
11. Hess RS. Insulin resistance in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:309-316.
12. Kador PF, Webb TR, Bras D, et al. Topical KINOSTAT ameliorates the clinical development and progression of cataracts in dogs with diabetes mellitus. Veterinary Ophthalmology 2010;13:363-368.
13. McLauchlan G, Knottenbelt C, Augusto M, et al. Retrospective evaluation of the effect of trilostane on insulin requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism. The Journal of Small Animal Practice 2010;51:642-648.
14. Meij BP, Auriemma E, Grinwis G, et al. Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. Journal of Feline Medicine and Surgery 2010;12:406-410.
15. Moretti S, Tschuor F, Osto M, et al. Evaluation of a novel real-time continuous glucose-monitoring system for use in cats. Journal of Veterinary Internal Medicine 2010;24:120-126.
16. Niessen SJ. Feline acromegaly: an essential differential diagnosis for the difficult diabetic. Journal of feline medicine and surgery 2010;12:15-23.
17. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2010;24:1098-1105.
18. Nishii N, Takasu M, Kojima M, et al. Presence of anti-insulin natural autoantibodies in healthy cats and its interference with immunoassay for serum insulin concentrations. Domestic Animal Endocrinology 2010;38:138-145.
19. Nishii N, Yamasaki M, Takasu M, et al. Plasma leptin concentration in dogs with diabetes mellitus. The Journal of Veterinary Medical Science 2010;72:809-811.
20. O'Brien MA. Diabetic emergencies in small animals. The Veterinary Clinics of North America Small Animal Practice 2010;40:317-333.
21. Oliver JA, Clark L, Corletto F, et al. A comparison of anesthetic complications between diabetic and nondiabetic dogs undergoing phacoemulsification cataract surgery: a retrospective study. Veterinary Ophthalmology 2010;13:244-250.
22. Reineke EL, Fletcher DJ, King LG, et al. Accuracy of a continuous glucose monitoring system in dogs and cats with diabetic ketoacidosis. Journal of Veterinary Emergency and Critical Care 2010;20:303-312.
23. Rucinsky R, Cook A, Haley S, et al. AAHA diabetes management guidelines. Journal of the American Animal Hospital Association 2010;46:215-224.
24. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs
25. Scott-Moncrieff JC. Insulin resistance in cats. The Veterinary Clinics of North America Small Animal Practice 2010;40:241-257.
26. Verkest KR, Fleeman LM, Rand JS, et al. Basal measures of insulin sensitivity and insulin secretion and simplified glucose tolerance tests in dogs. Domestic Animal Endocrinology 2010;39:194-204.
27. Zeugswetter F, Handl S, Iben C, et al. Efficacy of plasma beta-hydroxybutyrate concentration as a marker for diabetes mellitus in acutely sick cats. Journal of Feline Medicine and Surgery 2010;12:300-305.
28. Zeugswetter FK, Rebuzzi L, Karlovits S. Alternative sampling site for blood glucose testing in cats: giving the ears a rest. Journal of Feline Medicine and Surgery 2010;12:710-713.
29. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2010;24:1314-1321.

Q & A: Pseudo-Addison’s Disease in a Dog with Whipworms

This consult concerns a 7-year-old female spayed Pit-bull. Her last veterinary examination was over 5 years ago. She presented today with the main complain of chronic diarrhea of 3-weeks duration. On exam, the dog was very lethargic, weak, and 7-8% dehydrated.

On her in-house screening blood tests, primary abnormalities included severe hyponatremia (113 mEq/L; reference range, 139-154 mEq/L) and hyperkalemia (6.5 mEq/L; reference range, 3.5-5.5 mEq/L). The sodium:potassium ratio was low at 17.

On her fecal examination, I found a large number of whipworm eggs on a very poorly formed, mainly liquid sample, so I suspect she is loaded with these parasites.

Based on the finding of whipworms, I suspect that she does not have true hypoadrenocorticism (Addison’s disease) but rather pseudo-Addison’s disease. Do you agree? Do I need to do an ACTH stimulation test on this dog?

Do these dogs need IV fluids and other supportive treatment or is just treating them for the whipworms going to resolve the electrolyte disturbances without further treatment? Do we need mineralocorticoid replacement (e.g., Florinef or Percorten)?

My Response:

These are severe electrolyte derangements and definitely should be addressed as an emergency. Therefore, I would definitely hospitalize the dog and very slowly correct the low serum sodium concentrations. If hyponatremia is corrected too rapidly, central nervous system dysfunction and death can result.

During the chronic hyponatremia, the brain adapts to prevent cerebral edema. With rapid correction of serum sodium concentration, osmotic shifts and cerebral dehydration can occur. This may result in CNS changes including central pontine myelinosis. This can lead to severe neurological signs, including generalized weakness, ataxia, mental depression, and head pressing several days following correction of severe hyponatremia (1,2). Thus, we are faced with a conflict between the need to rapidly correct the dog’s hypovolemia while ensuring the serum sodium concentration does not increase too rapidly.

In dogs whose sodium depletion has been chronic or is severe (Na < 120 mEq/L), sodium replacement must be cautiously and slowly corrected, such that serum sodium rises by no more than 0.5 mEq/liter/hour or 15 mEq/liter in a 24 hour period (1,2). Overzealous and too rapid correction of serum sodium to normal levels must be avoided.

If serum sodium is < 120 mEq/L, it may be better to avoid normal saline because of the high sodium content (154 mEq/L), and instead administer either Lactated Ringer's (130 mEq/L sodium) or Normosol-R (140 mEq/L sodium). Although these two fluids also contain a small amount of potassium, intravascular volume correction will offset the potential risk of exacerbating hyperkalemia. Hypertonic saline administration (strengths of 513 or 858 mEq/L sodium) is contraindicated in initial treatment of severe hyponatremia.

As far as the definitive diagnosis, whipworm (Trichuris) infestation is a well-known cause of pseudo-Addison’s disease and those parasites should be treated (3). I would also do either an ACTH stimulation test or at least a resting serum cortisol concentration to rule out true Addison’s disease. If the basal cortisol is normal (>2.0 μg/dl) and/or the cortisol response to ACTH stimulation is normal, then we can be more certain that the serum electrolyte imbalances are due to the whipworms (3,4).

As long as fluid therapy is being administered, mineralocorticoid supplementation should not be necessary. Hopefully, the serum cortisol results will be back within the next day or so and then we can decide if other treatment for Addison’s disease is required.

Follow-up Report:

A basal serum cortisol concentration on this dog was normal at 3.3 μg/dl (reference range, 1-4 μg/dl). She responded very well to the initial fluid therapy and deworming, with normalization of the serum electrolytes and resolution of all of her diarrhea and other clinical signs.

The final diagnosis was indeed pseudo-Addison’s disease secondary to severe Trichuris (whipworm) infestation.

References:

1. Brady CA, Vite CH, Drobatz KJ. Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis. Journal of the American Veterinary Medical Association1999;215:222-225, 210.
2. MacMillan KL. Neurologic complications following treatment of canine hypoadrenocorticism. Canadian Veterinary Journal 2003;44:490-492.
3. Graves TK, Schall WD, Refsal K, et al. Basal and ACTH-stimulated plasma aldosterone concentrations are normal or increased in dogs with trichuriasis-associated pseudohypoadrenocorticism. Journal of Veterinary Internal Medicine 1994;8:287-289.
4. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). Journal of the American Veterinary Medical Association 2007;231:413-416.

Q & A: How to Calculate the Maximal Dose of ACTH (Cortrosyn) for Large-Breed Dogs

I have a 180 pound (82 kg) St. Bernard that was referred to me for supportive care overnight and to have an ACTH stimulation test done to rule out Addison's disease.

In the past, the maximal dose of synthetic cosyntropin (Cortrosyn) I've used in these large-breed dose is 250 μg per dog, or the whole vial of Cortrosyn. But there seems to be differing opinions on whether to give this dose or to use a 5-μg/kg dose calculated based upon the dog's body weight. Since this is such a large dog, should I administer 1 vial (250 μg), or should I give the 5 μg/kg-dose? In this dog, that would amount to giving 1.6 vials of the Cortrosyn!

Thanks so much for helping with my dilemma.

My Response:

The human dose for cosyntropin (Cortrosyn), no matter what the body weight, is a total dose of 0.25 mg (250 μg). So I would never administer more than 1 entire vial to any large dog, even if the calculated dosage turned out to be less than 5 μg/kg. For more information on the best protocol for ACTH stimulation testing in dogs and cats, see my previous blog post on the topic.

Studies (1,2) have reported that there is actually little difference in the serum cortisol responses in dogs when tested with the standard dose of Cortrosyn (5 μg/kg) and compared to a much lower dosage (0.5-1 μg/kg). So even with the low-dose protocol we now recommend 5 μg/kg), we already know that we are administering supra-physiological doses of ACTH to these dogs.

The bottom line about dosing with Cortrosyn for ACTH stimulation testing: 

• The maximal dose of Cortrosyn for any sized dog is a total dose of 250 μg.
• Even if a dog gets a bit less than the calculated 5 μg/kg-dose (no matter what the body weight), this will still produce a maximal serum cortisol response and the ACTH stimulation test results will still be completely valid.

References: 

1. Kerl ME, Peterson ME, Wallace MS, Melián C, Kemppainen RJ. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999,214:1497-501.
2. Martin LG, Behrend EN, Mealey KL, Carpenter DM, Hickey KC. Effect of low doses of cosyntropin on serum cortisol concentrations in clinically normal dogs. Am J Vet Res 2007;68:555-60.

Q & A: Atypical Cushing's Disease in an 11-Month-Old Dog

My patient is a 4-year-F/S Shetland sheepdog who has been treated with melatonin and flax seed oil since she was 11-months-old.  Her main clinical sign was a chronic decrease in appetite, which started at 8-months of age when she had her first heat cycle.

Vaginal smears and cytology at that time was consistent with early estrus. She did not have noticeable bleeding, but she is very "tidy" and licks herself a lot.   No polydipsia or polyuria was noted, and her hair coat has always been completely normal. Results of her physical examination were completely normal.

Two months later, we decided to spay her in case there was any connection between going into heat and the lack of appetite. A CBC and serum chemistry panel done before surgery were both normal. Routine ovariohysterectomy was performed. Examination of the uterus showed that it was more turgid than normal, but it did not show any evidence for pyometra or mucometra.  

After surgery the dog became totally anorexic and vomited multiple time. She was referred to a local internal medicine specialist for workup. Based upon results of abdominal ultrasound, endoscopic exam and intestinal/stomach biopsies, a diagnosis of helicobacter pylori infection and inflammatory bowl disease (IBD) was made.  Treatment with amoxicillin, metronidazole, and a food allergy diet was instituted, which quickly cleared up the intestinal signs and anorexia. 

Because of the finding of bilateral adrenomegaly on abdominal ultrasound, however, an ACTH stimulation test was also performed shortly after surgery. Serum samples for an adrenal panel were submitted to the University of Tennessee Clinical Endocrinology Service Laboratory. 

Atypical Cushing's disease was diagnosed on the basis the finding of a high baseline estradiol concentration (105.1 pg/ml; reference range, 30-69. pg/ml) as well as a high ACTH-stimulated estradiol value (111.1 pg/ml; 28-69 pg/ml). The other sex steroids tested (including 17-hydroyxprogrogesteone) were all within normal limits.  Based on these results, she was started melatonin and flax seed oil for the atypical Cushing's syndrome.  

Now 3 years later, the owner is asking me if her dog really needs the melatonin and flax seed oil.  She has declined the offer of retesting the sex steroid panel on several occasions. The owner says her dog has been normal in every way, except for mild lethargy during the morning after she gives the melatonin.  The owner believes the melatonin is causing sleepiness.

My questions are:

1. Do you think this dog has atypical Cushing's disease? It doesn't appear that she ever had any clinical signs of the disease.
2. If we stop the melatonin, how would we determine the need to go back on the drug?

My Response:

I really must admit that I've heard it all now — diagnosing atypical Cushing's disease in an 11-month old dog with the primary complaints of anorexia, inflammatory bowl disease, and helicobacter!

You cannot base a diagnosis of Cushing's disease — typical or atypical — on the finding of large adrenal glands on an ultrasound exam. This dog was severely ill when the ultrasound and ACTH stimulation test were performed. One would expect a sick dog to have a "stress" response, which would include increased secretion of pituitary ACTH leading to increased cortisol section. With chronic illness and continued stress, bilateral adrenocortical hyperplasia would be an expected finding as cortisol hypersecretion continues.  

Cushing's syndrome (either typical or atypical disease) is a clinical diagnosis and must be based primarily on the dog's clinical features and physical examination findings. Dogs with Cushing's syndrome do NOT have anorexia and vomiting. They have a good to increased appetite, together with polyuria, polydipsia, hair loss, potbelly, and weakness. In my opinion, it was totally inappropriate to even test the dog for atypical Cushing's disease, given the total lack of any clinical features of the disease. Plus, this disease develops in older dogs, not dogs that are less than a year of age.

Bottom line: 

• In any dog with chronic nonadrenal disease, the finding of enlarged adrenal glands with abdominal ultrasonography is not an uncommon finding due to the chronic stress of illness. 
• This finding of "big adrenals" can never be used to confirm a diagnosis of Cushing's syndrome  — be it typical or atypical hyperadrenocorticism. 
• Diagnosis must be based on a combination of the typical clinical features of Cushing's disease together with results of standard pituitary function testing (i.e., low-dose dexamethasone suppression and ACTH stimulation testing).

I agree totally with the owner here. I would stop the melatonin and flax seed oil and monitor the clinical response. Why monitor for hormones when we don't even know what the elevations mean? We see many dogs tested with the sex steroid panel that have high serum estradiol values when the other hormone concentrations are normal.

In fact, I rarely see ANY dog tested that has normal values for estradiol. I can only assume that the labor seen a high incidence of false-positive results.

In support of my clinical experience, a recent research paper published by the head dermatologist at the University of Tennessee, College of Veterinary Medicine showed that serum estradiol concentrations varied considerably in clinically normal dogs (1). They concluded in this study that the finding of high estradiol concentrations alone cannot be used to diagnose atypical Cushing's syndrome, because of the high variability of these hormone results.

References:

Frank LA, Mullins R, Rohrbach BW. Variability of estradiol concentration in normal dogs. Vet Dermatology. 2010; 21:490-493.