SAM: Exam 3 - Endocrine

Diabetes Mellitus Pathophysiology

• Types

  • Type 1: dogs, absolute insulin deficiency, requires insulin

    • B cell destruction / loss → immune system

  • Transient (dogs): diestrus, glucocorticoids(depo/cats), pancreatitis (may be reversible)

  • Type 2: cats, relative insulin deficiency, insulin resistance 

    • Might need exogenous insulin

• Classic Triad: 7-9y older animals

  • PU/PD: osmotic diuresis, renal glucose threshold 180–220 mg/dL

    • proximal tubule → glucose 

  • Polyphagia: insulin needed for satiety → energy use 

  • Weight loss: starvation in the face of plenty

Canine Diabetes Mellitus

• Type 1

• Et: IM, genetic, chronic pancreatitis, obesity, Cushing’s, diestrus, steroids/progestins

• Sig: older, female, Keeshond, Terriers, Mini Schnauzers, Poodles, Beagles

• Cs: PU/PD, polyphagia, weight loss, cataracts, hepatomegaly, poor healing, recurrent infections

• CBC: ↑ Glucose, ↑ Cholesterol and triglycerides, ↑ Liver enzymes (ALP(higher) and ALT)

  • UA: Glucosuria, +/- Ketonuria, +/- Pyuria, bacteriuria, hematuria

• Dt: fasting hyperglycemia(blood) + glucosuria(urine)

  • Hyperglycemia only = postprandial(after meal), stress

  • Glucosuria only = renal tubular dz, artifact

• Tx: ↑ fiber, complex carb ↓ fat diet, exercise, Vetsulin, NPH

  • Minimize CS, avoid hypoglycemia

• Most important aspect of treatment: CLIENT Ed!!

Regular Insulin

• Short acting → Hospital setting only 

• Humulin R: DKA

  • IV, IM

• Duration: 1-4 hours 

Using Insulin

• Syringe: U40

• Storage: refrigerate, lasts 4m, roll dont shake (except Vetsulin)

• Injection Sites: Rotate between lateral thorax and abdomen

  • Not scruff, CT makes absorption variable

• starting dose → Vetsulin or NPH: 0.25 - 0.5 IU/kg SQ q 12h

  • Degludec U100 or Glargine U300: 0.6 IU/kg SQ q 24h 

  • Cats: Glargine (lantus) :1U 4kg q 12h

  • Cats: ProZinc : 1U q 12h 

• Have owner log into a book daily → better for management/rechecks

• Changing dosage:

  • Dosage increase by 25%

  • Dosage decrease by 50%

Diabetes Mellitus Therapy

• Short-acting: Regular insulin

  • Use: emergency

• Intermediate-acting: Vetsulin (U-40), NPH(U-100, pen)

  • Use: dogs, first choice, BID, Shake vetsulin

    • Vetsulin: ~ 14h , NPH: 6-10h

• Long-acting: Glargine u-100, Detemir u-100 (levemir), PZI(pro zinc) u-40 

  • Use: Cats, q 12hrs - 1-2U BID total dose

    • Glargine not peakless in cats

• Ultra-long acting: Degludec u-100 (Tresiba), Glargine U-300 

  • Use: dogs, q 24hrs

• SGLT2 inhibitors: Bexacat®, Senvelgo®

  • Use: Never give to sick cats, insulin-treated cats, renal dz

  • Risk: DKA

Monitoring Diabetes Mellitus Patients

• 1st Recheck: 7 days after starting insulin

  • Target BG: 80-200 (dog), 80-300 (cats)

• Watch: Cs + weight (#1), serial glucose curve, log book

• When: 2h curve q24h, full PE in 1 week

  • Don't spot check(only hypoglycemia) or assess before 1w → DO NOT increase dose @ spot check

  • Check 5-7d after dose change

• Tools: Clinical Signs are best

  • Glucose Curve: goal difference form start to nadir: 80–150 mg/dL

    • Nadir: lowest glucose / peak

    • Differential: >100 mg/dl = insulin working

    • ↑ Nadir = underdose

    • ↓ Nadir = overdose on that day

      • Somogyi effect = overdose rebound hyperglycemia & resistance

      • Decrease dose by 50% in 1w recheck

  • INADEQUATE CONTROL = recheck curve

    • Wrong duration = wrong insulin type

  

• Fructosamine: Glycated proteins: albumin → checks the past 2w glucose maintenance — Not effected by stress!

  • Confirm adequate Control

  • Every 2-4m initially, every 4-6m w/no CS!

• Flash monitors: FreeStyle Libre

• Urine glucose strips: supportive only → not a stand alone test

  • Glucosuria: poor control

  • Never glucosuria: over dosed

Feline Diabetes Mellitus

• Type 2 - B cell exhaustion (not dead)

• Et: obesity, insulin resistance, chronic pancreatitis, amyloidosis (amylin accumulation - antagonizes insulin)

• Sig: 9-12y, neutered males, obesity

• Cs: PU/PD, polyphagia, weight loss, peripheral neuropathy, plantigrade stance, ± hypokalemia 

• Dt: hyperglycemia + glucosuria (same as dogs)

• Tx: SGLT2 inhibitors, Glargine insulin, ProZinc,

  • ↑ protien ↓ carb diet “catkins” → canned food if no rx diet  : change slowly

    • Resolve signs, Prevent hypoglycemia, GOAL: Remission, treat obesity

    • Goals: Nadir 80-150, Glucose differential >150

  • Recheck 5-7 days after ANY dose change

    • increase dose by 0.5-1U at a time

SGLT2 inhibitor

• “healthy cats”

• Bexacat – Bexaglifozin - Elanco : pill

• Senvelgo − Velaglifozin - BI : liquid

• promotes loss of glucose in urine → improves B cell function

  • Never give to cat that has/is receiving insulin

  • Never give to cat that is ill

  • Any signs on medicine → stop drug

•  Monitoring at 2 d, 1 wk, 2 wk, 1 mo, 3 mo

  • WATCH for DKA: more severe / life threatening 

• Unknown if Remission occurs with SGLT2 inhibitor

Remission of Feline Diabetes Mellitus

• When: occurs in the 1st 3 months w/ in 1 year of Tx

• Cs: Hypoglycemia, excellent control on curve, no glucosuria

  • Euglycemia for 2w w/o insulin

• Suspicious: 

  • 1. Hypoglycemia

    2. Excellent control on curve

    3. No glucosuria

• Dt: Cut insulin dose in ½ and recheck in 1w → w/o glucosuria d/c insulin

  • Recheck glucosuria/furosemide every 3-6m for relapse

Insulin Resistance

• What: normal insulin dose has subnormal response

  • insulin dose >1.5 U/kg BID

  • inconsistent control

• Why: Obesity, Inflam(pancreatitis), Hormone issues, Hyperlipidemia(D)

  • Insulin problems: under/overdosing, Somogyi 

  • Client problems: poor storage, injection errors, improper handling, dosage in syringe

  • Patient problems (true): obesity, infection, Cushing’s, acromegaly(cats), neoplasia, hyperlipidemia (Schnauzers), hyper/hypothyroid

• Dt: CBC, chem, UA + culture, T4 (cats), imaging, specific endocrine testing (ACTH stim, IGF-1 MRI), CPL 

  • Commonly no clinical signs 

• Tx: treat underlying disease, Cabergoline, Low fat diet, Bezafibrate, Fenofibrate

Acromegaly

• Cats > dogs 

• Pituitary adenoma (of somatotrophs)

  • (IGF-1)

• Clinical signs: 

  • – Broad face

    – Widened interdental spaces

    – Respiratory stridor

    – Abdominal organomegally (liver, spleen)

• Dx: #1 Blood IGF-1 level → can be normal 1-2m after insulin

  • Brain MRI → IGF elevated

• Tx: external beam radiation 

Primary and secondary Hyperlipidemia

• commonly hypertriglyceridemia

  • Fasting (>12h) hypertriglyceridemia

• Miniature schnauzer

• Secondary hyperlipidemia

• Dogs

• Protein losing nephropathy

• Pancreatitis, severe obesity

• Tx: Low fat diet, Bezafibrate or Fenofibrate(best)

Diabetic Ketoacidosis

• Et: uncontrolled / undiagnosed DM → ketone production → metabolic acidosis + dehydration

  • Lyte losses: K, P, Mg

• Cs: vomiting, diarrhea, lethargy, acetone breath(sweet), kussmaul resp, dehydration/shock

• Dt: pre-renal azotemia, metabolic acidosis, ketonuria, electrolyte disturbances

  • Ketometer: blood ketones

  • Dipstick: acetoacetate and acetone in urine 

• Tx: Fluids (Norm-R, Plasmalyte, NaCl), K/P/Mg replacement, Regular insulin IM

  • Dehydration corrected:

    • Dogs → 6-12h

    • Cats → 12-24h

  • Supplement phosphorous to avoid hypophosphatemia (<1.0)

    • Provide ½ of K+ as Kpho

  • May need Magnesium supplement (<0.7)

  • Sodium bicarb → Anion gap >30, acidosis

• Treat hypokalemia before insulin (if K <2.5)

Pathophysiology of Hypothyroidism

• Axis: Hypothalamus (TRH) → Pituitary (TSH) → (follicular cells)Thyroid

• Hormones: Thyroxine (T4) > Triiodothyronine (T3) negative feedback

  • Increases metabolic rate.

  • Bound to plasma proteins.

  • Only bio active (T3)

• Types: 

  • Tertiary: hypothalamus, rare.

  • Secondary: pituitary,  rare.

  • Primary: thyroid gland, common

    • Lymphocytic thyroiditis or Idiopathic atrophy.

Hypothyroidism

• Et: primary;  lymphocytic thyroiditis, idiopathic atrophy

• Sig: 7 yrs, Doberman, Golden

• Cs: lethargy, weight gain, exercise intolerance, neuro deficits (Myasthenia Gravis, LARPAR), poor hair bilateral truncal alopecia , dry skin , hypothemia, bradycardia, Myxedema 

• Dt: TT4 (↑ sen, ↓ spec), fT4 (↑ spec), TSH ↑ with low T4, non regen anemia, ALP>ALT , ↑ cholesterol & triglycerides, Anti-Thyroglobulin Ab (not diagnostic)

  • Never ID on TT4 alone → Sick euthyroid can mimic

    • Always investigate non thyroid dz

  • TT3 an fT3 not useful 

  • Sighthounds have lower T4 reference interval 

• Tx: levothyroxine

  • Recheck 1m, 4-6h post-Tx

  • Neuro signs do not resolve with Tx

  • Tx fail try T3 supplemention

Hyperthyroidism

• Thyroglobulin stored in follicles

• Et: benign thyroid hyperplasia/adenoma

• Sig: older cats 12-13y

• Cs: weight loss, polyphagia, PU/PD, vomiting, hyperactivity, unkempt coat, thyroid slip, cardio workup

• Atypical (apathetic form): anorexia, lethargy → concurrent dz

• Dt: TT4 & CS, Thyroid slip, ↑ Hct, ↑ ALT/ALP, ↑ Glucose, ↑ BUN: Creat, proteinuria, dilute urine <1.035 T-99 scan, T3 suppression test

  • ALT or ALP no work up needed if <500

    • Monitor: TT4 q2–3w initally, then q 6-12m

• Tx: Methimazole, Radioactive I-131, Hill’s iodine restricted y/d diet, Sx (neoplasia)

T3 Suppression Test

• Measure T4

• Administer T3

• Measure T4 &T3

• Normal = suppression

• HyperT = fails to suppress

Hypoadrenocorticism (Addison’s)

• Et:  med-giant breeds 2m-16y

  • Primary adrenal: IM, ↓ cortisol + aldosterone

    • typical: mineralocorticoid + glucocorticoid

    • Atypical: only glucocorticoid + normal electrolytes

  • Secondary pituitary(rare):  ↓ cortisol only

  • Iatrogenic: rapid glucocorticoid withdrawal

• Cs: lethargy, vomiting, anorexia, PU/PD, weight loss, shivering, hypoglycemia, non-regen anemia, hypercalcemia

  • Wax and wane CS

  • Hypotension, hypoperfusion, shock → Addison crisis

• Dt: ACTH stim test (#1), hyponatremia + hyperkalemia, lack of stress leukogram, dilute urine, ECG with hyperkalemia signs (Wide QRS, spiked T, no P)

  • Lymphocytosis & eosinophilia

• Tx: 

  • Emerg: fluids!!! (0.9% NaCl), manage hyperkalemia (insulin, Ca gluconate, bicarb), dex(does not react w/ cortisol), hydrocortisone(reacts w/cortisol)

    • ¼ shock dose (15-22 ml/kg) over 20-30 minutes: crisis treatment

      • then 90-120 ml/kg/day for 1-2 days

  • typical: Prednisone + DOCP(percortin) (if lytes are abnormal), fludrocortisone

  • Atypical: glucocorticoids → prednisone only

    • stressful events needs to double dose

• Px: great

Hyperadrenocorticism (Cushing’s)

• Et: 

  • 2ndary PDH: fxnal pituitary tumor, bilateral adrenal hyperplasia → pumping ACTH

    • Adenoma: micro (<3mm) > macro (>10mm)

      • pars distalis – >70% of dogs

  • primary FAT: fxnal adrenal tumor, unilateral shrinkage, 50% malignant → pumping cortisol

  • Iatrogenic: chronic steroids, large dogs

• Cs: PU/PD, polyphagia, pot-belly, alopecia, thin skin, panting, infections, calcification of skin, Thromboembolism, renal DZ

• Dt: LDDST (#1, PDH), ACTH stim test (iatrogenic, HAC or monitoring), Urine cortisol:Cr (rule out only!), Endogenous ACTH (PDH vs FAT)

  • CBC: stress, ↑↑ ALP & cholesterol, UA:1.008-1.025 dilute/proteinuria

    • Ddx: stress, chronic adrenal dz

    • FAT not responsive to ACTH or LDDST

• Tx: monitor at 2w +4w + q 3-6m with biochem, CBC, ACTH stim or cortisol test 

  • PDH: Trilostane, Ketocazole, Mitotane, Sx

  • FAT: Trilostane, Mitotane, Sx

  • Iatrogenic: taper steroids

Cortisol test for cushing’s

• <9.0

  • If clinical signs improving - keep same dose

  • if no clinical improvement - increase to q 12h dosing

• >9.0

  • increase by 20-25%

• <1.5

  • stop trilostane

  • If ill administer corticosteroids

  • Repeat ACTH stim. if CS reappear 

ACTH Testing

• Stimulation

• Use: monitoring, iatrogenic hyperadrenocorticism

  • Not sensitive for FAT

• Accuracy: specific but less sensitive 

• Expense: 1h, expensive

  • Monitoring: 2-4h after pill, recheck 4w after dose changes

• Endogenous

  • Use:

    • PDH: normal to high

    • FAT: low

  • Expense: special handling, must be done ASAP

Dex Stimulation Test

• Low Dose LDDST

  • Use: FAT Cushing’s 

    • Cannot diagnose iatrogenic hyperadrenocorticism

  • Normal: will suppress at 8 hours

  • Cushing’s: will not suppress at 8h

    • PDH: suppress and escape

• Accuracy: sensitive but less specific

• Expense: 8h, extra blood draw, cheaper 

• High Dose HDDST

  • Use: PDH, FAT cushings localization 

    • FAT will never suppress 

      • suppressed @ 4 & 8h = PDH 

        • no suppression = 50/50 chance

    • Expense: 4-8h

Calcium Disorders

• Hormone players: Parathyroid hormone (PTH), Vitamin D (calcitriol) Organs: PT gland, kidney, bone, intestine

  • PTH: stimulated by low Ca, or high P

  • Calcitriol: increases Calcium and Phosphorous in blood

• Hypercalcemia 

  • Et: Hyperparathyroidism, Addison’s, Renal dz, Vitamin D toxicity, Idiopathic, Osteolysis, Neoplasia, Spurious, Granulomatous dz

    • “HARD IONS G”

  • Cs: PU/PD, weakness, vomiting, diarrhea, shivering, kidney tubule injury

    • soft tissue mineralization if Ca × P product = >70

    •  PTHrP test : Humoral hypercalcemia of malignancy

  • Dt: ↑ ionized Ca + PTH, low P

  • Tx: underlying dz, fluids!, furosemide, bisphospates, steriods, Sx

• Hypocalcemia:

  • Et: Hypoparathyroidism, eclampsia, pancreatitis, renal dz, Hypomagnesemia

  • Cs: tremors, seizures, muscle fasciculations, eclampsia, Facial pruritis, stiff gate

  • Tx: 

    • Emerg: 10% Ca gluconate IV

    • Long-term: calcitriol PO

Primary Hyperparathyroidism

• Et: hypercalcemia

• Sig: older dogs 4-17y, parathyroid adenoma → benign fnx

• Cs: PU/PD, weakness, Incontinence, vomiting, diarrhea, shivering, Lower UTI signs→ stones, dilute urine(1.004-1.037)

  • soft tissue mineralization if Ca × P product >70 

• Dt: ↑ ionized Ca + PTH, low P, PTHrP is negative

• Tx: parathyroidectomy, RF ablation, ethanol ablation

  • Post-tx: risk of hypocalcemia w/in 5 days → calcitriol + Ca

Pheochromocytoma

• Medulla = ¼ of adrenal gland

  • Malignancy of chromaffin cells

  • local invasion

  • metastasis

• Et: adrenal medulla tumor, excess catecholamines

  • Epinephrine, norepinephrine

• Rare, 12y, dogs>cats

• Cs: Restlessness / anxiety / pacing, intermittent collapse, hypertension, PU/PD, tachypnea, Epistaxis, blindness

• Dt: CS & PE, imaging, urine normetanephrines

• Tx: adrenalectomy (pre-op phenoxybenzamine →α-adrenergic antagonist)

Insulinoma

• Et: Functional β-cell tumor,  hypoglycemia → Unresponsive to negative feedback

  • hypoglycemic events: increases

    • Glucagon – most important

    • Catecholamines – second line

• Sig: Lg breed dogs, 3-14y

• Cs: seizures, collapse, weakness

• Paired blood insulin & glucose level

  – Only submit if BG <60 mg/dL

• Dt: low BG + inappropriately high insulin, Hypokalemia, Hypophosphatemia

• Imaging low sensitivity

• Tx:

  • Emerg: sugar on gums, IV dextrose, glucagon CRI

  • Long-term: prednisone, diazoxide, octreotide, multiple meals

  • surgery → R or L limb = resectable

    • post op issues: Pancreatitis, Diabetes, Persistent hypoglycemia

Drugs used of Cushing’s Disease (Hyperadrenocorticism)

• Trilostane

  • MOA: Competitive inhibitor of 3β-hydroxysteroid dehydrogenase

  • SE: hyperkalemia, “steroid withdrawal,” transient or permanent hypoA, death

• Mitotane

  • MOA: Adrenocorticolytic, cytotoxic

  • SE: GI upset, Addison’s, lethargy, weakness, collapse

  • Use: send home prednisolone

• Ketoconazole

  • MOA: Inhibits cytochrome P450 enzymes

  • SE: anorexia, vomiting, diarrhea, hepatotoxicity

  • Use: Not effective in ~33%

• L-deprenyl (Selegiline, Anipryl®)

  • MOA: MAO-B inhibitor

  • Use: Not effective, for cognitive dysfunction

Drugs used for Thyroid Disease

• Methimazole

  • MOA: Inhibits iodide incorporation

  • Use: Hyperthyroid

    • PO or transdermal, monitor CBC/biochem/T4 q2–3w

  • SE: GI upset, hepatopathy, bone marrow suppression, rare facial excoriation

• Radioactive Iodine (I¹³¹)

  • Use: Hyperthyroid

    • Definitive treatment, cure with one dose

    • Requires special facilities, isolation (~1w)

  • MOA: destroys only thyroid tissue (β + γ radiation)

• Levothyroxine

  • Use: hypothyroid 

    • Monitor TT4 at 1 mo (peak 4–6h post-dose)

  • MOA: Synthetic T4 replacement

  • Goal: TT4 upper half of RI or slightly above

Drugs used for Hypoadrenocorticism (Addison’s)

• Fludrocortisone

  • MOA: mineralocorticoid + glucocorticoid activity

  • Use: May need prednisone too

    • Monitor lytes weekly → monthly → q3-6m

• DOCP (Desoxycorticosterone pivalate)

  • MOA: Mineralocorticoid only 

    • no glucocorticoid effect

  • Use: Monitor electrolytes @ 2w, then q4–6m

Drugs used for Insulinoma / Hypoglycemia Management

• Diazoxide

  • MOA: K⁺ channel activator

    • Stimulates gluconeogenesis + glycogenolysis

• Octreotide

  • MOA: Somatostatin analogue

• Streptozotocin

  • MOA: Chemo destroys pancreatic β-cells