October 2007 Internal Medicine Louise Murray, DVM, DACVIM ASPCA, New York, NY Update on Feline Hyperthyroidism TOPICS Diagnostic challenges Hyperthyroidism and renal function Alternative therapies Recent literature DIAGNOSTIC CHALLENGES If you suspect hyperthyroidism but are having trouble proving it, always consider: Maybe the cat is not actually hyperthyroid? Maybe hyperthyroidism is not the cat's biggest problem? Causes of "occult" hyperthyroidism include: Early/mild hyperthyroidism: serum T4 value may still be within the normal range. If truly hyperthyroid the disease will progress and the value will move out of the normal range. Variation in individual normals: A value at the high end of the normal range may be higher than that cat's own previous normal value. If the cat has such early/mild disease, it's unlikely to be causing significant clinical signs. If there are significant clinical signs, such as marked weight loss, look for another cause. Fluctuation of hormone concentrations Concurrent nonthyroidal illness Fluctuation of hormone concentrations Thyroid hormone levels have normal fluctuation This can be clinically significant with mild hyperthyroidism Serum T4 level likely to increase with progression of disease Concentration varies over days: recheck 1-2 weeks later Concurrent nonthyroidal illness Peterson and Gamble, 1990: significantly lower serum T4 in cats with various nonthyroidal diseases Mooney et al, 1996: significantly lower serum T4 in sick cats than healthy controls Peterson, Melian, and Nichols, 2001: median serum T4 in normal cats significantly higher than in cats with nonthyroidal disease Nonthyroidal disease may suppress the serum T4 level of hyperthyroid cats into the normal range. If this occurs, a high normal (2.5 - 4.0) serum T4 would be expected in most cases. Without concurrent hyperthyroidism, the serum T4 in sick cats would be expected to be low/undetectable. Suspect concurrent hyperthyroidism in middle-aged/old cat with significant nonthyroidal illness and mid-normal to high-normal T4. Retest the cat's thyroid function after resolution of the nonthyroidal disease Hyperthyroid cats with grave/terminal nonthyroidal disease may have low T4 Priority is to identify and treat nonthyroidal disease Many cats suspected to have "occult" hyperthyroidism because they are losing weight actually have GI disease (e.g., inflammatory bowel disease, lymphoma). Cats with serious GI disease may JUST lose weight (without any vomiting or diarrhea). When in doubt, remember to check for a thyroid nodule A good rule of thumb: If you're working too hard to "prove" a cat is hyperthyroid, something else is probably wrong with the cat Cat may be hyperthyroid…but what else is going in? What is making the T4 normal? The "something else" is usually more important! Testing for suspected "occult hyperthyroidism: T3 suppression test TRH stimulation test Free T4 (FT4) Provocative testing: T3 suppression test, TRH stimulation test Useful for diagnosis of mild hyperthyroidism with equivocal serum T4 concentrations Tests probably equally useful; each has advantages and disadvantages Can be cumbersome to interpret, grey zones Rarely used Free T4 Free T4 = T4 not bound to carrier proteins: free in plasma Healthy euthyroid dog/cat: about 0.1% of T4 is free Free hormone fraction is available to peripheral tissues, and converted there to the more active T3 Better assessment of thyroid status at tissue level Theory: FT4 measurement accounts for changes in serum binding with illness, highly protein-bound drugs Peterson et al, 1995: Cats with nonthyroidal disease generally maintain normal FT4 concentrations High FT4 level seen in some euthyroid cats with nonthyroidal illness FT4 by dialysis of use in diagnosis of hyperthyroidism when TT4 normal/slightly high Mooney et al, 1996: TT4 lower in sick cats than healthy cats TT4 level inversely correlated with mortality No difference in serum FT4 level in sick vs. healthy cats Some sick euthyroid cats had high serum FT4 FT4 fraction greater in sick vs. healthy cats Mortality in humans/cats correlated with FT4 fraction Humans/Cats: As TT4 decreases and FT4 fraction increases, prognosis worsens Predictive value Very high FT4: poor prognosis? Peterson et al, 1998: 501 hyperthyroid cats: 8.4% high normal TT4, 1.4% had normal FT4 Useful for diagnosis mild hyperthyroidism Of 153 cats with nonthyroidal disease, 5.9% had high FT4 (and low/low normal TT4) FT4 must ALWAYS be evaluated with TT4: sick euthyroid cat with high FT4 should have low/low normal TT4 Peterson, Melian, and Nichols, 2001: 917 hyperthyroid cats: 91.3% had high serum T4, 8.7% had serum T4 in reference range 917 hyperthyroid cats: 98.5% had high FT4, 1.5% had FT4 in reference range 221 cats with nonthyroidal illness: 37.6% had serum T4 below reference range 221 cats with nonthyroidal disease, 6.3% had high FT4: false positive results Occurred with GI disease, diabetes, hepatic disease, neoplasia, chronic renal disease Specificity of FT4 for hyperthyroidism significantly lower than TT4 (Free T4 has good sensitivity/poor specificity) FT4 alone cannot be used to diagnose hyperthyroidism! False positives occur Other criteria must be present, esp. palpable thyroid nodule FT4: Proceed with caution: Nondialysis methods of measurement may be inaccurate; of questionable validity for veterinary use Only FT4 by dialysis recommended currently Sick cats may have "false high" FT4; interpret with TT4, nodule If used correctly, useful for diagnosis of early mild hyperthyroidism, hyperthyroidism masked by illness Misuse of free T4: Should NOT be used as screening test Always interpret with total T4, physical (nodule), full workup for nonthyroidal disease Suspect nonthyroidal disease if high free T4, low/low normal total T4 Suspect GI disease…? Don't perform radioactive iodine based solely on high free T4 HYPERTHYROIDISM AND RENAL FUNCTION Relationship between thyroid and renal function: Humans with hyperthyroidism from Graves' disease have increased renal blood flow and glomerular filtration rate (GFR), which reverse with treatment Graves et al, 1994: No significant difference in GFR, serum creatinine, or BUN in untreated hyperthyroid vs. control cats Significant difference in urine specific gravity (lower in hyperthyroid cats) Hyperthyroid cats post thyroidectomy had significant decrease in GFR, significant increase in serum creatinine, BUN Statistics identical in cats made euthyroid vs. hypothyroid, excluding hypothyroidism as cause DiBartola et al, 1996: Evaluated hyperthyroid cats treated with thyroidectomy, radioactive iodine, methimazole Significant increase in serum creatinine and BUN 30 and 90 days post treatment (changes did not resolve with time) Becker et al, 1998: Evaluated effect of methimazole treatment of feline hyperthyroidism on GFR GFR of pretreatment hyperthyroid cats higher than control cats (not statistically significant) Post treatment GFR significantly decreased Theories: Hyperthyroidism masking renal disease vs. resolution of thyrotoxicosis causing renal dysfunction Loss of muscle mass and altered metabolism with hyperthyroidism may reduce serum creatinine and mask renal disease Increased GFR and renal blood flow with hyperthyroidism may mask renal disease Hyperthyroidism may contribute to development of renal disease, e.g., hypertension Recommendations: Meticulous pretreatment evaluation of hyperthyroid cats: CBC, chemistry panel, UA (specific gravity) Initial medical treatment: allows monitoring of effect on renal function before more definitive therapy (radioactive iodine, surgery) Prolonged survival post I 131 if treated with methimazole first Rigorous follow up after initiation of therapy: chemistry one week post treatment if possible renal dysfunction, two weeks post treatment in others Partial control of hyperthyroidism may be indicated in some cases (creatinine vs. T4) Monitor renal function closely after radioactive iodine/surgical thyroidectomy Monitoring during treatment of hyperthyroidism: Any method of treatment may cause decline in renal function Tapazole may cause anemia, leukopenia, thrombocytopenia, liver toxicosis, etc. Hyperthyroid monitoring profile: Antech test code 1135 (includes T4, CBC/diff/platelets, liver enzymes, kidney values) Don't forget about blood pressure! 87% of hyperthyroid cats hypertensive 61% of cats with chronic renal failure hypertensive Blood pressure monitoring pre-treatment, and at each recheck. Monitor q 3 months once normalized Hypertension in Hyperthyroid Cats Syme and Elliot, 2003: During 6 initial months of treatment, hypertension developed in 22.5% of cats with well controlled hyperthyroidism who were initially normotensive -> Essential to periodically monitor blood pressure in cats being treated for hyperthyroidism Feline hypertension: Measure blood pressure before PE, blood draw, etc. With owner if possible Initial therapy: Amlodipine 0.625 mg/cat PO SID (1/4 of 2.5 mg tablet) Increase dose PRN (to 1.25 SID, etc.) Less expensive generic now exists ALTERNATIVE THERAPIES OF FELINE HYPERTHYROIDISM Cholecystographic agents Iopanoic acid (Telepaque) Radiopaque organic iodine agents Used for cholecystography, cholangiography Absorbed from GI tract, excreted into bile, stored and concentrated in gall bladder Mechanism of action: Inhibition of conversion of T4 to T3 Iodine release during peripheral metabolism blocks thyroid hormone release +/- Direct inhibitory effect on thyroid hormone secretion May curtail adverse effects of thyroid hormone on some tissues Effects in cats (ipodate study): Serum T3 falls (active hormone), may not normalize in more severely hyperthyroid cats Serum T4 remains high Improvement in clinical signs in responders About 2/3 of cats may respond Duration of effect variable, long-term unknown When to use iopanoic acid: In desperation! Adverse reaction to tapazole, and surgery/radioactive iodine not possible Cats with mild/moderate hyperthyroidism Short-term use pre-surgical, pre-I 131, e.g. while owner saves money for procedure Contraindicated with liver/biliary disease Protocol: Dose: 100 mg/cat/day initial (reformulate) No longer generic: expensive Monitoring: pre-treatment T3 (plus usual workup), weight, heart rate, blood pressure 2-week recheck: T3, chemistry, weight, heart rate, blood pressure Goal: normal T3, weight gain, normal HR/BP Poor response: double dose Must discontinue 10-14 days prior to radioactive iodine therapy!!!! DESPERATION PROTOCOL: Cat cannot tolerate tapazole Surgery, radioactive iodine not options Partial/incomplete response to iopanoic acid Add atenolol, 6.25 mg/cat/day (control heart rate, blood pressure, some clinical signs) "RECENT" LITERATURE ON FELINE HYPERTHYROIDISM Effect on serum fructosamine Risk factors for development of hyperthyroidism Survival post I 131 Methimazole dosing PBDEs Fructosamine Reusch and Tomsa, 1999: Effect of hyperthyroidism on serum fructosamine: Fructosamine formed by irreversible nonenzymatic reaction between glucose and amino groups of plasma proteins Fructosamine influenced by concentration and turnover of serum proteins Hyperthyroid humans have increased protein turnover Serum fructosamine of hyperthyroid cats significantly less than healthy cats Serum fructosamine of hypoproteinemic cats significantly less than healthy cats 50% of hyperthyroid cats had serum fructosamine less than the reference range Due to accelerated protein turnover? After correction of hyperthyroidism, serum fructosamine returned to normal Serum fructosamine should not be evaluated in hyperthyroid cats Serum fructosamine cannot be used to differentiate between stress hyperglycemia and diabetes mellitus in hyperthyroid cats Serum fructosamine cannot be used to monitor glycemic control with hyperthyroidism Risk Factors for Hyperthyroidism Martin et al, 2000: Identify dietary and environmental risk factors for hyperthyroidism in cats: Not associated: housing; fertilizer, herbicide, or plant pesticide exposure; flea products; smoke Increased risk with preference of fish (esp. salmon) or liver and giblets canned food Survival Post I 131 Slater et al, 2001: Examine survival of cohort of older, hyperthyroid cats, describe age and common health problems at death, assess association of factors with survival: 231 cats treated with I 131 Mean age at diagnosis 13 +/- 2.5 years, (range 4-21 years) Mean age at death 15 +/- 2.7 years, (10-21 years) Clinical abnormalities just before death: renal (41%), cancer (16%) Median survival 25 months (3 days-8 years) Predictors of survival: age at diagnosis and sex Increasing age at diagnosis increased likelihood of death Males had poorer survival across time Male cat diagnosed at 12 years had 59% chance of 2-year survival; female 70% chance Milner et al, 2006: Survival times of 167 cats treated in 3 different ways: 28% treated with methimazole alone 39% treated with methimazole followed by I 131 33% treated with I 131 Cats with pre-existing renal disease had significantly shorter survival times Excluding these, survival was: Methimazole alone 2.0 years I 131 alone 4.0 years Methimazole and then I 131 5.3 years Methimazole Dosing Trepanier et al, 2003: once vs. twice daily methimazole: Newly diagnosed hyperthyroid cats 5 mg SID vs. 2.5 mg BID Serum T4 higher in cats treated SID % Euthyroid cats higher with BID (87%) vs. SID (54%) BID dosing superior PBDEs and Feline Hyperthyroidism PBDE = polybrominated diphenyl ether Flame retardants used in: Mattresses Furniture Carpet padding Electronics PBDEs introduced co-incident w/ rise in feline hyperthyroidism (1979, 1980s): First reports of environmental contamination w/ PBDEs = 1979 1980s: found in fish, waterfowl, mammals Cats sentinels for human exposure? Dye et al 2007: Evaluated PBDE levels in euthyroid and hyperthyroid cats 23 client-owned cats studied (small sample size) 3 groups: young, old hyperthyroid, old euthyroid High variability within each group No significant difference between groups "Outliers" in all groups Humans in North America have world's highest PBDE levels Cats in study had levels 20-100 times higher than North American humans Sources: cat food and house dust Grooming -> ingestion Dye et al also analyzed cat food (dry, canned): PBDE content of canned fish/seafood flavors higher than non-seafood canned flavors PBDE also in dry food (at lower level): related to processing? Cats likely ingest 7x more dust than adult humans Toddler dust ingestion similar to cats No causality proven, but high levels of PBDEs in pet cats concerning (for cats & toddlers!) Prevention and Management of Feline Diabetes Mellitus Feline Nutrition Cats are obligate carnivores Dogs, humans omnivores Many feline differences in nutritional biochemistry Natural diet of cat = high protein/low carb (prey) Feline differences: Lacking metabolic pathways for utilization of carbohydrates Reduced hexokinase activity, little glycogen synthetase activity Less able to convert carbs to hepatic glycogen, so glucose instead stored as fat Lack salivary amylase Decreased pancreatic and intestinal amylase Fewer disaccharidases & other brush border enzymes in SI for digesting/absorbing starches Lack fructokinase -> cannot digest simple sugars Results of dietary carbohydrates in cats: Glucose stored as fat -> obesity Glucose intolerance -> hyperglycemia-> hyperinsulinemia-> pancreatic beta cell down regulation and exhaustion -> eventual permanent beta cell loss Chronically high insulin demand -> beta cell exhaustion -> diabetes Vicious circle of carbohydrates in cats: Beta cell exhaustion -> hyperglycemia-> glucose toxicity ->suppression of insulin secretion by beta cells, downregulation of glucose transport systems, defect in posttransport insulin action (insulin resistance Administration of insulin reverses this The case for avoiding dry food: Dry food high in carbs -> obesity due to glucose stored as fat, diabetes IBD? Carbs may be less digested in cats ->increased microbial fermentation -> possible changes in flora Feline SI much shorter than omnivore; less able to handle complex carbs Water! Cat evolved to obtain fluid from prey -> water intake based on food intake Cats eating dry food ingest 50% less water -> Urinary issues, renal issues Feeding cats: Meals vs. Grazing: Farrow, Rand and Sunvold: Once daily feeding vs. ad lib Measurement of plasma insulin levels Ad lib feeding -> 40% higher mean plasma insulin concentration Greater demand on beta cells with ad lib Treatment of Feline Diabetes Diet: Low carb, high protein Dry foods higher in carbs Likely, ANY canned better than ANY dry food Purina DM, Hills m/d, Royal Canin diabetic Any canned/pouch kitten Any canned/pouch Farrow, Rand and Sunvold 2002: High protein/low carb diets reduced postprandial hyperglycemia and insulin concentration in normal cats Mazzaferro, Greco, and Turner 2003, Marshall and Rand 2004, Frank, Anderson, and Pazak et al 2002: All found that high protein, low carb diets in diabetic cats -> reduced insulin requirements, better clinical control, increased remission rates Prevention of Feline Diabetes Lederer et al, risk factors for feline diabetes: Indoor cat Chronic medical problems Dental disease Corticosteroid use Glargine (Lantus®) insulin: Long acting synthetic human insulin analogue Recombinant DNA technology Modification of human insulin molecule to produce stable compound that's soluble at ph 4, with decreased solubility at neutral pH Once in SQ tissue (pH 7) forms gradual release microprecipitates In humans: "peakless" In cats: longer duration of action than PZI or Lente Available at pharmacies (vs. PZI) U-100 syringes (PZI U-40) Insulin duration of action: Intermediate acting insulins (lente, isophane) have much shorter duration of action in cats than humans May be due to rapid lowering of blood glucose -> counterregulatory responses (secretion of glucagon, epi, cortisol, growth hormone) -> increased BG Marshall and Rand, 2003: Glargine duration of action in cats 23 hrs, 77% of cats still had decreased BG at 24 hrs Marshall and Rand, 2005: Comparison of lente, PZI, and glargine in diabetic cats: All fed high protein/low carb diets 100% of diabetic cats treated with glargine went into remission within 4 months Clinical hypoglycemia did not occur in glargine treated cats Glargine insulin in cats: Glargine given BID provides longer glucose lowering effect (vs. SID) Weaver et al 2006: Glargine SID -> only 1/6 cats went into remission -> Glargine should be given BID if at all possible, only SID if owner cannot do BID Treatment of Feline Diabetes: Non-dry food High protein/low carb BID glargine insulin For newly diagnosed diabetics, this regime will result in high remission rates Use of glargine in diabetic cats: Proposed regime = 0.25 - 0.5 U/kg BID, with 3 days of hospital or home BG curves, then serial curves at weeks 1, 2, and 4, then PRN Problems: cumbersome, expensive, invasive Due to prolonged duration of action, urine glucose can be used to monitor response to therapy or achievement of remission Intermediate insulins -> shorter duration of action -> uneven control -> urine sugar less reliable Glargine, alternative regime: Start with 1-2 U/cat BID based on size and initial BG Owner dips urine for glucose/ketones, daily if possible Ketodiastix® Urine collection litter box: www.felinediabetes.com Adjust dose based on urine dip results Ketodiastix measurement of urine; urine sugar range: negative, 1/10, ¼, ½, 1, 2 (neg., 100, 250, 500, 1000, 2000) Upwards adjustment by ½ unit BID q3 days until urine sugar 100-500 (1/10 to ½) Downwards adjustment daily if negative Remission - once urine dip negative for glucose, decrease dose by ½ unit BID daily If at ½ unit BID and dip still negative; discontinue Dips daily, then weekly, monthly Diagnosis and Treatment of Feline Small Cell Lymphoma Feline Gastrointestinal LSA LSA is the most common neoplasm of cats Cats are the species with the highest known incidence of LSA GI is the most common location of feline LSA Incidence of feline GI LSA increasing? In various studies, GI location % increased from 1970s to 1990s True increase? Better diagnostics? Higher suspicion? Earlier diagnosis? Previous studies and statistics clouded by lack of differentiation between lymphoblastic and lymphocytic (small cell) LSA Prior lack of differentiation between cats with and without mass lesions Poor prognosis implied by prior studies likely applies to cats with lymphoblastic LSA but not those with lymphocytic LSA lacking mass lesions Essential to differentiate between the two More new studies needed Cause of feline GI LSA: Viral? FeLV, feline coronavirus? Most cats w/ GI LSA FeLV ELISA negative Latent FeLV? "Hit and run" effect of FeLV? FeLV latency may be short-term, or last for months, years Jackson et al 1993: 63% of feline GI LSA tumors positive for FeLV by PCR 63% of LSA tumors in FeLV ELISA negative cats were PCR positive for FeLV Relationship between feline GI LSA and feline IBD? Spectrum of one disease process? Causality (Untreated or treated IBD -> GI LSA?) Misdiagnosis? (LSA misdiagnosed as IBD?) Cause of feline inflammatory GI disease: Viral? Dietary? Genetic? Diet? Environment? Dietary: Carbohydrates Maillard compounds Food antigens Carbohydrates in the feline diet: Incomplete gut fermentation -> increased microbial fermentation Decreased fecal pH May lead to bacterial overgrowth May change bacterial flora numbers or species Human inflammatory GI disease: Crohn's, ulcerative colitis Current focus on role of bacterial flora Changes in bacterial numbers or species Causing abnormal GI immune response Risk factors: Family history Jewish descent Smoking Maillard compounds: Nonenzymatic chemical reaction Condensation of an amino group and a reducing group Responsible for "browning" of foods May be harmful compounds Food antigens: Food sensitivity may lead to IBD, or IBD may lead to food sensitivity Evidence that both occurs Food sensitivity Guilford et al 2001, food sensitivity in cats: 29% of cats with chronic idiopathic GI symptoms were food sensitive Symptoms resolved on novel diet, recurred with previous diet rechallenge, resolved on novel diet again Looked at cats with vomiting, diarrhea, or both Large bowel diarrhea more common than small bowel in food sensitive cats Some food-sensitive cats had both GI and dermatologic symptoms GI biopsies ranged from no histological abnormalities to moderate or severe histological abnormalities Most common allergens = beef, corn gluten, wheat Study in New Zealand: influenced common diet ingredients Quick resolution of clinical signs on novel diet; traditional 8 week trial may not be necessary No clinical features differentiated food-sensitive from non-food sensitive cats Consider food trial in cats with vomiting and/or diarrhea, esp. large bowel Dysregulation of normal mucosal immunity with feline inflammatory GI disease: Likely multifactorial: Pathogens, genetic/familial factors, diet, environment One day we'll be able to treat or prevent the cause! Feline GI Disease Only sign may be weight loss! Vomiting, diarrhea, anorexia may be absent Vomiting more common in cats with IBD than dogs "Hairballs" may represent GI disease; don't ignore Lymphocytic LSA in cats Cannot differentiate between IBD and LSA by symptoms! Cannot differentiate between IBD and LSA by ultrasound (though it's still a useful test). Neutrophilia w/ LSA?? Studies needed. Diagnosis: GI biopsies Must be taken pre-treatment "Pred trial" not recommended Both diseases (IBD, LSA) may respond Clouds diagnosis May cause resistance to treatment GI biopsies in cats: Endoscopic, surgical, laparoscopic All have pros, cons Owner may have strong preference All operator dependent Endoscopic GI biopsies: Least invasive Least expensive Very operator/equipment dependent Very pathologist dependent Antech -> Dr. Engler MUST enter duodenum May miss lower GI disease Evans et al 2006: Most common owner complaint for both disease (IBD, LSA) was weight loss 50/50: ½ of cats had each disease 5 cats with LSA misdiagnosed as IBD on endoscopy These 5 cats: duodenum not properly entered Endoscopic GI biopsies: Experienced operator Proper equipment Right pathologist Suspect misdiagnosis if histopath does not match signs ("mild" IBD w/ significant symptoms, ultrasound abnx) -> consider full thickness biopsies) Surgical biopsies: Invasive Expensive Delay treatment Accurate if multiple areas biopsied; biopsy stomach, duodenum, jejunum, ileum, +/- LN, liver, etc. Laparoscopic GI biopsies: Lower invasiveness than surgery Equal biopsy quality (full thickness) Shorter recovery Allows full explore, excellent visualization Good choice w/ experienced operator Differentiation of IBD vs. LSA: New methods Immunohistochemistry Visualization of Ag-Ab reaction Immunolabeling for lymphoid markers and MHC class II May help distinguish LSA from severe inflammation Treatment of lymphocytic LSA in cats: PrednisOLone! Prednisone a pro-drug that must be converted to prednisolone in the liver Cats may not have good capability Some humans cannot convert Use prednisolone for all patients? Prednisolone for lymphocytic LSA: 2 mg/kg/day, in increments of 2.5 mg SID likely fine Most cats: 10 mg PO SID NEVER taper, unless complications (diabetes, etc.) Chlorambucil (Leukeran®): 2 mg tablets Must be kept refrigerated Various protocols My chlorambucil protocol: 1 mg (1/2 tablet) per cat PO SID 1 mg per cat PO EOD in tiny cats (<7 pounds) Technicians wear gloves, mask to break Owner wears gloves to administer Recheck CBC one month, one month again, then q 3 mos Chlorambucil, other protocols: 15 mg/m2 SID x 4 days, every 3 weeks To avoid breaking tablets: 2 mg/cat PO EOD, or less frequently if side effects Side effects (rare): neutropenia, anorexia, V/D, lethargy -> lower dose or decrease frequency Treatment of feline lymphocytic (small cell) LSA: prednisolone + chlorambucil, FOREVER NEVER taper (unless complications) Complications: diabetes mellitus, UTI Monitor for PU/PD U/A and culture q 3 mos w/ CBC (often no clinical signs) Treatment of lymphocytic LSA in cats requires patience on part of owner and veterinarian Improve often slow but steady Improvement may continue for months Counsel owner initially When cat comes out of remission: Lymphocytic LSA may become refractory to treatment Sometimes repeat biopsy required to evaluate May progress to lymphoblastic LSA Referral to oncologist for "rescue" Injectable chemotherapy drugs often buy significantly more time when needed Cobalamin in Feline GI Disease Cobalamin = Vitamin B12 Water soluble Deficiency may lead to poor response to therapy for GI disease Cobalamin homeostasis: Released from food in stomach Bound to haptocorrin in stomach Transferred to intrinsic factor (IF) in duodenum Cobalamin-IF complex binds to receptors in ileum ->Marker for ileal disease In dogs, IF made in stomach and pancreas In cats, IF made only in pancreas -> EPI in cats predisposes to cobalamin malabsorption GI disease may cause malabsorption Ileal localization Simpson et al 2001: 49 of 80 feline samples (sick cats) had low cobalamin Tested cats had wt loss, anorexia, diarrhea, vomiting Weight loss most common clinical sign in cats w/ subnormal cobalamin 69% of cats w/ low cobalamin had weight loss 43% diarrhea, 43% anorexia, 39% vomiting Most common histologic diagnosis = IBD, then LSA Other diseases: cholangiohepatitis, cholangitis, pancreatitis Some cats had multiple diseases Decreased half-life of cobalamin in sick cats vs. healthy Lowest cobalamin levels in cats w/ intestinal LSA Some of these cats had low folate as well Not known at what level consequences of low cobalamin occur Most affects rapidly dividing cells (e.g.,GI) Ruax, Steiner, and Williams 2005: Response to cobalamin supplementation in severely deficient cats Mean body weight increased significantly Reduced vomiting and diarrhea Some cats w/ low cobalamin have reduced folate utilization Could -> false normal folate level Re-evaluate folate after cobalamin supplementation Low folate could -> increased immunological and genetic damage w/ alkylating agents Update on Feline Infectious Disease Mycoplasma hemofelis The infection previously known as hemobartonella felis Prior classification as rickettsia Rickettsiae have cell walls and multiply within host cells Mycoplasma hemofelis has no cell walls and multiplies on host cells Classified into 2 strains: Mycoplasma hemofelis Severe hemolytic anemia Mycoplasma hemominutum Minor clinical signs and hematological changes When infected with both -> more severe disease Mechanism of anemia: Organism attachment -> membrane damage -> increased osmotic fragility -> shortened RBC lifespan Membrane damage -> exposure or alteration in RBC antigens -> antiRBC antibodies Antibodies against organism -> RBC destruction Carrier status: Infection may result in chronic carrier state post recovery Cat clinically normal Reactivation can occur Implications for other cats in household? Diagnosis: Examination of blood smears: false positives and negatives PCR: more sensitive, may be negative during antibiotic treatment PCR + does not equate with clinical dz "Normal" cats may carry Hackett et al 2003: Tested 133 Colorado cats for M hemofelis and M hemominutum 9.8% positive (7.5% M hemominutum, 2.3% M hemofelis) When excluded SPF free colony cats, 12.4 % positive Of cats allowed outside, 19.6% positive Treatment: Doxycycline: can cause esophageal strictures; administer H20 after pilling Enrofloxacin? 5-10 mg/kg/day Dowers et al 2002: enrofloxacin 10/mg/kg/day effective Imidocarb for resistant/recurrent infections? Transfusion prn +/- Corticosteroids? Canine Parvovirus in Cats Parvoviruses: Replicate best in rapidly dividing cells Germfree cats w/ FPLV have none to mild intestinal lesions, implying GI lesions caused by secondary bacterial infections Csiza et al 1971: FPLV persists over 50 weeks in lungs & kidneys of recovered cats Canine Parvovirus in Cats: In vitro, CPV-type viruses replicate well in feline and canine cell lines In vitro, FPLV-type viruses only replicate well in feline cell lines Abs against CPV detected in large felids, wildcats, civets, otters, bears Ikeda 2002: "Interspecies transmissions probably result in accelerated emergence of other new antigenic types of CPVs…" Ikeda et al 2002: In vivo: FPLV replication in cats: e.g., LNs, thymus, spleen, GI epithelium, shed in feces FPLV replication in dogs: Only thymus and bone marrow (not gut -> no fecal shedding) Viral evolution: ancestor of CPV-2 had only to develop ability to replicate in gut to cause fecal shedding and be spread dog -> dog Canine Parvovirus: CPV-2 emerged in the 1970s First positive titers in dogs: Europe 1975, USA/Japan/Australia 1978 Spread rapidly around the world; killed thousands of dogs Theory: Emerged from variant of FPLV or a closely related virus of another carnivore (mink, fox) CPV-2 more likely arose from virus of fox or another carnivore Virus isolated from Finnish Arctic fox intermediate between CPV-2 and FPLV Mink, foxes susceptible to FPLV-like viruses; may be reservoir for CPV-2 ancestor German red foxes may harbor CPV-2 ancestor New types of CPV-2 have now emerged and largely replaced CPV-2: -> CPV-2a, CPV-2b Canine parvovirus in cats: First isolation of CPV-2a in a cat: 1987 CPV-2a and CPV-2b then isolated from cats in USA and Germany (Truyen et al 1996) Ikeda et al 2000: 15 of 18 isolates from unvaccinated cats = CPV-2a or CPV-2b CPV-2a/2b have advantages over conventional FPLV (spread thru cats and dogs) -> CPV-2a/2b may replace FPLV as dominant virus in cats -> Could an outbreak result? Evolution of feline parvoviruses: CPV-2a and 2b found in felids worldwide (cheetahs, tigers, others) CPV-2c: Isolated from leopard cats; not domestic cats in the area Will likely spread to domestic dogs and cats Pathogenicity of CPV-2a/b/c in cats: Mochizuki et al 1996: Isolation of CPV-2a from cat w/ panleukopenia Steinel et al 2000: CPV-2a/2b from cheetahs w/ chronic diarrhea/enteritis, tiger w/ anorexia/diarrhea Goto et al 1984: Experimental infection of cats w/ CPV-2a. Depression, vomiting, diarrhea, leukopenia, death Nakamura et al 2001: Compared virulence of FPLV, CPV-2a, and CPV-2c in SPF cats CPV-2a: diverse pathogenicity; none to typical panleukopenia CPV-2c: all cats developed disease, but milder than FPLV -> 2c more infectious/higher frequency of disease than 2a? Persistent infection: FPLV: will be completely eliminated from infected cats CPV: found in feces of healthy cats Isolated from peripheral blood mononuclear cells (PBMCs) of cats w/ high Ab titers CPV may persistently infect cats, even w/ Ab titers PBMC may be reservoir Sporadic shedding of virus?? Effectiveness of FPLV vaccines against CPV in cats: Chalmers et al 1999: modified live FPLV vaccine protected against CPV-2b (SPF cats) Nakamura et al 2001: Cats vaccinated w/ inactivated FPLV developed neutralizing Abs against CPV-2a/b/c Titers lower against CPV than FPLV Steinel 2000: Cheetahs vaccinated w/ killed FPLV vaccine developed CPV infection Proposed need for CPV-2a/b vaccines for cats FPLV vaccines may not protect cats against CPV long-term Nakamura et al 2001: Cats infected w/ CPV-2a developed high titers against 2a and 2b but low levels against FPLV CPV-2c infected cats developed equal Ab titers against 2a, b, & c as well as FPLV -> CPV-2c vaccine might be promising Feline Bordetella Infection Bordetella bronchiseptica Aerobic, gram-negative coccobacillus Respiratory pathogen of multiple species Previously thought to be secondary respiratory pathogen in cats Now known to be primary pathogen in cats Willoughby et al 1991: Isolated from cattery kittens w/ bronchopneumonia Binns et al 1999: Sampled 740 cats Bordetella isolated from 11% of cats Rescue catteries: 19.5 % Breeding catteries: 9% Research colonies: 13.5% 0% in household pets Significant predictors: Living in rescue cattery Larger numbers of animals Households containing a dog w/ recent respiratory infection Clinical signs: sneezing, coughing, ocular and nasal discharge Seemed to cause disease independently Williams et al 2002: Testing intranasal Bordetella vaccine (Intervet) in cats Control kittens: rhinitis, ocular and nasal discharge, fever, sneezing, coughing Vaccination effective AAFP guidelines: vaccine optional (noncore) Helps et al 2005: Upper respiratory tract disease in cats Tested 1748 cats Prevalence by PCR on swabs Cats w/ URI: FHV 16%, FCV 47%, C. felis 10%, Bordetella 5% Without URI: FHV 8%, FCV 29%, C. felis 3%, Bordetella 1.3% Seroprevalence Bordetella: 61%/41% Contact w/ dogs w/ URI a risk factor Welsh 1996: 11 cats from 10 households diagnosed w/ B. bronchiseptica TTW or lung tissue cultures grew Bordetella in all cases 7 cases fatal (pneumonia) Most cases in kittens < 8 weeks Coughing in all cases Feline Bordetella Infection: May be shed for 19 weeks post infection Carrier state exists: up to 9% of healthy cats may carry Can be transmitted from dogs to cats Can infect humans, especially immunocompromised Virulent Feline Calicivirus Caliciviridae: highly diverse group of RNA pathogens causing wide range of human and animal disease Feline calicivirus: High level of antigenic and pathogenic variability High evolution rate Coyne et al 2006: Studied 5 multicat households Studied endemic infection within households to elucidate mechanisms and rates of evolution, mechanisms of persistent infection of individuals "Opportunity to study their evolution, diversification, and mechanisms of persistence in their natural host population…" "Feline calicivirus infection within stable household groups of cats provides a useful model system to characterize evolutionary strategies employed by caliciviruses to ensure long-survival in their host population." Mean overall prevalence of FCV = 35% 10 distinct viral strains across 5 households 31 individual cats who shed virus over prolonged periods How/why? Coyne et al 2006; 2 mechanisms of viral persistence/evolution: Progressive evolution: mutation accumulation in given variant of a strain within an individual (4 cats) Sequential reinfection: Cats periodically reinfected from within the household (27 cats) At least one cat infected with 2 distinct strains simultaneously Study illustrates the high level of diversity that can occur over time within a viral strain circulating in a population New strains of FCV emerging Grouped endemically infected cats (e.g. rescue, cattery, foster) "provide ideal conditions for the generation of viral biodiversity and possible increased virulence". Multiple outbreaks of virulent systemic feline calicivirus have been recently reported: Hurley et al 2004: CA Pedersen et al 2000: CA Schorr-Evans et al 2003: New England Coyne et al 2006: UK France ? Clinical signs of feline calici: URI Oral ulcerations, acute/chronic stomatitis Arthritis Skin ulcerations/dermatitis Pneumonia Cystitis Hepatitis Neurological dz Virulent systemic feline calicivirus: Widespread vasculitis Multi-organ failure Edema of limbs & face Alopecia/ulceration/crusting of skin, esp. muzzle, pinnae, footpads Icterus Pancreatitis (+/- More typical symptoms) Death 32-50% Patterns of outbreaks: Private vet practice, 6 cases, 3 deaths Shelter kitten hospitalized w/ URI in practice -> employee and client cats All cats had been vaccinated prior Small animal hospital, 24 cases: shelter cats w/ URI -> spread rapidly among patients, employee -> housecat Prior vaccination not protective 32% mortality Mother cat and 3 kittens from rescue group spayed/neutered at vet practice -> outbreak at the vet clinic Mother cat and kittens treated at another vet clinic -> outbreak Cat who had GI surgery at 1st vet -clinic -> owner vectors -> feline housemates (no direct contact) -> another vet clinic -> outbreak Healthy boarding cat, no symptoms, carried home to housemate -> died UK: Outbreak in 4-cat household, adult cat from neighboring household 3 of 4 cats in household died Different strains in each outbreak Resistant to vaccination Adult cats more affected, increased mortality Index cases tend to be shelter or rescue cats Viral strain disappears in 1-2 months Control: Strict sanitation in facility, between patients, when employees go home Isolation of URI patients, gowns/gloves/shoe covers/caps Separate area for rescue/shelter cats? Early recognition and quarantine Nursing by staff who don't own cats? Tracing index case(s) Inform neighboring practices, shelters, rescue Survives in environment 14-28 days Transmitted by aerosol, contact, fomites, feces, urine Bleach best disinfectant? Consider all exposed cats contagious 50% of feline calici strains now resistant to commonly used vaccine Client Handout: Glargine Insulin Treatment of the Diabetic Cat General information regarding diabetes Diabetes mellitus is a condition of insulin deficiency. Insulin allows glucose (sugar) that the body absorbs and manufactures to get into the body cells for utilization. Without insulin, the glucose cannot enter cells, and the body experiences a state of starvation. Because the glucose cannot get into the cells, it builds up in the blood and overflows into the urine. The symptoms that your pet may have been exhibiting (excessive drinking and urination, increased appetite, weight loss) are due to high glucose in the blood and urine, and starvation of the body cells. A diabetic may develop ketones. Ketones are the result of the body's abnormal metabolism of fat during severe diabetes. Ketones are toxic acids. A life threatening condition called ketoacidosis may develop (diabetic ketoacidosis or DKA). Uncontrolled diabetes can also result in a decreased immune system or poor wound healing. To treat diabetes mellitus, we administer insulin by injection, usually twice a day. If insufficient amounts are given, diabetes remains uncontrolled. Conditions that can contribute to uncontrolled diabetes include: incorrect handling, storage, or administration of insulin; infections; other diseases such as hormonal problems or too much variation in diet or exercise. If too much insulin is given, the blood sugar may drop too low (hypoglycemia), which can be dangerous or even life threatening. Our aim is to establish the correct insulin protocol for your pet without significantly affecting your pet's lifestyle, or your own. This involves close communication with your veterinarian, and may involve periodic trips to the veterinarian's office. It is very important to follow instructions closely, and to keep in touch with your veterinarian. Diabetic pets can live long healthy lives. Many cats if treated and fed appropriately will stop being diabetic and no longer need insulin. You can greatly increase the chance of this occurring by following these instructions carefully. Treatment Diabetes mellitus is treated by injecting insulin under the skin twice a day, using an insulin syringe. Pick the times (twelve hours apart) you are most likely to be home, e.g., 7am and 7pm. It's okay for the insulin dose to be given one hour early or late. It is okay to skip a dose once in a while if unavoidable. Log Book It is helpful to keep a logbook during treatment so we can keep track of your pet's therapy and symptoms. The log should include the date, the urine dipstick glucose and ketone results that day (if obtained), the insulin doses and times, and any other notes you feel are important, such as vomiting or appetite. You should bring your log whenever you bring your cat to the vet. Feeding We often recommend Hill's M/D canned, Purina DM canned or Science Diet Feline Growth canned kitten food, since high protein canned food has been shown to be very helpful for many diabetic cats, and can even cure diabetes in some cases. Please ask your veterinarian which food is recommended for your cat. It is very important that your cat eats consistently, so we will feed a less ideal diet if we have to. Any canned food, particularly kitten food, is good if your cat won't eat the above. Diabetic cats should be fed twice a day, 5 or 10 minutes BEFORE getting insulin (to prevent hypoglycemia from an empty stomach). If your cat won't eat canned food, please ask your vet for recommendations, as it is very important that cats eat every day. Insulin Insulin should be kept in the refrigerator. Insulin bottles should be replaced every three months even if not expired. Be careful to monitor the expiration date as well. Avoid exposure to heat or sunlight. The insulin must be gently but thoroughly mixed just before administration. It can be rolled between your hands or tilted back and forth. It should NEVER be shaken. Give the injection as shown, under the skin, after your pet has eaten. If you ever feel some of the insulin did not go under the skin, DO NOT give it again. Urine Dipsticks Urine dipsticks are extremely useful to help monitor your cat's diabetes at home. They give us a rough estimate of the blood sugar, and also monitor for ketones. We recommend Ketodiastix (available over the counter) which measure urine glucose and ketones. Some suggestions for obtaining a drop of urine to sample: place saran wrap lightly over litter; use non-absorbable litter material such as aquarium gravel, regular gravel, or NoSorb; use a torn paper towel as litter. Even very wet clay litter will not work. The web site www.felinediabetes.com has a special litter box that allows urine to drip through onto a tray for easy collection. Adjusting the insulin dose The dose of insulin can be adjusted at home, based on the urine dipsticks, as follows: If the glucose is 1%, 2%, or more for 2-3 days: Increase by ½ unit over previous dose If the glucose is 1/10%, ¼%, or ½%: Stay at the same dose If the glucose is negative: Decrease by ½ unit from previous dose Do not adjust the dose daily. Wait to see a trend over 2-3 days. The exception is a negative reading. If this occurs, decrease the dose immediately. Do not increase the dose above 3 units without calling. At first, call us every other day with a progress report so we can help you adjust the dose. TROUBLE SHOOTING Hypoglycemia The most important problem that can occur is hypoglycemia (too low blood glucose). This can occur in the following situations: Incorrect calculation or measurement of dosage. Insufficient mixing of insulin solution. Insulin given in spite of the cat's failure to eat, or if he/she vomits his/her food. A change in the cat's insulin requirements. If the cat's diabetes resolves, he may not need insulin. The signs of hypoglycemia are: weakness, loss of balance, incoordination, blindness, collapse, muscle twitches or seizures. If you see any of these signs: If your cat is alert and conscious, offer food. If he/she eats, watch closely and, if all appears well, decrease the insulin dose by 1 unit the next time you give it. You should also call your veterinarian. If your cat is unable or unwilling to eat, give 1 tsp of Karo syrup orally. If no improvement is seen, take him/her to the veterinarian IMMEDIATELY. Once pet is recovered, do not give any more insulin with out speaking to a veterinarian. The best way to avoid a hypoglycemic crisis is to abstain from giving insulin when you are not sure whether to give it or not. Definitely, do not give insulin in the following situations: You are not sure whether he/she received the insulin. You think you gave the wrong amount of insulin. The cat moved when you gave the injection and some of the insulin may not have been injected. Not Eating If the cat does not eat, or vomits after eating, give only half the usual amount of insulin. If this occurs again, call. Ketones If the ketones on the urine dipstick are positive, call right away. This is a sign that we need to check him/her and readjust our dosages. Fluctuating Readings If you notice that the dipstick results fluctuate a lot, and you have had to frequently increase and decrease the insulin dosage, please give us a call. MONITORING Assessment of how well we are doing will be determined by: (1) your cat's attitude, urination and drinking, (2) urine dipsticks, and (3) periodic blood glucose curves or fructosamine levels. While urine glucose measurements are a useful tool for at-home monitoring, they are not completely reliable. They give a rough idea of the blood glucose level over the past several hours. They do not indicate the peak or trough blood levels, nor the duration of the action of the insulin. This can only be done by determination of a glucose curve, i.e., by measuring the blood glucose every 2-4 hours over a 12-hour period after insulin administration. These can be done by your veterinarian, or by you at home using ear-sticks. A curve may be done initially to be confident that we have the diabetes as well controlled as possible. Thereafter, some veterinarians recommend a curve every 3-6 months, or when you think you are having problems. SUPPLIES Glargine (Lantus®) Insulin *Remember - Keep the insulin refrigerated, and discard opened bottle after 3 months. Syringes: Requires a prescription from your veterinarian. Ketodiastix for urine testing: Over-the-counter pharmacy item. *It is important to leave the cap on the bottle when not in use. Read label on when to discard. **Please try to anticipate your needs, and refill supplies in advance. REMEMBER: Call your doctor if: Signs of hypoglycemia, as described above. Ketones seen on dipstick Persistently high glucose readings, despite increased insulin dose, necessitating an increase in insulin dose above 5 units. (Some cats need more than 5 units, but give us a call.) Persistently negative glucose readings, despite decreasing the insulin dose. Fluctuating glucose readings. Not eating well (2 consecutive meals). Vomiting, diarrhea, or any other unexpected problems. Daily Routine Summary Try to dip urine once a day if possible and record. Feed twice a daily, 12 hours apart. Give insulin injections twice daily, after meals (12 hours apart) according to urine dipstick results.

© 2007 - Louise Murray, DVM, DACVIM - All rights reserved