Practical Clinical Pathology Ups and Downs of Sugars

Wendy Blount, DVM Attendee 1 – City TX Danger values - <40 g/dl; >1000 g/dl • – Brain due to hyperosmosis – CNS signs (cerebral, brain stem) and seizures DDx Hyperglycemia other than DM and (especially in prediabetics): • Beta adrenergics (, albuterol, etc.) • Glaucoma treatments – acetazolamide, etc. • , levothyroxine, progestagens, estrogens • ( , Diazoxide) • Near death experience • Ticked off Cat Glucose Danger values - <40 g/dl; >1000 g/dl • Hyperglycemia – Brain dehydration due to hyperosmosis – CNS signs (cerebral, brain stem) and seizures DDx Hyperglycemia other than DM and stress (especially in prediabetics): • Beta adrenergics (terbutaline, albuterol, etc.) • Glaucoma treatments – acetazolamide, etc. • Corticosteroids, levothyroxine, progestagens, estrogens • (Thiazide diuretics, Diazoxide) • Near death experience • Ticked off Cat DM - Clinical Presentation • Most dogs & cats >5 years • History – PU-PD – bigger clumps in the litter box – , – , illness of DKA – Recent administration of corticosteroids – History of triaditis, – Recent heat – Vision problems (cataracts) – Skin problems – , alopecia DM - Clinical Presentation • Exam – Endocrine alopecia, pyoderma, poor grooming in the cat – Pot bellied – hepatomegaly – Cranial abdominal mass – pancreatitis + pain – 10% in the cat – Pregnancy, vulvar discharge, coming out of heat, abdominal distension – Cats are more likely to be overweight with recent weight loss – Dogs more likely to be underweight Stress Hyperglycemia or DM? • Stressed cats can have transient hyperglycemia (200-400) • Critically ill non-diabetic dogs can have marked hyperglycemia (>400) • Stress hyperglycemia due to , epinephrine and resistance • Acute hyperglycemia has adverse effects on the , coagulation, heart and brain • Chronic hyperglycemia is toxic to beta cells • Treat with judicious insulin PRN – time will tell Hyperglycemia due to DM can be intermittent at first Stress Hyperglycemia or DM? • “No ” makes untreated DM unlikely • Stressed cats can have glycosuria • Renal threshold 180-220 mg/dl in the dog • 200-300 mg/dl in the cat • Ketones in the urine indicate catabolism – investigate DKA • DKA = Diabetic • Any sick cat who has not eaten for days can have ketonuria • If all else fails, run a • Fructosamine elevated with DM >> a few other systemic diseases • Decreased with a number of systemic diseases • Normal with stress hyperglycemia Fructosamine glycosylated protein • Averages blood glucose levels over the past 1-3 weeks • Not affected by acute stress hyperglycemia • Falsely decreased by - pancreatitis – , Hemolysis – Hyperlipidemia – – Prolonged storage at room temperature – , thin body condition • Falsely increased by – Hyperglobulinemia – Hypothyroidism • In house – HESKA, Idexx, Abaxis • Or send out (freeze until shipped) Pattern Recognition - Mellitus

1. CBC • low HCT with normal Hb (hemolysis) if Phos <1.6

2. Blood pressure • predisposition to hypertension Pattern Recognition - Diabetes Mellitus 3. Serum panel • Hyperglycemia (of course) • Hypophosphatemia – especially if DKA • Hypokalemia – especially if DKA • Elevated liver enzymes and hepatomegaly - Almost all unregulated diabetics have both – Symptoms of DM and Cushing’s overlap • Endocrine alopecia • PU-PD • Elevated liver enzymes with hepatomegaly – Cushing’s alone causes mild hyperglycemia that is not usually insulin dependent – Begin diabetic regulation before Dx HAC, fine tune after Dx & Tx Pattern Recognition - Diabetes Mellitus 3. Serum panel • high • high • Azotemia if dehydrated • Albumin increased if dehydrated without pancreatitis Pattern Recognition - Diabetes Mellitus 4. Urinalysis • Look for UTI – predisposed by glucosuria, dilute urine and immunosuppression • 25% of new diabetics have UTI • >50% UTI if also Cushingoid • Immunosuppression may result in benign sediment & lack if symptoms • Dilute urine may make bacteriuria hard to detect on urine sediment • Many rec. either culture or empirical treatment for UTI for new diabetics • – pancreatitis, HAC, UTI Pattern Recognition - Diabetes Mellitus 5. Thyroid testing • TT4 and fT4 for all diabetic cats >5 yrs old • Retest cats if regulation difficult • If regulation difficult and other signs of hypothyroidism in the dog – TSH, TT4, fT4 • TT4 in euthyroid unregulated diabetics will often be low Glucose >350-450 mg/dl means condition is potentially life threatening Look for CRF if glucose >800 mg/dl Pattern Recognition - Diabetes Mellitus Indications of DKA • need hospitalization and careful monitoring, higher level of K+ and phos supplementation • Metabolic acidosis - Low HCO3, low TCO2, low blood pH, high • Ketosis - ketonuria, vomiting, lethargy • Phos <1.5 can cause severe hemolysis • K+ <2.5 can cause weakness and paralysis Pattern Recognition - Diabetes Mellitus Pancreatitis pattern • need fluid support, pain meds, antiemetics, maybe plasma if really bad

• CBC – Thrombocytopenia – vasculitis, DIC – neutrophilia + left shift – pancreatic necrosis, fat necrosis – Anemia – Anemia of Chronic Inflammatory Disease (ACID), hemolysis Pattern Recognition - Diabetes Mellitus Pancreatitis pattern • Panel - lipemia while (esp. the cat) – Hypocalcemia – saponification of fat – – systemic inflammation, vasculitis – elevated liver enzymes, icterus – whacked out glucose – Hypophosphatemia – lack of insulin, renal loss, lack of intake – Hypochloridemia – vomiting – Hypokalemia – lack of insulin, acidosis, vomiting, diarrhea, lack of intake Pattern Recognition - Diabetes Mellitus Pancreatitis pattern • cPL, fPL – cPL best test for pancreatitis in the dog – US best test for pancreatitis in the cat • is seldom helpful, and a weak indicator • has very low sensitivity, but specific pancreatitis is the most common cause of hyperlipidemia in the cat Pancreatitis is on the short list of things that will cause icterus without anemia or elevated liver enzymes in the cat Pattern Recognition - Diabetes Mellitus Fatty liver pattern – need nutritional support for cats (feeding tube?) • Hx – heavy cat has not eaten in several days • Exam - liver enlarged, + icterus, sick – Fatty liver with HE indicates poor prognosis • Panel - ALKP significantly exceeds GGT only in feline hepatic lipidosis – + elevated bili – Elevated ALT is common – Changes associated with co-morbidities that may be initial cause • Abd US – diffusely hyperechoic liver – Co-morbidities that may be initial cause – Fatty liver Often diagnosed on cytology Pattern Recognition - Diabetes Mellitus Fatty liver pattern – need nutritional support for cats (feeding tube?) • Hx – heavy cat has not eaten in several days • Exam - liver enlarged, + icterus, sick – Fatty liver with HE indicates poor prognosis • Panel - ALKP significantly exceeds GGT only in feline hepatic lipidosis – + elevated bili – Elevated ALT is common – Changes associated with co-morbidities that may be initial cause • Abd US – diffusely hyperechoic liver – Co-morbidities that may be initial cause – Fatty liver Often diagnosed on cytology K+ & Phos in DKA Patient

– Insulin carries K+ & Phos into the cell • Insulin administration can make hypokalemia and hypophosphatemia worse – supplement first – Without insulin, both get washed out the kidneys due to PU-PD – 90-95% of the body K+ is intracellular – Total body K+ can be depleted even if serum K+ is normal – H+ is exchanged for K+  Correcting acidosis worsens K+ Continuous Glucose Monitoring (CGM) Systems (Flash) • Probe measures glucose in interstitial fluid continuously to plot a curve • Wireless transmission to a pager size display • Human device validated in dogs 2016 • Previous devices worn in a vest – Freestyle Libre is disposable – Available in the US as of Dec 2017 – Requires a prescription – Approved for people – off label for pets Continuous Glucose Monitoring (CGM) Systems (Flash) • Shave fur over the dorsal neck • Clean with alcohol and let dry • Apply sticky disc this size of a quarter • Secure with a light bandage • Stay on dogs pretty well – cats can be a problem – Applying sport spray can help adhere • Disk stores data for 8 hours • Wave reader over the disk to read & save up to every 8 hrs, for 10 days • Disk $75-100, Reader $50 Continuous Glucose Monitoring (CGM) Systems (Flash)

Dr. Greg Matt, Houston TX Continuous Glucose Monitoring (CGM) Systems (Flash)

Dr. Greg Matt, Houston TX Continuous Glucose Monitoring (CGM) Systems (Flash)

Dr. Greg Matt, Houston TX Continuous Glucose Monitoring (CGM) Systems (Flash)

Dr. Teleah Grand, McKinney TX Attendee 2 – City TX Monitoring DM – Fructosamine (FRA) Low (<200) • Mild to moderate hypoglycemia • Not enough to cause Somogyi (glucose 65-80) • Decrease insulin by 10-20% Normal range (200-350) Good diabetic control (350-450) High (>450 mcmol/L) • >600 – danger zone • Significant periods of hyperglycemia • Not enough insulin, or too much insulin – , rebound hyperglycemia (too much) – Or sustained hyperglycemia (not enough insulin) Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation – Smut – 12 year old SF DLH – Recently diagnosed as diabetic (8 wks) – Diet – Innova EVO, Lantus 6 units SC BID – She comes in for glucose curve weekly – Each week, she loses weight – All glucose checks >400 Owner says she does not feel good Considering euthanasia Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation – Smut – 12 year old SF DLH – Smut allows only 2-3 glucose readings – each day – We try seeing her on three days in a row, – to complete a full glucose curve (6-9) – We fool with this for 3 weeks - 9U SC BID All values >400, throughout the day Smut loses more weight and feels worse Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation – Smut – 12 year old SF DLH – Thoracic rads + Abd US - NSAF – CBC, panel, UA WNL except glucose – TT4, fT4 - WNL Urine culture negative FeLV/FIV negative No signs other than lethargy, poor appetite and weight loss Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation – Smut – 12 year old SF DLH – Plan – regulate with fructosamine – fructosamine 140 – Reduce insulin to 7 U BID, recheck 1 week – CC: not much better, FRA 180 – Reduce insulin to 5 U BID, recheck 1 week Hx: no weight loss, Smut feels a lot better (7/10) FRA 190 – reduce insulin to 4U BID, recheck 1 wk Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation – Smut – 12 year old SF DLH – Hx: Smut gains 0.5 lb, back to old self – fructosamine 250 – Recheck 30 days – Smut is gradually weaned off insulin, – using only FRA, symptoms and weight 18 months later goes back on insulin Euthanized at 16 yrs for renal failure Monitoring DM - Fructosamine (FRA) Low FRA with poor glycemic control – check T4 Remission is defined as normal FRA w/o insulin • Regulation using FRA can work well when curves are not practical – But keep in mind that FRA is ideal in only 60% of diabetic pets with good clinical regulation Why Do Glucose Curves? • Early detection of occult hypoglycemia • Ensure that dose changes are effective • To document dysregulation as the first step to correcting it Glucose Curve Protocol • Owner feeds and gives insulin • Bring pet to clinic within 2 hours • Glucose (+ fructosamine) on arrival • Glucose every 2 hours when >100 – Once you know the insulin duration, you may be able to take the first glucose 3-4 hrs after insulin • Glucose every hour when <100-150 – Can miss nadir (low point) if you don’t do this • Continue until you get 2 values 2 hours apart that are upwardly trending – If nadir not <120, it’s difficult to determine duration • Usually can be completed in a business day, but not always – Some require 12-24 hours - finish at home or EC • Dogs on Lantus® can often do q3-4 hrs Home Glucose Curves

• Really are better than “in clinic” • Stress increases glucose – Especially in cats • Many owners can learn to do it • It’s very helpful for owners to be able to check blood sugar in an emergency • Entire curve does not have to be finished the same day • Have owners come in for appointment to discuss the glucose curve – bring pet at least quarterly • If the pet tolerates the CGM, this can be much easier on the owner Home Glucose Curves

1. Warm the ear • Lateral to the ear vein in cats, or inner surface • No need to warm lip, foot pad, elbow callus 2. Apply vaseline if area is haired 3. If you use alcohol, allow it to dry 4. Prick with human lancet • Can use 27 gauge needle • Use roll of gauze inside the ear for cats Cat - Ear Prick Dog – Lip, Elbow, Footpad, Ear Home Glucose Curves

Choosing a glucometer • Low sample volume • Inadequate sample volume prevents sample from running • EDTA (purple top) and LiHep (green top) blood are fine in clinic Home Glucose Curves

Choosing a glucometer • Low sample volume • Inadequate sample volume prevents sample from running • EDTA (purple top) and LiHep (green top) blood are fine • Plasma calibrated rather than whole blood

풑풍풂풔풎풂 = ____ 풘풉풐풍풆 풃풍풐풐풅___ . − ( . × %) Home Glucose Curves

Choosing a glucometer • Auto-calibration of test strips • Calibrate to in house machine • Enter species code for veterinary meters if needed • Glucometers are most accurate <100mg/dl AlphaTrak 2 Starter Kit $55 Meter, lancets, strips, lancing device Interpreting Glucose Curves

Duration of the curve • If your curve is 12 hours or less, you need to give insulin BID, not SID • I have never been able to use ProZinc SID in the dog Glucose range • If all values are 100-250, leave it alone if symptoms are controlled • Avoid values above 300 and below 80 • Average of 6 values taken in a 12-hour curve should be less than 250 Interpreting Glucose Curves Glucose nadir • If < 80 reduce the insulin dose • If >130, consider increasing insulin dose, unless all values less than 250 • Ideal nadir is 80-130 Glucose Peak • If nadir 80-130 and peak too high, change to longer duration insulin regular < NPH < Lente < PZI < glargine < detemir Somogyi Effect • Rebound hyperglycemia follows blood glucose < 60 – usually within 12 hours – Lasts 24-72 hours – Often >400 mg/dl • Due to epinephrine and release (counter-regulation) • cyclic response of 1-2 days of “good control” followed by several days of poor control increases suspicion • Fructosamine usually >500 mcmol/dl • Reduce insulin and recheck FRA + curve in 1 week Home Urine Testing

• I don’t use urine strips for glucosuria • Renal threshold 180-300 mg/dl – Most diabetics exceed this daily • Many well regulated diabetic dogs and cats will have daily glucosuria • It is reasonable to have owners keep KetoDiastix • Ketonuria indicates seeing the vet ASAP • Increasing insulin based on glucosuria can result in Somogyi effect Willie Willie

• 17 year old DLH, has been a diabetic for about 3 years • Had an “insulin vacation” for about six months during the first year • Was taking 2 units NPH BID for about a year prior to boarding for 10 days – Eats Innova EVO dry free choice (crunchy junkie) – He doesn’t eat well when he boards • Since coming home from boarding a month ago, Willie has felt terrible – PU/PD – Doesn’t eat chicken jerky snacks as voraciously – Very lethargic Willie

• In the past month – Weekly visits to regular vet for spot checks at insulin time – Fasted overnight and no insulin prior to coming in for glucose checks – Insulin given at clinic, Willie doesn’t eat all day – All glucose values > 400 – Insulin gradually increased to 6 units BID – Willie just keeps getting worse, now he won’t eat at home, still PU-PD • No new findings on exam, except weight loss of 1.5 lbs over past year – Other than glucose, last bloodwork done 2 yrs. ago Willie

• Bloodwork at 2pm (insulin 7am) • CBC – NSAF • Profile & – BUN 68, creat 4, phos 9, glu 31 • UA – SG 1.015, no bacteriuria • Urine culture negative • TT4 – 6.5, fT4 – 63 • No chest x-rays or abdominal US – This may have sent Willie over the edge – Sedation might compromise the kidneys • New Diagnoses – hyperthyroidism, CRF, insulin overdose Willie

• Plan – 100 ml LRS SC (owners not ready for home fluids) – No insulin tonight, reduce insulin to 4 units BID – Recheck in 1 week, or sooner if problems continue – Provide owner with list of canned moderate protein, low carb foods – wishful thinking • 1 week later, Willie “is a new cat” ;-) – well and happy, but still PU-PD – With CRF & hyperT4, we likely won’t be able to use PU-PD as a marker for good regulation – 2 pm glucose 67, BUN 49, creat 2, phos normal – Reduce insulin to 3 units BID, recheck 1 week Willie

• 1 week later, Willie still feeling good – still PU-PD – Fructosamine 492 (poor control) • BUN 59 (was 49), creat 5 (was 2), phos normal – Glucose curve • Time 0 – 365 • 2 hours – 71 • 4 hours – 143 • 6 hours - 310 – Change to Lantus 3 units BID, recheck 1 week Willie

• 1 week later, Willie still feeling good – still PU-PD – Fructosamine within normal range – Begin methimazole 2.5 mg PO SID – Decrease Lantus to 2 units BID, recheck 1 week • Why? • Hyperthyroidism causes relative Attendee 2 – City TX Willie

• We eventually weaned Willie down to 0.5 unit every other day – If we stopped, he got hyperglycemic and did not feel good – If we increased, he got hypoglycemic and did not feel good – We continued this for 2 years, until he suffered an episode of acute renal failure at 19 years of age – His temperament was not suitable for hospitalization, and he was humanely euthanized Willie

Lesson from Willie – PU-PD in an unregulated diabetic does not always mean more insulin is needed • Insulin overdose can cause PU-PD, due to rebound hyperglycemia • Other problems can cause PU-PD – CRF & hyperT4 in this case – Regular rechecks can nip problems in the bud and prevent illness from dysregulation – Glucose curves are not always necessary – one mid-day glu + FRA can tell a great deal Willie

Lesson from Willie – I prefer owners to give insulin and feed prior to bringing in for glucose curve – In-house fructosamine can preclude need for glucose curve

SPOT CHECKING GLUCOSE ONLY AT INSULIN TIME SUCKS BIG TIME!!!!! Spot Checking Diabetics

If you were only allowed two glucose checks in every 24 hour period, when would you want to take them?

At Insulin Time? Glucose peak Glucose nadir? 2-12 hrs after One of each? Spot Checking Diabetics

• Which values in a glucose curve are used to determine dose? – Nadir (lowest glucose values - insulin peak) • Which values are used to determine interval and insulin type? – Peak glucose values (insulin nadir) – If glucose nadir is ideal, and glucose peaks are too high, then you need to give insulin more often, or you need a longer acting insulin Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 • Increasing insulin would probably make this dog or cat hypoglycemic • Need to change to longer acting insulin 3. 245, 265 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 • Need to change to longer acting insulin 3. 245, 265 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 • Need to change to longer acting insulin 3. 245, 265 • Need to increase insulin 4. 200, 200 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 • Need to change to longer acting insulin 3. 245, 265 • Need to increase insulin 4. 200, 200 Spot Checking Diabetics Quiz – Glucose at insulin time 1. 250, 260 • Need to decrease insulin 2. 350, 335 • Need to change to longer acting insulin 3. 245, 265 • Need to increase insulin 4. 200, 200 • PERFECT!! no changes needed Summary PowerPoint – Ups and Downs of Blood Sugar • .pptx • .pdfs – 1 and 6 slides per page Vet Articles and Handouts • JVIM – Validation of Flash Glucose Monitoring Device (FreeStyle Libre) in Dogs • ASVCP - Guidelines for Glucometers in Vet Med • AAHA – Guidelines for Managing Diabetes Mellitus in Dogs and Cats • AAHA – Algorithm – Managing Hypoglycemia Summary Vet Articles and Handouts • AAHA – Monitoring Blood Glucose in Diabetics • Feldman &Nelson – Algorithm – Interpreting Glucose Curves Client Handouts • Diabetes Mellitus in Dogs • Diabetes Mellitus in Cats • • FreeStyle Libre • Home Glucose Testing, Ear Prick, Lip Prick • Hypoglycemia Acknowledgements • Richard Nelson. Small Animal Clinical Diagnosis by Laboratory Methods, 5th Edition. Ch 8 – Endocrine, Metabolic and Lipid Disorders. Eds. Michael Willard, Harold Tvedten. • Teleah Grand, DVM. Animal Care Center at Stonebridge, McKinney TX. Photo of dog with reaction to FreeStyle Libre adhesive. • Greg Matt, DVM. Beechnut Animal Hospital, Houston TX. FreeStyle Libre CGMD videos. Acknowledgements • Ward Animal Hospital. Case – Smut – using FRA. • Southwood Drive Animal Clinic. Dr, Shawn Penn, Dr. Doug Ashburn – Case - Willie – Diabetic Dysregulation. Acknowledgements

• Eastex Vet Clinic. Dr. Jimmy Weatherly - Case – Dot with Addison’s Disease. J Catharine Scott-Moncrief. Canine & Feline , 4th Edition. Ch 12 – Canine Hypoadrenocorticism. Lathan & Thompson. Management of hypoadrenocorticism (Addison’s Disease) in dogs. Vet Med Res & Rpts. 2018:9 1–10.