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Endocrinology Ellen Behrend, VMD, PhD, DACVIM Auburn University Approach to Hypercalcemia CASE 1 Signalment: 12 year-old, castrated male mixed breed dog History: Polyuria/polydipsia past few weeks; having accidents in the house. Lives in Alabama. Mainly indoors. Up-to-date on vaccines and heartworm preventive. No travel history.
DO THE CLINICAL SIGNS FIT? Clinical signs of hypercalcemia can be severe but are usually insidious and unnoticed by owners. Polyuria/polydipsia is the most common sign in dogs, and muscle weakness/atrophy, depression, anorexia, vomiting, shivering, constipation, bone pain, a stiff gait and cardiac arrhythmias can also be seen.1 In 20 cats with idiopathic hypercalcemia, presenting complaints included vomiting, weight loss, dysuria, anorexia, inappropriate urination, lethargy, diarrhea, hematuria, pollakiuria, and stranguria. Signs of lower urinary tract disease may be seen in up to 1/3 of hypercalcemic dogs or cats as they are prone to forming calcium-containing uroliths.1-5 IS THE PATIENT TRULY HYPERCALCEMIC? Whenever hypercalcemia is noted, it should be confirmed before further diagnostics are undertaken. A search for causes of hypercalcemia can be time-consuming and costly. Always recheck the calcium (Ca) measurement on a non-hemolyzed, hon-lipemic sample. The different forms of Ca need to be considered. It is present in 3 forms: approx. 40% is protein bound, 10% is bound to other factors such as citrate or phosphate and 50% is ionized. Ionized Ca is the active form and what is really important in diagnosis of hypercalcemia. If ionized Ca is normal, even if total Ca is elevated, no further diagnostics are warranted. It was previously recommended to correct an abnormal serum Ca for serum albumin concentration to take the protein binding of Ca into consideration. The correction formula never worked for cats and, based on recent studies, is no longer being recommended for dogs! If calcium is in question, measure an ionized calcium concentration. Ionized calcium can be measured directly by some in-house analyzers, but may best be done by a reference laboratory. The i-STAT analyzer measures ionized calcium, but the values obtained underestimate the actual value. If using the I-STAT, make sure to allow the collection tubes to fill fully (i.e. let the vacuum draw in the correct amount of blood) and use a tube with dry lithium heparin. CASE SUMMARY: Ionized calcium was measured and was normal. Urine culture was submitted and an E. coli grew (>100,000 cfu/ml). Dog placed on appropriate antibiotic for 4 weeks. Culture performed 1 week after starting antibiotics and 1 week after antibiotic therapy stopped. Both negative. Pu/pd resolved. Plan: Reculture urine 4 weeks later. TAKE HOME POINTS:
Signalment: 9 year-old, spayed female Beagle History: Lethargy and anorexia past 10 days. Progressively worse. Moved to Alabama from Illinois 8 weeks ago. Spends a lot of time outdoors. Up-to-date on vaccines and heartworm preventive.
WHAT ARE THE DIFFERENTIAL DIAGNOSES? Multiple rule-outs for hypercalcemia exist. They are:
HOW SHOULD I RANK THE DIFFERENTIALS? Assessing the phosphorus (P) levels can aid in differentiating possible causes. Parathyroid hormone (PTH) is secreted by the parathyroid glands in a manner exquisitely sensitive to changes in serum Ca. PTH increases Ca and P absorption from bone. In the kidneys, PTH rapidly causes phosphaturia but increases Ca reabsorption. Thus, the net effect is to increase Ca in serum but decrease P. With elevated levels of PTH, hypercalcemia occurs with a low normal or low serum phosphorus concentration. Most neoplasias cause hypercalcemia by secreting a hormone called "Parathyroid hormone related-peptide" or PTHrP. PTHrP binds to PTH receptors mimicking primary hyperparathyroidism. Since PTHrP binds PTH receptors, it affects serum calcium and phosphorus concentrations just as PTH does. Vitamin D metabolism is more complicated. In people, vitamin D (cholecalciferol) can be ingested or made by irradiation of cutaneous 7-dehydrocholesterol. In dogs, the cutaneous pathway is not present. What occurs in cats is not clear. Cholecalciferol is converted to 25-hydroxycholecalciferol (25-OH-cholecalciferol) in the liver. The amount of this metabolite is kept relatively constant by negative feedback of 25-OH-cholecaliferol on its own synthesis. 25-OH-cholecalciferol can be converted to the most potent form, 1,25-dihydroxycholecalciferol (calcitriol), in the kidneys. Formation of calcitriol is inversely affected by serum Ca concentration. Ca itself has a slight inhibitory effect on its formation. Second, Ca has a great effect on PTH concentration - when serum Ca is high (i.e. >9-10 mg/dl), PTH is suppressed so there is no calcitriol synthesis. Calcitriol increases formation of a Ca-binding protein in intestinal epithelium. This protein functions to absorb Ca into the blood. Once made, the protein remains for several weeks so there is prolonged vitamin D effect. This can be a problem with vitamin D toxicity- excess absorption of Ca from the gastrointestinal tract continues even after the vitamin D itself is gone. Phosphorus is absorbed by the intestines along with the Ca in response to Vitamin D. Therefore, elevations in Vitamin D lead to both hypercalcemia and hyperphosphatemia. Vitamin D toxicosis can result from over-supplementation or from ingestion of cholecalciferol-containing rodenticides or human anti-psoriasis creams that contain calcipotriene, a synthetic form of Vitamin D3 (e.g. Dovonex).7 In granulomatous disease macrophages can activate Vitamin D and no feedback mechanisms are present. As a result, granulomatous disease leads to Vitamin D toxicosis with hypercalcemia and hyperphosphatemia. Unfortunately, the presence of renal failure can make interpretation of results difficult. Hypercalcemia can lead to renal failure and vice versa. If azotemia is present, however, P is likely to be elevated and can not help in ranking differential diagnoses. In addition, it can be hard to determine if the renal failure or the hypercalcemia came first. Make sure to always assess an ionized calcium. Many times in the presence of azotemia, ionized calcium is normal (and therefore not a worry) when total serum calcium concentration is high. If ionized Ca is high, the diagnosis is likely primary hyperparathyroidism whereas if the ionized Ca normal to low, it is likely primary renal failure. WHAT DIAGNOSTIC TESTS SHOULD I DO? Never underestimate a complete physical examination and historical presence of any clinical signs in helping to order possible differential diagnoses. Always palpate lymph nodes and, in dogs, do a rectal exam. Any enlarged node or pararectal mass should be aspirated for cytology. Look for a squamous cell carcinoma in cats - reported locations include cutaneous, mandibular and in the ear canal.2,8,9 A parathyroid mass is rarely palpated in hyperparathyroid dogs but may be so in cats.1 Hypercalcemia is not common in Addisonians (about 25% are hypercalcemic) but these are typically very ill patients.10,11 With granulomatous disease, signs of the primary disease process are likely. Osteolysis typically causes bone pain and mild hypercalcemia. Other diagnostic tests and imaging techniques may be necessary. In dogs, if the cause of hypercalcemia is not apparent on physical exam, ALWAYS radiograph the chest to look for a mediastinal mass or metastases. Abdominal ultrasound and a bone marrow exam may be required to look for neoplasia. Radiograph any areas of bone pain. Any lytic lesions should be aspirated and submitted for cytology. If cytology is non-diagnostic, biopsy will be necessary. If Addison's disease is suspected, an ACTH stimulation test is required to confirm the diagnosis. 25-OH-cholecalciferol levels can be measured to document Vitamin D toxicosis. Hyperparathyroidism is confirmed by measurement of PTH. A PTH in the upper half of the normal range or above in the face of hypercalcemia is absolutely inappropriate and consistent with a diagnosis of hyperparathyroidism. Some people believe that a PTH anywhere in the normal range in the face of hypercalcemia should be considered evidence of hyperparathyrodism. Cervical ultrasound may help to identify a parathyroid mass, but this technique requires much experience by the ultrasonographer. Technetium-99M-sestamibi radionuclide scans are no longer recommended for identification of a parathyroid mass.12 Serum PTHrP concentration can be measured to look for occult neoplasia. Neoplasia is likely if PTHrP is elevated. If PTHrP concentration is normal, neoplasia is not likely but not impossible. CASE SUMMARY: Thoracic radiographs, abdominal ultrasound and bone marrow cytology were all within normal limits. No abnormalities were detected on cervical ultrasound. A blood sample for measurement of serum PTH and PTHrP concentrations was sent out while the diagnostic tests were being performed. The results were obtained after 5 days. PTHrP was negative. PTH was 9.3 pmol/L (reference range 2-13 pmol/L). This level of PTH was considered to be consistent with a diagnosis of hyperparathyroidism. The dog was taken to surgery and 2 parathyroid glands were removed; histopathological diagnosis on both was parathyroid adenoma. The other 2 parathyroid glands were grossly atrophied at surgery. TAKE HOME POINTS:
Signalment: 4 year-old, spayed female Persian History: Urinating on the rug. Seen by another veterinarian for this problem previously. Two different antibiotics prescribed with no response. Initial work-up: CBC/UA/profile (see profile below). CBC non-remarkable. Culture negative. Abdominal radiographs: cystoliths seen.
Ionized calcium: 1.65 nmol/L (normal: 1.0-1.4 nmol/L) IS HYPERCALCEMIA IN CATS DIFFERENT FROM DOGS? As mentioned above, the clinical signs and rule-outs can vary a bit in cats from dogs. A big difference is that a syndrome of idiopathic hypercalcemia has been described in cats.2,5 (In dogs a cause for true ionized hypercalcemia can almost always be found and an idiopathic form is not recognized.) Reported ages range from 2 to 13.4 years with a mean of approximately 5.8 yrs.2,5 A breed predisposition of domestic long-haired cats has been suggested but not proven.5 Physical examination is relatively non-remarkable with respect to possible causes of hypercalcemia.2,5 A possible link between idiopathic hypercalcemia and ingestion of an acidifying diet has been suggested2,5 however the relationship, if one exists, is likely not that simple.5 The diagnosis of hypercalcemia is made on the basis of ionized calcium as some cats may have a total Ca within normal.2,5 The designation of "idiopathic" is given after all known causes of hypercalcemia have been ruled out, ideally, by extensive testing, and PTH, PTHrP, 25-OH-cholecalciferol and calcitriol are low. Unfortunately, diagnostic testing in some cats has rarely suggested the possible presence of another disease. For example in 20 cats ultimately determined to have idiopathic hypercalcemia, PTHrP was elevated in 1, calcitriol was elevated in 1 and 25-OH-cholecalciferol was elevated in 5. The elevation in 25-OH-cholecalciferol was mild and not in the range typically seen with Vitamin D toxicosis, serum P was normal and there was no known exposure to Vitamin D-containing compounds, so toxicity was unlikely. The elevation in PTHrP and calcitriol was unexplained. In the cat with increased PTHrP, no evidence of neoplasia was detected and the cat survived for more than 3 years making malignancy unlikely. Elevated calcitriol could be due to granulomatous disease, but no evidence of this was found at post-mortem 2 years later.5 A more difficult differential diagnosis to rule-out is primary hyperparathyroidism. In 10 of 25 cats, serum PTH was <1.0 pmol/L (normal 0-4 pmol/L) making primary hyperparathyroidism very unlikely. In the remaining cats, PTH was between 1 and 2.5 pmol/L, a range that could be consistent with hyperparathyroidism. Response to non-specific treatment and cervical exploratory or ultrasound ruled-out the diagnosis of hyperparathyroidism.3,5 WHEN DOES HYPERCALCEMIA NEED TO BE TREATED? Hypercalcemia can be damaging, especially to the kidneys. If the product of multiplying serum Ca concentration by serum P concentration is > 60-80, nephrotoxicity is likely.1 Hypercalcemia is best treated by addressing the underlying disorder. However, if the etiology can not be identified rapidly or is idiopathic, the hypercalcemia should be addressed directly. HOW CAN I TREAT HYPERCALCEMIA? Fluid therapy should be initiated. Dehydration may be present and should be corrected as it can perpetuate hypercalcemia through decreased GFR. Saline (0.9% NaCl) is the fluid of choice. Fluid deficits should be replaced and then fluid rates maintained at 120-180 ml/kg/day to promote calciuresis. Potassium supplementation is usually required to prevent hypokalemia.1 Furosemide may be given to increase calciuresis, but patients should be well hydrated first. Protocols typically recommend 5 mg/kg IV followed by a 5 mg/kg/hr infusion.1 Lower doses (2-4 mg/kg BID to TID, IV, SQ or PO) may produce a milder reduction in hypercalcemia. Thiazide diuretics should be avoided. Glucocorticoids have many beneficial effects including decreased intestinal Ca absorption, reduced bone resorption and increased renal Ca excretion. Prednisone (1-2.2 mg/kg BID, PO, SQ or IV) or dexamethasone (0.1-0.22 mg/kg BID, PO, IV or SQ) can be used. Glucocorticoids should be avoided unless a definitive diagnosis is known. Even one dose can make a patient with lymphosarcoma go into remission. This will make diagnosis impossible until remission ends. If combination chemotherapy is started when remission is lost, it will be less effective. Calcitonin (salmon calcitonin, 4-6 IU/kg SQ, BID to TID) can be used if other treatments fail. Calcitonin is a hormone, secreted from thyroid C cells, with a mild calcium-lowering effect mainly by decreasing absorptive activity and formation of osteoclasts. The response may be short-lived and anorexia, vomiting or allergic reactions may occur. Information in cats is lacking. Bisphosphonates are "osteoclast poisons" that may also be used if bone resorption is a major source of the Ca. Pamidronate disodium has been used to treat Vitamin D toxicosis secondary to calcipotriene ingestion at a dose of 1.3-2 mg/kg.13 This is typically diluted in saline and infused IV over a 2-hr period. In dogs with calcipotriene toxicity, Ca and P normalized in 24-48 hr and only 1 treatment was necessary.13 Etidronate is an oral drug that has limited use in dogs but may be helpful (5-15 mg/kg SID to BID). Sodium bicarbonate (1-4 mEq/kg IV slow bolus) can be given during a hypercalcemic crisis.1 This does not always lower serum Ca but decreases the ionized portion so adverse effects of the hypercalcemia are less common. For primary hyperparathyroidism, the only effective long-term therapy is ablation of the parathyroid gland(s) involved. This is most commonly done surgically, but ablation by ethanol injection14 or application of radiofrequency15 have been reported. These latter 2 techniques are not widely available and require considerable expertise. For treatment of feline idiopathic hypercalcemia, dietary therapy (W/d) was reported to be successful in 5 cats based on measurement of total serum Ca and/or resolution of clinical signs.3 However, dietary management was not effective (W/d or K/d) in others.5 Ionized Ca may not normalize even though total Ca does,5 so measurement of the ionized form is required for accurate assessment of therapeutic success. Prednisone therapy may be successful.5 Glucocorticoids have numerous beneficial effects for the treatment of hypercalcemia (see below). The recommended dose is 5 mg BID but can be increased to 10 mg BID if needed. Again, ionized Ca needs to be monitored.5 IV pamidronate has been used in 1 cat with good effect (unpublished data from Ohio State). Subtotal parathyroidectomy has not been successful.5 CASE SUMMARY: A diagnosis of idiopathic hypercalcemia was made based on ionized calcium concentration, serum PTH concentration (0.2 pmol/L [normal: 0.0-4.0 pmol/L]), serum PTHrP: concentration (<1.0 pmol/L [normal: < 1.0 pmol/L]), normal thoracic radiographs, abdominal ultrasound and bone marrow cytology. Therapy was instituted by changing the diet to W/d. After 4 weeks, total serum calcium concentration was still normal and serum ionized calcium concentration was elevated. Prednisone therapy was initiated at 5 mg once daily. TAKE HOME POINTS:
Cushing's Syndrome: What's new? Note: to convert cortisol reported in nmol/L to mcg/dl, divide the concentration in nmol/L by 27.59. Diagnosis Endocrine testing is commonplace in daily clinical practice. Knowing which test would be most likely to provide clear-cut, diagnostic information is helpful in providing quick diagnoses and client satisfaction. Since endocrine function can be affected by non-endocrine disease, however, choosing the appropriate test and interpreting results can be complex. Furthermore, with changes in the availability of tests and the publishing of new studies, current thought concerning suitable tests to use in any one situation might be modified. The information below reflects new information as well as common questions practitioners ask about diagnosing hyperadrenocorticism (HAC) . Which test to use to diagnose HAC, a low-dose dexamethasone suppression test (LDDST) or ACTH stimulation test, depends on the situation. In general, the LDDST is more sensitive but less specific than the ACTH stimulation test.1 In other words, the LDDST is more likely to be positive in dogs with HAC, but it is also more likely to give a false-positive test result if non-adrenal illness (NAI) is present.1 Therefore, the following general recommendations can be made: 1. If the dog has no known NAI and moderate to severe clinical signs of HAC, do the LDDST. 2. If clinical signs are mild or only laboratory abnormalities are present (e.g. increased ALP), do the ACTH stimulation test. 3. If NAI is present1, if the dog has received any form of exogenous glucocorticoid including topicals,2 or if the dog is receiving phenobarbital,3 do the ACTH stimulation test. Since false positive and false negative results are possible with either the LDDST or ACTH stim, if there is any doubt about the accuracy of the results, perform the other test for confirmation. Results of the ACTH stimulation test will be normal (i.e. be false-negative) in approximately 5-15% of dogs with HAC, while for the LDDST the false-negative rate is approximately 5%.4 On the other hand, false-positive results are also possible, so assessment of test results in dogs with NAI who also have signs consistent with HAC is challenging. In dogs with NAI, a false-positive on the LDDST is approximately 3 times as likely as for the ACTH stimulation test.1 It may be better to always perform both the LDDST and ACTH stimulation test in dogs with moderate to severe NAI. The urinary cortisol:creatinine ratio (UCCR) is best used to rule out the diagnosis of HAC. Most studies have found that almost all dogs with HAC have an elevated UCCR, but the majority of dogs with an elevated UCCR do not have HAC.1,5-7 Accordingly, if the ratio is normal there is little chance the dog has HAC, but if the ratio is high, another screening test such as the LDDST or ACTH stimulation test must be done to confirm the diagnosis. However, one study did find the sensitivity to be only 75%1, giving a chance for a false negative of 25%. Therefore, even if the ratio is normal, if there is still a very high suspicion of HAC, another test should be performed. The cost of Cortrosyn (cosyntropin, synthetic ACTH) has recently increased dramatically so an alternative to use of this compound for ACTH stimulation testing is commonly sought. Unfortunately, there is no good substitute. The best option to reduce the cost of the test is to use a low dose of Cortrosyn (5 mcg/kg IV) with blood samples drawn before and 1-hr post injection.8 Unused, reconstituted Cortrosyn can be stored refrigerated in plastic vials for up to 4 months and frozen for 6 months.9 If freezing Cortrosyn, do so in smaller aliquots as the effect of thawing and refreezing is unknown. Whether lower doses of Cortrosyn can be used for diagnosis of HAC is unknown. Occasionally, an ACTH stimulation test is performed when hypoadrenocorticism is suspected, and the post-ACTH cortisol is above normal, a result consistent with hyperadrenocorticism. A common question then asked is whether the dog has HAC. Most likely, it does not. Non-adrenal illness, especially severe disease that mimics an Addisonian crisis, can cause an elevation in the post-ACTH cortisol giving a false-positive test result for HAC.1 The non-adrenal illness has presumably activated the normal physiological stress mechanisms leading to over-activity of the adrenals. Furthermore, clinical signs suggestive of Addison's disease are not usually also consistent with HAC, so the clinical picture that caused suspicion of the Addison's disease would not fit a diagnosis of HAC. In the opposite situation, an ACTH stimulation test can be performed because HAC is suspected, and the post-ACTH cortisol is below normal. In this scenario, a few possible explanations exist: 1. The dog is receiving exogenous steroids. Glucocorticoid therapy of any type, even topical, can suppress the adrenal response to ACTH.2 2. An inactive form of ACTH was used. 3. An inadequate dose of ACTH was used. 4. The dog has an adrenal tumor. Typically, dogs with a cortisol-secreting adrenal tumor have an ACTH response in or above the normal range, but occasionally the response can be below normal. A progesterone-secreting adrenal tumor can also cause a subnormal response in dogs and cats10,11, but this is an uncommon diagnosis. A syndrome termed "occult" hyperadrenocorticism (HAC) has recently been coined and refers to dogs that have clinical signs highly suggestive of HAC but normal ACTH stimulation test and/or LDDST results. Measurement of 17-hydroxyprogesterone (17OHP) has been advocated for diagnosis of "occult" HAC and is available through some commercial laboratories. The protocol requires ACTH stimulation testing as above with measurement of serum 17OHP concentration pre- and post-ACTH. Results have been reported in a study of 23 dogs with clinical and laboratory findings suggestive of hyperadrenocorticism (HAC). Of the 23 dogs, 11 had an elevated cortisol response to ACTH. Of 10 dogs with normal ACTH stimulation test results, 6 had a positive LDDST. All 23 had an elevated 17OHP response to ACTH12. The conclusion of the study was that serum 17OHP concentration post-ACTH stimulation is elevated in dogs with classic as well as occult HAC and that measurement of serum 17OHP concentration is a marker of adrenal dysfunction. This author believes that interpretation of the results of Ristic et al is not as clear-cut. Of the 23 dogs, 17 had an ACTH stim or LDDST consistent with HAC and thus were not truly cases of "occult" HAC. In addition, 2 of the 23 dogs were treated with trilostane, a cortisol synthesis inhibitor, and they had clinical improvement despite an increase in 17OHP concentrations.12 Consequently, the role of 17OHP in the pathogenesis of "occult" HAC must be questioned. Lastly, the specificity of the test may be as low as 70%, i.e. the chance of a false positive result is 30%.13 In one study of 35 dogs with neoplasia who did not have adrenal disease, 30% had an elevated serum 17OHP concentration post-ACTH stimulation.13 Besides 17OHP, the endocrine lab at Tennessee will also measure cortisol, estradiol, progesterone, testosterone, and androstenedione pre- and post-ACTH. However, the clinical significance of this test has not been determined. Although measurement of serum sex hormones in this fashion was previously recommended for diagnosis of Alopecia X, a recent paper found that Alopecia X has no relation to serum sex hormone concentrations.14 Furthermore, treatment with mitotane of dogs with elevated serum sex hormone concentrations and normalization of sex hormone concentrations may or may not result in clinical improvement. In differentiating between pituitary and adrenal-dependent HAC, a common misconception exists in how to interpret a high-dose dexamethasone suppression test (HDDST). Lack of suppression in response to the high dose does NOT mean a dog has an adrenal tumor. For those animals that do not suppress on a HDDST, approximately 50% have an adrenal tumor and 50% have pituitary-dependent disease.15,16 TREATMENT Trilostane - In Europe, trilostane is now being used to treat HAC. Trilostane inhibits adrenal 3 -hydroxysteroid dehydrogenase, thereby suppressing production of progesterone and its end-products including cortisol and aldosterone. A few studies have now been published regarding the use of trilostane in a total of 119 dogs with PDH.17-19 Since little is known about how trilostane should be used and monitored for greatest efficacy, the 3 studies are hard to compare as treatment goals, doses and monitoring protocols were different. Overall, trilostane appears to be highly effective in suppressing cortisol secretion.17-19 In 3 studies polyuria/polydipsia resolved over the first 6 months (mainly within the first 1-2 months) in 91% while polyphagia resolved in 81%.20 In 62% of dogs with dermatological abnormalities, there was marked improvement that took up to 3 months. In 8 dogs, signs were poorly controlled.17 A second study looked at 11 dogs with PDH. All had dermatological problems and 10 were pu/pd. Coat and skin condition returned to normal in 9 within 6 months; in 1 dog improvement was noted after 1 yr. All 10 had a decrease in water intake within 7 weeks and 9 had complete resolution at a median of 11 wks. Polyphagia decreased in 9 of 10; in 1 dog it took approximately 6 months. Of 4 dogs that had increased panting, improvement was noted in 4 and resolution in 2. By 6 months, 9 of 11 owners were pleased with the results.18 Initial starting daily dose should be 2-10 mg/kg once daily.20 Unfortunately, trilostane is available as 60 and 120 mg capsules (30-mg capsules are coming!) so the drug may need to be compounded for smaller dogs. In most dogs, dosage adjustments, both up and down, will be required. Authors of one study noted that in most dogs there was an initial sensitivity to the drug followed by a need for an increase in dose. After time, the dose required hit a plateau.19 Interestingly, the final dose required for control has varied greatly between studies. Part of the discrepancy may relate to the differences in what was considered the ideal post-ACTH serum cortisol concentration. However, in one study the median final dose was 6.1 mg/kg18, while another study found the therapeutic dose for most dogs is likely to be 16-19 mg/kg.19 In any case, the point remains, that each dog should be started on the recommended dose, and then the dose adjusted according to ACTH stimulation test results. Survival is at least as good as achieved with mitotane therapy.17-19 Reported adverse effects for the most part are relatively mild, including lethargy and vomiting, but fatality has occurred.17-19 Although some studies found relatively low incidence of side effects, mild, self-limiting side effects such as diarrhea, vomiting and lethargy were noted by 63% of owners in one study.20 Trilostane can affect aldosterone secretion as well as cortisol, so an Addisonian crisis can occur.17,19 Excess adrenal suppression can occur at any time during therapy.17,19 One dog died despite appropriate treatment for hypoadrenocorticism, and the true cause of death remained undetermined.17 As with mitotane therapy, excess adrenal gland suppression can occur and warrants discontinuing medication temporarily (see below) and lowering of the dose. Although, in theory, the effects of trilostane as an enzyme inhibitor should be rapidly reversible (e.g. within a couple days), suppression can last weeks to months. In a few cases, trilostane was discontinued when cortisol secretion was noted to be too low, and cortisol secretion remained low for 6 weeks to 4 months but eventually returned to pre-therapy levels.19 In an additional case, signs of glucocorticoid and mineralocorticoid deficiency occurred in a dog being treated with trilostane and bilateral adrenal necrosis was documented. The etiology of the necrosis was undetermined.21 The hypoadrenocorticism lasted for at least 3 months21, but likely will be permanent for the life of the dog. How often acute iatrogenic hypoadrenocorticism will occur in dogs treated with trilostane is unknown. A few questions still need to be answered. First, the optimal post-ACTH serum cortisol concentration should be determined. The different studies done so far had different target ranges. The goal for post-ACTH cortisol concentration in one study was to be below 250 nmol/L (9 g/dl)17 but the goal was 30-70 nmol/L (1-2.5 mcg/dl) in the second study18 and 25-125 nmol/L (1-4.5 g/dl) in the third.19 The ideal timing of post-pill sampling also needs to be elucidated. Post-ACTH cortisol may vary with the interval between dosing and testing.22 Based on their experience, the authors of the third study recommended doing an ACTH stimulation test 3-8 hr after the last dose19 while another author specifically recommends testing at 4-6 hrs post-pill.20 Lastly, the appropriate starting dose and interval (daily or BID) needs clarification. The authors of one study recommended starting with once-daily dosing19 while other authors recommended initiating therapy twice-daily.23 How long control must be maintained throughout the day needs to be elucidated. For example, is control for 12 hours adequate or does it need to last 24 hours? Currently, the recommendations of this author are based mainly on those of Dr. Reto Neiger who has the most experience in using this drug.20 Recommendations are to start administration of trilostane (2-10 mg/kg) once daily. If minor side effects are seen, stop the drug for 3-5 days and then restart giving trilostane every other day for one week before continuing with the initial dosing scheme. An ACTH stimulation test should be performed at 10-14 days, 30 days and 90 days after being on a full dose of trilostane. The test should be performed 4-6 hrs post-pill. If the post-ACTH cortisol concentration is <20 nmol/L, stop the trilostane for 48-72 hrs.20 At this point, Dr. Neiger recommends restarting the trilostane at a lower dose20, but given the long-term suppression seen in some cases, I believe that, ideally, an ACTH stimulation test should be performed and trilostane should not be reinstituted until cortisol secretion has recovered. If the post-ACTH cortisol is >200 nmol/L, increase the dose of trilostane. If the post-ACTH serum cortisol concentration obtained is between 20 and 200 nmol/L but the clinical signs are continuing, then twice-daily therapy should be used. The same dose that was given once-daily should be given twice (e.g. if giving 30 mg once daily then double it to 30 mg twice daily). Once the clinical condition of the dog and the dose have stabilized, an ACTH stimulation test should be performed every 3-6 months and serum potassium concentration should be measured to check for hyperkalemia. Trilostane has been used to treat a few dogs with adrenal tumors.20,24 Not enough information is available to ascertain whether the treatment protocol or efficacy varies if treating dogs with PDH versus those with an adrenal tumor. However, it should be remembered that trilostane is not cytotoxic as mitotane is. In other words, mitotane is truly a chemotherapeutic drug in this instance, killing primary neoplastic cells and, perhaps, metastatic cells as well. Trilostane simply would control tumoral secretion, not growth. In fact, in dogs with PDH treated with trilostane, the size of the adrenal glands increased.25 Whether trilostane would be a better alternative to ketoconazole therapy to control the clinical signs of HAC pre-adrenalectomy remains to be determined. A few disadvantages exist for using trilostane. The largest is availability. At the current time, trilostane is not approved for use in the United States. To obtain trilostane in the U.S 20:
Hypophysectomy - For treatment of PDH, pituitary removal is used in parts of Europe with good success. Hypophysectomy was performed on 150 dogs with PDH.26 Complete remission was obtained in 85%. Thirteen (9%) died within 8 weeks of surgery, but mortality decreased as the surgeon became more experienced. Incomplete tumor removal occurred in 6%.26 For all 150 dogs, estimated survival rate after hypophysectomy was 84% at 1 year, 76% at 2 yrs, 72% at 3 yrs and 68% at 4 yrs. In the group that achieved remission, the proportion of disease-free dogs was 88% at 1 yr, 75% at 2 yrs, 66% at 3 years and 59% at 4 yrs. Survival and disease free fractions were significantly lower for dogs with enlarged pituitaries.26 These survival data compare very favorably to those achieved with lysodren treatment. The main peri-operative and long-term complications were transient mild, post-operative hypernatremia, transient KCS (35%), prolonged (31%) or permanent (22%) diabetes insipidus. Secondary hypothyroidism is an expected complication seen in the vast majority, if not all, dogs. In dogs with KCS, normal tear production resumed after a median of 2 months. HAC recurred in 25% at 2-56 months after surgery (median 18 months).26 Auburn University is now performing hypophysectomies in dogs with PDH. Reference List
Diabetes Mellitus: Update on Treatment and Monitoring INSULIN THERAPY Managing diabetics can be frustrating. In order to minimize the stress to veterinarians and patients, the "best" insulin is sought. Until recently, there were 5 main forms of insulin available on the market: Lente, NPH, PZI, Ultralente and regular. However, no one insulin was the best in dogs or cats. In one study in cats, for example, no significant difference was found in glycemic control among cats treated with PZI, Ultralente or Lente.1 In general, which insulin to start with is a matter of personal preference and experience. In addition, some patients will not respond to one insulin but will respond well to another, e.g. 20% of cats do not respond to high doses of Ultralente insulin but will be effectively managed by twice-daily Lente.2 Therefore, if one insulin does not work, another should be tried. One study has assessed the PZI available from Idexx.3 Sixty-seven privately owned diabetic cats were used, of which 34 were newly diagnosed, 32 were being treated with insulin and 1 was receiving glipizide. The cats were studied for 45 days. Initial dosage of PZI ranged from 0.2-0.6 U/kg BID. At the end of the 45 days, mean dose was 0.9 U/kg (range 0.2-1.8). Mean blood glucose nadir occurred approximately 5-7 hrs after insulin injection, but ranged from 1-9 hrs.3 Overall, 90% of owners believed their cat improved. Clinical hypoglycemia occurred in 5 cats and hypoglycemia without clinical signs occurred in another 21 (31%). Ten cats were not controlled by day 45. Whether longer treatment and more dosage adjustment would have achieved control is unknown. In general, cats with newly diagnosed diabetes had a better response than those cats with previously treated diabetes; perhaps the cats that failed previous treatment had an underlying cause of insulin resistance.3 Most diabetic cats will require PZI BID for adequate control, but once-daily injections may suffice in up to 25%. Initial PZI dosage should be low (e.g. 1 U/injection) to avoid hypoglycemia.3Information has been presented recently regarding the use of a new human synthetic insulin analogue called insulin glargine in healthy and diabetic cats. Insulin glargine is produced by recombinant DNA technology, and is advertised as being "peakless" in people. The chemical structure of insulin glargine has been altered slightly from native human insulin. Glargine is a clear aqueous solution in 100U strength with a very acidic pH (pH=4). When insulin glargine is injected subcutaneously into a more neutral pH, the insulin forms micro-precipitates with a supposedly relatively constant absorption into the systemic circulation. The micro-precipitate formation and slow absorption are dependent on the pH of the glargine, so glargine cannot be mixed with other insulins or diluted.4 In healthy cats insulin glargine was compared to Lente and PZI and produced definite peaks in insulin concentration and glucose-lowering effects.5 In comparison to PZI and Lente, glargine peaked later but there was no difference in the nadir blood glucose concentration.5 Comparing SID to BID administration of glargine in healthy cats, there was no difference in time to onset of action, nadir glucose concentration or time to reach nadir glucose. Not surprisingly, however, time for glucose to return to baseline was significantly longer for BID than SID. In diabetic cats, the use of glargine appears extremely promising. Glargine has a very long duration of action and a predictable blood glucose lowering effect.4 In 6 newly diagnosed cats treated with a high protein-low carbohydrate diet (Purina DM canned), the diabetes resolved in all 6 cats within 4 months.6 It should be noted that 4 of the cats were Burmese cats, and the pathophysiology of diabetes in this breed may differ from that in most cats. For this reason, it may be that resolution of diabetes is more likely in Burmese cats. In any case, glargine appears to be a very good insulin to use in any cat giving control of blood glucose concentrations throughout most of the day. Long-term diabetic cats have been switched to and treated with glargine as well with good success, but the diabetes has not resolved. Cost-wise, insulin glargine is comparable to PZI from Idexx. Recommendations are to start cats on glargine at 0.5 U/kg if the blood glucose concentration is >360 mg/dl and at 0.25 U/kg if the blood glucose concentration is <360 mg/dl. In either case, BID administration is recommended. Since the doses are small, 0.3 ml syringes should be used for accurate dosing For the first 3 days, 12-hr blood glucose curves should be performed (i.e. the curve should be performed for the interval between the a.m. and p.m. dose). The purpose of the blood glucose curve is to detect hypoglycemia, if present, and lower the dose of glargine as needed. The insulin dose should not be increased for the first week no matter what the curves look like!!! After the first 3 days, the cat should be sent home and then return for a curve 7 days later. Subsequent blood glucose curves should be performed 1, 2 and 4 weeks and then as required. If at recheck, the pre-insulin blood glucose concentration is >360 mg/dl and/or the nadir concentration is >180 mg/dl, increase the glargine dose 0.5 U/cat. The dose should not be changed if the pre-insulin blood glucose concentration is 240-360 mg/dl and/or the nadir concentration is 90-180 mg/dl. The dose should be decreased 0.5 U/cat if the pre-insulin blood glucose concentration is <180 mg/dl or decreased by 1.0 U/cat if the nadir concentration is <54 mg/dl. If clinical signs of hypoglycemia are present, the glargine dose should be decreased 50%. Administration of glargine insulin should not be discontinued within 2 weeks of starting treatment regardless of the curve - decrease the dose if needed, but do not stop the insulin (J. Rand, personal communication). If performance of a curve is impossible due to temperament or financial issues, start insulin glargine at 2 U/cat SQ BID and have the owner monitor urine glucose concentration or water intake. A cat well-regulated on glargine should have trace urine glucose at most and urine glucose should be negative most of the time. If after 2 weeks of receiving glargine insulin, urine glucose is > trace, the dose should be increased 1 U/cat/wk until urine glucose is negative or water intake is <20 ml/kg/24h if eating canned food and <70 ml/kg/24h if eating dry food. At this point, keep the cat on the same dose for 2 weeks then start decreasing the dose by 1 U/cat/wk until urine glucose is positive or the insulin has been discontinued (J. Rand, personal communication). Although in 6 diabetic cats treated with glargine hypoglycemia was not documented6, in 1/3 of normal cats treated BID, mean blood glucose remained significantly suppressed at 24 hrs, indicating a carryover effect of glargine.7 Therefore, hypoglycemia is a possibility and should be monitored for as when using any other type of insulin. The pharmacodynamic and pharmacokinetics of glargine, PZI and purified pork Lente insulins have been compared in healthy dogs.8 Each insulin was administered at 0.5 U/kg SQ. Interestingly, in 2/9 dogs the blood glucose concentration did not change after injection of glargine insulin. Lente had the longest duration of action (19.0 1.6 hr) compared to PZI (10.4 .5 hr) and glargine (13.2 1.9 hr). Overall, conclusions were: 1. Subcutaneous Lente insulin produces a predictable insulin concentration peak and results in a shorter onset and duration of action than PZI. 2. PZI administration results in significant glucose-lowering effect and prolonged duration of action in all dogs. 3. Glargine administration results in an unpredictable serum insulin concentration response and, in some dogs, fails to produce a significant glucose-lowering effect.8 To the author's knowledge, no study has been performed assessing glargine in diabetic dogs. Vetsulin (Intervet) is a purified pork Lente insulin recently approved by the FDA for use in dogs. It has been available for many years in other countries under the name Caninsulin. Since the amino acid sequences of pork and canine insulins are identical, porcine insulin may be the ideal form to use in dogs. Vetsulin is the only insulin approved for use in dogs. A study has recently been completed where 53 dogs with uncomplicated diabetes were treated with Vetsulin for 60 days after a variable initial dose determination period. Therapy started SID and was changed to BID as needed. The starting dose was 1 U/kg with a supplemental dose depending on body weight (dogs <10 kg received 1 U supplement, 10-11 kg 2 U, 12-20 kg 3 U and dogs >20 kg 4 U). Efficacy and safety were evaluated at the end of the dose determination period (time 0) and 30 (time 1) and 60 days (time 2) later. With treatment, 80-96% of dogs had resolution of polyuria, polydipsia and ketonuria. Mean blood glucose concentration was 370 mg/dl before treatment but was 151-185 mg/dl while receiving Vetsulin . At time 0, 1 and 2, 100%, 66% and 75% of the dogs were judged to be adequately controlled based on blood glucose concentrations and clinical signs, respectively. At the end of the dose determination period, 57% were receiving Vetsulin BID (43% were receiving SID injections) and by day 60, 66% were receiving BID injections. Overall, the median number of days to achieve adequate glycemic control was 35 (range 5-151 d). No unexpected side effects were observed, but 22 dogs had signs at some time that could have been caused by hypoglycemia and one dog died of presumed hypoglycemia. Hypoglycemia was documented (with or without clinical signs) 24 times. For 7 dogs, owners reported swelling and/or pain at the injection site, but none were noted by investigators on physical examination (W.E. Monroe, unpublished data). The site of insulin injection is another important aspect to consider. An appropriate location for an injection site must be chosen, as absorption of insulin from various sites in the body differs. For example in humans, insulin absorption from the abdomen is more rapid than from the thigh, and injection into an extremity may result in inconsistent insulin absorption depending on exercise and limb movement. In dogs and cats, the dorsal neck or scruff has commonly been used as a site for injection, but this site may not be ideal due to low blood flow and increased fibrosis caused by repeated injections. A better option may be to administer the insulin at sites along the lateral abdomen and thorax. The chosen area should be rotated daily in order to prevent fibrosis at an injection site.9 DIETARY MANAGEMENT Through unknown mechanisms, dietary fiber can delay gastrointestinal glucose absorption, reducing post-prandial fluctuations in blood glucose and enhancing glycemic control. High fiber diets have been traditionally recommended for diabetics but this is now being questioned. The response of diabetic dogs to fiber can vary between individuals10 and a recent study showed that diets with high fiber and moderate starch were not advantageous for dogs with stabilized diabetes compared to a moderate fiber/low starch diet.11 Insoluble fiber, the type present in commercial feline high fiber diets, can improve glycemic control in diabetic cats.12 However, recent theories suggest that high carbohydrate diets may lead to DM in cats and that high protein may be beneficial. A number of cats on a high protein, low-carbohydrate diet had their diabetes resolve or experienced a marked reduction in insulin dose.13-15 Recent work showed a high-protein diet can decrease insulin secretion in normal cats.16 MONITORING Recent emphasis has been placed on finding better monitoring methods. Performance of in-hospital blood glucose curves has long been the gold standard for assessing diabetic control, but they are certainly not perfect. Blood glucose curves can be affected by the stress of hospitalization and deviation from normal routine. One study recently assessed day-to-day variability of serial blood glucose concentration curves in diabetic dogs.17 Glucose curves were performed on 2 consecutive days and all conditions were identical on the 2 days, e.g. type and dose of insulin, amount and type of diet, etc. Parameters such as minimum blood glucose concentration, mean blood glucose concentration, fasting blood glucose concentration before the morning injection or before the evening injection (all dogs were treated BID), time from insulin injection to nadir and maximum blood glucose concentration were significantly different between the 2 curves. In some dogs, the curve showed better control on day 1 while in others it was day 2. To examine the clinical implications of any day-to-day variability of the serial curves, a theoretical recommendation for adjustment of the dog's insulin dose was based on the results of each curve. Thirty sets of paired 12-hour curves lead to opposite theoretical recommendations for adjustment of the dog's insulin dose on day 2 compared to day 1 in 27% of occasions. For 17% of the curves, a different but not opposite recommendation resulted. The same recommendation for dosage adjustment on both days was made in 57% of the paired curves.17 One point made by this study is that the time of the blood glucose nadir can vary greatly from day to day. It is important to always perform serial measurements to ensure that the nadir is not missed. Predicting the timing of a diabetic's nadir on the basis of previous serial blood glucose curves and obtaining a single sample at that time is unlikely to give a reliable result.17 In order to avoid some of the problems associated with in-hospital curves, performance of glucose curves at home has taken on new importance. For home glucose curves, it is not necessary for venous blood to be collected. Capillary blood is suitable18, and the ear is the best site for blood collection. Two types of lancing device are available. If using conventional automatic devices designed for pricking human fingertips, a device with a variable needle depth should be chosen. The appropriate depth for each patient can then be used.19 Warming of the ear with a hair dryer or a warm, wet washcloth enclosed within a plastic bag may be necessary but not well tolerated, and it may take up to 2 minutes to obtain an adequate sample.19 A device which creates a vacuum after lancing the skin does not require warming of the ear and generates an adequate drop of blood within approximately 30 seconds19, but mastery may be a bit difficult and require repeated instruction.18 Glucometers that require minimal amounts of blood as well as those that "sip" the blood into the strip are desirable. Measurement of serum concentrations of the glycated proteins GHb and fructosamine can also be helpful, but are not perfect. Although a trend exists that the less poorly controlled the diabetes, the higher the serum concentration of either glycated protein is likely to be, this is not absolute. Poorly controlled diabetics can have normal concentrations of either protein and well-controlled diabetics can have very high concentrations of either.20,21 In one study, only 16% of serum GHb concentration and 20% of serum fructosamine concentrations were within reference range in well-controlled dogs.22 Current recommendations, in general, are to aim for a value slightly above normal as the belief is that diabetic animals with normal glycated protein concentrations are more prone to hypoglycemia. In addition, measurement of glycated proteins alone is probably not adequate for assessment of overall control. Alternatively, the best use for these may be as one more piece of information where conflicting data exist or, if measured at each recheck, to evaluate trends in glycemic control. Recently, home monitoring of clinical signs alone has been advocated as an accurate method of diabetic assessment.22 In one study of 53 dogs, control was judged to be good or bad based on clinical signs, physical examination findings and body weight. Then, the clinical determination of good or poor control was compared with fasting blood glucose, serial blood glucose curve and serum fructosamine and GHb concentrations. Although all parameters of glucose control were significantly lower in dogs with good control, considerable overlap existed between the 2 groups for all. All blood glucose measurements, fructosamine and GHb were consistent with good glycemic control in 60% of dogs judged to have good clinical control or with poor control in only 39% of judged to have poor clinical control dogs. The initial fasting blood glucose was 100-300 mg/dl in 80% of dogs with good clinical control and in 21% of dogs with poor clinical control. The study's authors concluded that history, physical examination and body weight are sufficient for initial assessment of glycemic control and a glucose curve may not be necessary in a dog with apparent good clinical control when the initial morning blood glucose is 100-300 mg/dl.22 Certainly, the importance of home monitoring of clinical signs cannot be over-emphasized. However, this author has some concerns with study methodology and conclusions and believes that glucose curves should be performed periodically in all diabetic patients (for aggressive animals or those who experience stress hyperglycemia in the hospital, the curves are most appropriately performed at home). Reference List
Hypothyroidism - Can It Really Be Diagnosed? CASE 1 Signalment: 8 yr old, CM, English Bulldog History: Presented for annual check-up. Owner noted no problems other than low activity and obesity despite limited feedings. Physical examination: Obese
WHICH TEST SHOULD BE RUN NOW TO TRY TO DIAGNOSE HYPOTHYROIDISM? The approach to a dog with no known non-thyroidal illness (e.g. renal disease, neurological disease, neoplasia, etc.) vs. a dog with non-thyroidal illness is a bit different. In dogs with no known non-thyroidal illness the diagnosis is more straightforward. Total T4 can best be used to rule out the presence of hypothyroidism. If total T4 is normal, it is highly unlikely that the dog is hypothyroid.1-4 Since non-thyroidal factors such as drugs and illness affect T4, if the T4 is below normal, the dog may or may not be hypothyroid.1-3 Further testing is required. For this particular dog, it would be reasonable, and economical for the client, to just start with measurement of serum T4 concentration to try to rule out a diagnosis of hypothyroidism. The clinical signs suggestive of hypothyroidism consist only of the obesity. The decreased activity could be due to age and/or the obesity. CASE SUMMARY: Serum T4 concentration = 28 nmol/L (reference range 20-50 nmol/L). Based on minimal clinical signs and normal serum T4 concentration, diagnosis of hypothyroidism ruled out. CASE 2 Signalment: 8 yr old, CM, English bulldog History: Presented for decreased activity, obesity despite being on a weight-loss program, thinning haircoat, heat-seeking behavior. Physical examination: Obese; partial, bilaterally symmetrical alopecia
WHICH TEST SHOULD BE RUN NOW TO TRY TO DIAGNOSE HYPOTHYROIDISM? The clinical findings suggestive of hypothyroidism are much stronger in this dog than in Case 1. Starting with measurement of serum T4 is a good first choice, but be prepared to do further testing if the serum T4 concentration is below normal. Free T4 (fT4) is the portion of total T4 not bound to protein and represents about 0.1% of total T4. Since the pituitary-thyroid axis functions to maintain free, not total, T4 within a certain range, fT4 is affected less by non-thyroidal factors and measurement of fT4 is a better test of thyroid function. Accordingly, fT4 is a more sensitive and more specific test for diagnosis of hypothyroidism1, but it is also not as good a stand-alone test as once believed (see below). It can be the initial test for the diagnosis of hypothyroidism or can be used in dogs that have been found to have low total T4 concentrations. Free T4 should always be measured by the equilibrium dialysis method. The other technique for measuring fT4, analogue RIA, is not reliable and provides no additional diagnostic value over measurement of total T4.5 Equilibrium dialysis is also the only RIA for measuring fT4 that is unaffected by the presence of autoantibodies.6 Primary thyroidal failure is believed to be the cause of canine hypothyroidism in 99% of cases.7 Accordingly, negative feedback of thyroid hormones on the pituitary would be lost and TSH should increase. However, an elevated serum TSH occurs in only 63-85% of hypothyroid dogs,1,4,8-10 and if measurement of canine TSH is used alone for diagnosis of hypothyroidism, up to 37% of cases would be missed. Serum TSH can also be elevated in approximately10% of euthyroid dogs with non-thyroidal illness.1,9,11,12 Therefore, measurement of TSH is best used not as a sole test but in conjunction with T4 or, ideally, fT4. Use of the combination will aid in identifying false-positive and false-negative results seen with assessment of TSH alone. Measurement of baseline serum T3 is of little value in differentiating hypothyroid from normal dogs. There is no apparent difference in serum T3 concentrations between these groups.1,2,5 CASE SUMMARY: Serum T4 concentration was 13 nmol/L (borderline range: 12-19; reference range 20-50 nmol/L). Measurement of serum fT4 concentration (by equilibrium dialysis) and serum TSH concentration were requested. The serum fT4 concentration was 8 pmol/L (reference range 15-45 pmol/L, 10-14 pmol/L borderline) and serum TSH concentration was 0.25 ng/ml (normal <0.5 ng/ml). The interpretation of the case now becomes a clinical dilemma. The question is whether this is a hypothyroid dog with a normal TSH or whether this is a euthyroid sick dog whose TSH has remained normal while the fT4 is falsely lowered. The danger of falsely diagnosing a dog with hypothyroidism are threefold: 1. If clinical signs are incorrectly attributed to hypothyroidism, then the true diagnosis will be delayed or never sought. 2. Thyroxine is a catabolic hormone. Administering a catabolic hormone to an ill patient may be detrimental. 3. The patient will needlessly be treated with thyroid hormone for the rest of its life. On the other hand, the danger of not treating hypothyroidism is that the clinical signs will progress. However, in a case such as this one, the clinical signs are relatively mild and benign and progression is typically insidious, i.e. not treating for a month will most likely not be detrimental in the long-term. At this point there are 2 choices: 1. Retest in 4-8 weeks. 2. Start trial therapy for hypothyroidism. If doing this, make sure that you have OBJECTIVE measures of the endpoint determined beforehand, i.e. normalization of serum cholesterol concentration and return to normal weight. Regrowth of hair is not a good endpoint to choose; the haircoat of euthyroid dogs will improve in response to thyroid supplementation. Be prepared to stop giving the thyroxine if the clinical signs do not improve given adequate post-pill levels and time. (You must measure post-pill levels to determine if the trial is successful or not.) CASE 3 Signalment: 8 yr old, CM, English bulldog History: Presented for lethargy, weight gain and obesity despite a poor appetite, bilaterally symmetrical alopecia (non-pruritic) that has been progressive over the past year, heat-seeking behavior. Physical examination: Obese; partial, bilaterally symmetrical alopecia
WHICH TEST SHOULD BE RUN NOW TO TRY TO DIAGNOSE HYPOTHYROIDISM? In a case that seems to be textbook for hypothyroidism, starting with measurement of serum T4 concentration is reasonable. If no other abnormalities are found other than those that can be explained by hypothyroidism and the serum T4 concentration is very low, a presumptive diagnosis of hypothyroidism can be made. It would be ideal to measure a fT4 concentration by dialysis for confirmation, but it may be unnecessary. Measurement of serum TSH concentration is not worth the money in this situation. Given that the sensitivity of measuring serum fT4 concentration is much higher than that of serum TSH concentration measurement, in a case such as this if serum fT4 concentration were low but serum TSH concentration was normal, I would believe the serum fT4 concentration and start treatment for hypothyroidism. CASE SUMMARY: Serum T4 concentration was measured and was non-detectable. Due to financial considerations, fT4 concentration was not measured. Therapy with L-thyroxine was instituted. Post-pill testing was done to ensure adequate serum T4 concentration was achieved. Within 3-4 months clinical signs had resolved. CASE 4 Signalment: 8 yr old, CM, English bulldog History: Originally presented to his veterinarian for a geriatric screen and then was referred to the Auburn University Small Animal Clinic for evaluation of an incidental finding of proteinuria. On a urinalysis, a 2+ proteinuria was noted with a specific gravity of 1.014. A urine protein/creatinine ratio (UP/C) was determined to quantify the protein loss and was found to be 5.8 (normal <0.5). The dog has received regular veterinary care at a private veterinary clinic. He lives in Alabama with no history of travel out of state. His vaccinations are up-to-date, and he is receiving Interceptor for heartworm prevention. He spends her days outdoors, but is a house dog at night. The owners report no problems, and have seen no evidence of coughing, sneezing, vomiting, diarrhea, polydipsia, polyuria or weight loss. The dog's activity has decreased slowly over the past year and was attributed to her aging. His appetite is normal. Physical examination: On physical examination, the dog was noted to be obese and he had moderate to severe dental tartar and gingivitis. Chest auscultation and abdominal palpation were within normal limits.
Blood pressure was measured and was normal. Due to the magnitude of the UP/C, a possible diagnosis of immune-complex glomerulonephritis (ICGN) was made. ICGN can be idiopathic or secondary to chronic immune stimulation. As the dental disease could be a source of antigens, a dental procedure was recommended and was performed. One month post-dental, the UP/C was essentially unchanged at 7.2 and blood pressure remained normal. Further diagnostics were initiated to find possible underlying disease processes that could initiate immune stimulation. Three-view chest radiographs were obtained to rule out neoplasia (primary or metastatic) as well as other pulmonic diseases, and they were within normal limits. Abdominal ultrasound was normal. An occult heartworm test was negative. Serology for Ehrlichia canis, Bartonella and Lyme's disease was negative. PCR for Bartonella spp. and Ehrlichia spp. was negative. Urine culture yielded no growth. At re-evaluation approximately 4 weeks later, after the results of all the tests had been obtained, the UP/C was 8.6, systolic blood pressure was moderately elevated at 190 mm Hg and the cholesterol was moderately elevated (412 mg/dl). In order to determine the pathology underlying the proteinuria (e.g. glomerulonephritis vs. amyloidosis vs. structural glomerulopathy) and whether the disease process was reversible, an ultrasound-guided renal biopsy was performed. The histopathological | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||