Exam 4 Flashcards
Hypothalamus and Pituitary Gland
What makes all the releasing hormones?
Where do they go?
-Hypothalamus making all the releasing hormones
-The releasing hormones go then to the Posterior or anterior Pituitary adenohypophysis and Neurohypophysis then,
-Those organs release the TROPHIC hormones then,
-They go to the end organ that makes the actual hormone that produces the effects.
Lecture 1 Disorders of the Hypothalamus and Pituitary Gland
Disorders of the Hypothalamus and Pituitary Gland
What organ makes
-TRH
-CRH
-GnRH
-Somatostatin
-Dopamine
-GHRH
Hypothalamus
What organ makes
-TSH
-FSH
-LH
-ACTH
-MSH
-Growth hormone
-Prolactin
Anterior Pituitary A Flat Pig
-Anterior pituitary
-FSH
-LH
-ACTH
-TSH
-Prolactin
-I makes you pig
-Growth hormone
-MSH
What organ makes
-Oxytocin
-ADH
Posterior Pituitary
What two hormones does the pancreas make?
-Insulin
-Glucagon
What hormones does the Adrenal medulla make?
-Norepinephrine
-Epinephrine
What hormones does the kidney make?
-Renin
-1, 25-Dihydroxycholecalciferol
Where is T3 and T4 made?
Thyroid gland
Where is PTH made?
-Parathyroid
What hormones are produced by the adrenal cortex?
-Cortisol
-Aldosterone
-Adrenal androgens
What two organs produce Estradiol and Progesterone?
- Ovaries
- Corpus luteum
Where is Testosterone produced?
-Testes
What hormones does the placenta produce?
-HCG
-HPL
-Estriol
-Progesterone
Acromegaly and Pituitary Gland
Pituitary Hypothalamus Axis: How does the thermostat gets disregulated?
What is the associated problem hormone at the level of the hypothalamus and Pituitary Gland, and at the level of the target tissues/organs? What is the resulting effect?
Which is the inhibitory hormone produced by the hypothalamus?
What is the physiological and pathophysiological process?
-Growth hormone
-Too much made
Hypothalamus produces
-GHRH (growth hormone releasing hormone): stimulatory
-Somatostatin: inhibitory acts at the Pituitary to decrease production of Growth hormone when too much is circulating
-Growth hormone acts at multiple tissues, most importantly the liver
-Liver produces INSULIN-LIKE GROWTH FACTOR.
-SOMATOMEDINS = insulin-like growth factors that produce the pathologic effects at target tissues.
Diabetes Insipidus
What are things that cause PU/PD?
-Diabetes mellitus
-Chronic Renal failure
-Diabetes Insipidus
-Psychogenic polydipsia: behavioral drinking too much
-Pyometria: E. coli antagonizes ADH at the receptor
-Hypercalcemia: antagonizes ADH at the receptor
-Hypokalemia: antagonizes ADH at the receptor
-Hyponatremia
-Hyperthyroidism
-Hyperadrenocorticism
**Any kidney disease, any liver disease, many endocrine diseases, DIABETES INSIPIDUS **
What drugs can cause PU/PD?
-Glucocorticoids: inhibit ADH secretion by hypothalamus/Pituitary. Inhibit action of ADH on kidney
-Barbiturates: PHENOBARBITOL inhibits action of ADH on kidney
-Diuretics
-Thyroxine (T4)
-Salt supplementation
What are the Anabolic Effects of Growth hormone? GH
What are the indirect and direct anabolic effects?
What somatomendins are involved in promoting growth?
- Indirect: increased muscle mass, increased linear bone growth, increased organ size and function
-Promote growth
-Mediated by somatomedins (IGF)
-IGF 1 = somatomedin C = body building, promote growth of organs and muscle, increased in organ size and function
-IG 2 = Somatomedin A = liver makes more protein
- Direct anabolic effects
-Not mediated by somatomedins
-Increased Protein Synthesis isn the liver
What are the Catabolic effects of Growth hormone?
Catabolic: breaking down to get more nutrients available for the body to build up/growth
Growth hormone is the enemy of insulin, directly causing insulin resistance, makes it harder for sugar to get into the cells because it wants it to stay in the blood stream to be used up by growing muscle to bulk up.
-Increased Gluconeogenesis and output by liver
-Decreased glucose uptake in the muscle
-Insulin resistance
-Increased lipolysis in adipose tissue
-Increased release of FFAs into blood (IR)
-Increased Ketone formation
Acromegaly - Etiology
Which patients species are more represented?
Feline = most common
-Benign tumor in Pituitary gland
-Functional adenoma of Somatotroph cells in Pars Distilis of Pituitary gland
-Chronic, excessive secretion of GH
Canine
-Prolonged exposure to progestogens
-Exogenous progestins
-Rarely: GH-producing pituitary or mammary tumor
Acromegaly - Signalment and clinical signs
-Male
-Mixed-breed cats
->8yo
-Anabolic effects of GH
-Catabolic effects go GH
-Neurologic effects of pituitary tumor: rarely
C/S
Anabolic
-Increased in body size
-Enlargement of abdomen
-Weight gain
-Protrusion of mandible: lower jaw sticks out = underbite
-Organomegaly (heart, liver, kidney, adrenal gland)
-HCM in cats
-Soft tissue thickening in pharyngeal region - respiratory distress
-Increased interdental space
Catabolic C/S
-Insulin resistance
-Diabetes mellitus
-PU/PD/Polyphagia
-Weight loss +/-, may see weight gain despite unregulated diabetes mellitus
-Insulin resistance can be marked, requiring 2-3units/kg
Neurologic C/S
-Circling, seizures, behavior changes, somnolence…
What are these C/S?
Acromegaly
-underbite
-increased head/body size
What are some laboratory findings of Acromegaly?
-Hyperglycemia
-Glycosuria
-Elevated cholesterol
-Mildly elevated ALT, ALP
-Elevated serum phosphate (without azotemia)
-Elevated serum protein
-Erythrocytosis
How is Acromegaly diagnose? Dx, Tx, and Px
Ddx list
-Based on clinical signs and history
-NO reliable GH test in Vetmed
-Identification of conformational alterations typical of acromegaly and a stable or increasing body weight in a cat with insulin resistant Diabetes Mellitus
-Elevated IGF 1 (somatomedin C)
-CT or MRI with pituitary tumor findings
Ddx
-Insulin resistent diabetes mellitus
-Acromegaly
-Hyperadrenocorticism
-Obesity related
Tx
-Eliminate tumor
-Radiotherapy
-Surgery
-Cryotherapy
-Management of Insulin resistance large doses >20 units/day
-Management of HCM if present
No medical protocol currently available
-Somatostatin analogs: Octreotide & Pasireotide
Px
-Survival 4-60mts
-Long-term: poor
Pituitary Dwarfism who is the breed most overly represented?
-German shepherd
-Autosomal recessive
-Pituitary cysts
C/S
-Lack of growth, endocrine alopecia
-Skin hyperpigmentation
-Body vs. legs disproportions
Tx
-Administration of growth hormone
Px
-Variable
Diabetes Insipidus
What are some causes of PU/PD?
- Renal disease
- Hepatic disease
- Endocrine disease
- Miscellaneous: elites (low K, low Na, high Ca), drugs, endotoxins
- Psychogenic polydipsia “Crazy lab syndrome”
Describe the Renal Medullary Solute Washout
-Loss of solutes (Na, Urea) in medulla results in loss of hypertonicity and impaired ability of the kidney to concentrate urine
-Due to conditions causing PU/PD
-Resolves once the underlying condition is treated
-Can interfere with water depravation test. It may take months for animal to re-establish normal osmolality
Central Diabetes Insipidus
-Defective synthesis or secretion of Arginine Vasopressin (AVP) AKA ADH by hypothalamus/post pituitary
Causes
-Insufficient secretion of ADH by hypothalamus/Pituitary (anterior pituitary) can be complete or partial
-Idiopathic: young
-Head trauma
-Neoplasia
-Malformations/cysts
-Misc: inflammation, parasitic migration
Signalment
-No breed, sex or age predilection
-Primary puppies, kittens, young adults
-Secondary - varies depending on underlying cause
C/S
-PU/PD
-Occasionally incontinence
-Hypothalamus/pituitary tumor
-Head trauma
-Hydration WNL as long as animal has access to water and is drinking
Dx
-Rulo out of acquired secondary
-PE
-Minimum database: CBC, chemistry panel, urinalysis with culture
-T4 (cats)
-Adrenal function test (ACTH stim, LDDST)
Nephrogenic Diabetes Insipidus
Hypercalcemia, Hypokalemia
-Defective Responsiveness of kidney to AVP/ADH in distal tubules
Causes
-Impaired responsiveness of the kidney to ADH
-Primary idiopathic
-Primary familial: HUSKIES
-Secondary acquired
Where does ADH acts, when is it release, and what is the effect?
-Acts on distal convoluted tubules and collecting ducts
-ADH (vasopressin) is released when plasma osmolality is increased or when extracellular fluid volume is decreased
-Results in decreased urine volume
-Promotes FREE water resorption
-It also constricts arterioles which increases peripheral vascular resistance and hence blood pressure
Diabetes Insipidus Tests
What is the normal urine specific gravity? what does an abnormal USG indicate?
When and why to perform a specific DI test?
- Response to Desmopressin: preferred test
-Evaluate patient’s response to trial therapy with desmopressin acetate (DDAVP)
-Oral tablets, nasal drops in conjunctiva
-Every 12 hours for 7 days
Central DI
-Owners will notice a definite decrease in PU/PD and increase in USG >1.030
Nephrogenic DI
-Minimal to no response will be noted in PU/PD and USG
Psychogenic DI
-Exhibits mild decrease in PU/PD
Hyperadrenocorticism: mimics partial DI - moderate response to DDAVP: must rule out prior to resting to avoid misdiagnosing
- Modified Water Deprivation Test: labor intense
- Random plasma osmolality: not very specific, overlaps
- Water depravation test
First Phase
A) Gradual water depravation by owner 3-5 days prior (10% decrease <30ml/lb/d)
B) In hospital: initially empty bladder, weigh, measure USG, BUN, etc. Repeat every 2-4 hours
Ends when USG >1.030 or loses 5% of body weight
Nephrogenic DI
-Primary: Can not concentrate urine in the face of 3-5% dehydration
-Secondary: rule these out prior to water deprivation test
Second Phase
Response to DDAVP (desmopressin)
-If you hold water and they concentrate urine, then it is psychogenic/behavioral. Central wouldn’t be able to concentrate
-Differentiates between central vs. Nephrogenic
-Central DI: will respond to ADH/AVP by concentration of urine
-Nephrogenic: will not respond to ADH/AVP
Treatment for Central DI
-No treatment: outdoor cat/dog if access to water
-Complete: DDAVP oral or nasal drops in conjunctiva
-Partial: DDAVP
-Thiazide diuretics: mildly effective
-Low Na diet
Treatment of Nephrogenic DI (Primary)
-Thiazine diuretics
-Low Na diet
-No treatment
DI - Prognosis
Central on underlying cause: excellent
Central due to trauma: good
Central due to secondary tumors: usually guarded to poor
Nephrogenic: guarded to poor
Psychogenic: good
Lecture 2
- Cushing’s: chronic disease, lifelong, frustrating disease
- Pheochromocytoma
Regulation of Cortisol Secretion by hypothalamus Pituitary Axis
-Hypothalamus secretes Corticoid Releasing Hormone,
-Pituitary Stimulated by it releases Adrenocortotropic Hormone
-ACTH stimulates adrenal glands CORTEX to produce Cortisol and other hormones
GFR
Zona glomerulosa: Mineralcorticoids
Zona Fasciculata: Glucocorticoids = Cortisol
Zona Reticularis: Androgen precursors
-Dehydroepiandrosterone (DHEA)
-DHEA Sulfate
-Androstendione
Medulla
-Catecholamines
What are some factors that influence ACTH Secretion and Inhibition?
What are some actions of Cortisol/Glucocorticoids?
Kidney
CV system
Hemopoetic System
Secretion
-Stress: hypoglycemia
-Infections/fever
-Low cortisol levels
Inhibition
-High cortisol levels
-Exogenous steroids
-Dopamine: inhibits
The Effects/Actions
-Increase glucose concentrations in blood
-Increase gluconeogenesis
-Build up of glycogen for epinephrine and glucagon to act on
-Enhances glucagon release
Causes insulin resistance
-Enhances lipolysis and ketogenesis
-Increases appetite and caloric intake
Cortisol mobilizes fats and glucose in the body so that we can do all the functions
Insulin antagonist
Effect on Kidney
-Increase GFR
-Decrease ADH and its action
-Increase free water clearance
Effect on CV system
-Maintains cardiac output
-Maintains Blood pressure
-Maintains blood volume
Patients with low cortisol levels are hypovolemic with low BP
Hemopoetic System
-Increase RBC formation
-WBCs = Neutrophilia, Lymphopenia, Eosinopenia, Monocytosis Stress leukogram
-Decrease lymphocytes
Cushing’s Disease - Hyperadrenocorticism
what are the two types?
Disease syndrome resulting from abnormally high levels of cortisol circulating in the body
- Pituitary dependent = Central
-Accounts for 85% of HAC
-Functional ACTH producing adenoma. Hyperplastic or reacting too much
-Endogenous ACTH levels elevated
C/S
-Bilateral adrenal hyperplasia
-Increased cortisol
Excessive CRH from Hypothalamus
-Rare
-Hypothalamic or CNS disease
C/S
-Bilateral adrenal hyperplasia
-Increased ACTH
-Elevated cortisol
- Adrenocortical dependent or iatrogenic
-15-20% of spontaneous HAC
-50% adenomas, 50% adenocarcinomas
-Excess cortisol secretion = suppression of CRH and ACTH
C/S
-Decreased ACTH
-Unilateral adrenal tumor
-One adrenal atrophic
-Elevated cortisol
Iatrogenic
-Excessive administration of glucocorticoids
-Exogenous suppress CRH and ACTH
-Bilateral adrenal gland atrophy
C/S
-Decreased cortisol
-Everything is suppressed including hypothalamus
Cushing’s Clinical Presentation
-PU/PD
-Polyphagia
-Panting
-Abdominal enlargement “pendulous abdomen”
-Muscle weakness
-Lethargy
No muscle tone in the abdomen, glycogen in liver production excessive = hepatomegaly likely
-Dermatitis
-Pyoderma
-Adult onset demodecosis
-Endocrine alopecia
-Hyperpigmentation
-Hyperkeratosis
-Calcinosis cutis: dystrophic calcification, Ca normal in the blood but accumulation in the skin.
-Prone to calcium oxalate stones in bladder
Pituitary tumor C/S
-Inappetence
-Wandering, pacing, ataxia, head pressing, circling
-If the hypothalamus is compressed then ANS dysfunction can occur
Potential Complications
-Systemic hypertension
-Urinary tract infection
-Pyelonephritis
Need urine culture
-Proteinuria
-Calcium calculi
-Dystrophic calcification
-Pulmonary thromboembolic disease (PTE)
-CHF
-Pancreatitis
-Diabetes mellitus
HAC in Cats
-Uncommon but similar signs as dogs
Causes
-PDH 80%
-AT 20% (adrenal tumor, adenoma or carcinoma)
-Iatrogenic: rare
C/S
Thin, fragile skin, and diabetes
-Hepatomegaly
-Skin infections
-Pot belly, muscle wasting
Diagnosis Cushing’s Dogs & Cats
Dogs
-Elevated ALP (aka SAP) but not specific
-Hypercholesterolemia (75% of cases)
-Hyperglycemia
Cats & Dogs
-Stress leukogram
-Mildly elevated PCV
Hyposthenuria
-Proteinuria
-UTI
-Glucosuria if concurrent diabetes mellitus
Cats
-Consistent with insulin resistant diabetes mellitus
-Mildly elevates ALT
-Elevated cholesterol
-Hyperglycemia
Radiographs
-Hepatomegaly likely
-Adrenal mass maybe identified due to calcification, but not indicative of malignancy for sure
-PTE evidence and metastases possible
**Bilateral normal or enlarged adrenal glands in dogs with clinical signs is supportive of PDH
-Single adrenal mass is consistent with Adrenal tumor
Ultrasound
-Normal US does not rule out Cushing’s
-Adrenal tumor maybe visible
MRI and CT
-If neurologic impairment present
-Used for planning and assessment of radiation therapy (stereotactic radio ablation surgery)
-Can be used to assess the symmetry of the adrenal glands
Testing for Cushing’s
- Diagnostic
- Differentiation
- Diagnostic tests
a. Urine cortisol-creatinine ratio (UCC)
b. Low-dose dexamethasone suppression (LDDS)
c. ACTH stimulation test: adrenal cortex = GFR zones, everything but catecholamines
- Differentiation PDH vs. AT
a. Abdominal ultrasound
b. High-dose dexamethasone suppression (HDDS)
c. Endogenous ACTH level
Sensitivity vs. Specificity
SpIN= Rule the condition IN = If the test if positive
SnOUT = Rule the condition OUT = If the test is negative
Diagnostic Test
Urine cortisol-creatinine Ration (UCCR)
-Sensitive
-Not specific
-So, if the test is negative = rule out Cushing’s
Best used for a dog in which you do NOT suspect cortisol dependent
Diagnostic Test
Low Dexamethasone Dose
The screening test of choice
-High sensitivity
-Moderate specificity
-So, if test is negative, the patient does NOT have the disease.
Dexamethasone
-Suppresses hypothalamus and pituitary
-If they are not suppressed, then they have Cushing’s
-If suppressed at 4 hours, but rebound at 8 hours Pituitary dependent
Results
-Non-adrenal illness will decrease specificity
-Long time: takes 8 hours
-Moderate cost
-Only assesses CORTISOL
Diagnostic Test
ACTH Stimulation Test
Pros
-Quick, 1 hour test
-Higher specificity (if positive then rule in the disease) than LDDS test
-Gives the baseline values pre-treatment
Cons
-Lower sensitivity than LDDS (can’t rule it out)
-Concurrent illness will decrease specificity
-Stress can cause a false positive/high result
-Cost of the rest: not much
The majority of dogs with classic Cushing’s disease screened with an ACTH response or LDDST will have at least one positive test
Differentiating Tests
Abdominal ultrasound
-Bilateral adrenomegaly = Pituitary dependent hyperadrenocorticism
-Adrenal mass with small contralateral adrenal gland = Adrenal tumor
Differentiation Test
High Dexamethosone Dose (HDDS)
-Higher dose of dexamethasone will cause PDH cases to suppress at 4 hours and rebound by 8 hours
-Adrenal tumor never responds, it would stay high and not suppressed
Differentiation Test
Endogenous ACTH level
-PDH = high endogenous ACTH
-AT = low endogenous ACTH
Technically difficult
-Spin and separate plasma immediately
-Add proteinase inhibitor aprotinin
-Challenging to ship: freeze, dry ice, overnight.
What is an atypical Cushing’s Disease?
-Routine screening tests LDDS and ACTH stimulation normal
-ONe or more sex steroids are elevated in an ACTH stimulation
-HS, PE, CBC, Biochemical, chemistry and UA results, and imaging consistent with hyperadrenocorticism
Adrenal Panel
-3Beta hydroxysteroid dehydrogenase enzyme
-Trilostane = inhibitor
-Trilostane and mitotane are preferred treatment and efficacious
When do we treat Cushing’s ?
-Signs affecting quality of life of dog and/or owner
-Signs concerning to veterinarian (complications)
-NOT just because ALP is elevated
Cushing’s Treatment
Trilostane
-Approved and most widely used
-Blocks production of aldosterone and cortisol
-Competitive inhibitor of 3Beta hydroxysteroid dehydrogenase enzyme system
Side Effects
-Excessive ACTH production continues
-Adrenal can increase in size during treatment
-Transient hypocorticism
Dose
Twice daily, lower dosing is safer and effective
0.5-1.0 mg/kg q12hr
-ACTH stim in 10-14 days following initiation and again in 2 weeks
-Then ACTH stim every 3-6 mts
Post cortisol 4 hours after Trilostane dose. Cortisol should be 2-5ug/dL
-If cortisol too low, discontinue or lower dose and re-test in 1-2 weeks
Cushing’s treatment
o,p’ -DDD (Mitotane, Lysodren)
-Potent adrenocorticolytic drug
-Induces necrosis of the zona fasciculata and reticular
Adrenalectomy & Radiation
Client Education
Adrenalectomy
-Treatment of choice for adrenal tumor unless metastases present or patient unstable
-MRI, contrast radiographs, prior to surgery
-Invasion of caudal vena cava evaluation
-Increased risk for PTE during anesthesia, heparin
Radiation
-Stereotactic radiation treatment of choice for pituitary macro tumor disease
-about 33% complete response and several years survival
What are some complications of Cushing’s?
-Infections
-Immune system suppression
-Muscle weakness
-Peripheral neuropathy
-Systemic hypertension
-Proteinuria: >0.5 treat
-Calcium Oxalate: increased calciuresis from excessive glucocorticoid production. Urinary bladder, renal, biliary/GB
-Dystrophic Calcification: Calcinosis cutis
-Diabetes mellitus: elevated ALP and diabetic patient NOT enough to test for Cushing’s
-Pancreatitis: no conclusive data
-Pro-coagulant: thromboembolism 10x more at risk
-Biliary Mucocele: 29 x more prevalent. Cholestasus, GB dysmotility
-CNS signs from pituitary tumor: uncommon
What are some complications of Cushing’s?
What are some complications of Cushing’s?
What are some complications of Cushing’s?
What are some complications of Cushing’s?
What are some of the Supplements used to treat Cushing’s complications/symptoms?
-Melatonin
-HMR ligans
-SDG ligans (flaxseed)
Supraglan
The watch and wait
Monitor
-Blood pressure: q 3-6 mts
-Urine culture: q 6mts
-Urine protein creatinine ratio: q 6mts. Culture
-Minimum database
-Q3-6 mts doctor exams
Pheochromocytoma
Tumor in medulla of adrenal gland = synthesis of catecholamines
-Usually seen in older animals
-Insulin antagonist also
C/S
Intermittent weakness and collapse, panting or tachypnea, anxious behavior, PU/PD, hypertension, weight loss, lethargy, INAPPETENCE, vomiting, diarrhea, abdominal distention
-Autonomic and CNS
-PSNS: cholinergic receptors
-SNS: adrenergic receptors = Alpha and Beta
-Increased HR, CO, BP
-Redistribution of Blood from skin, kidneys and GI towards skeletal muscle
-Increased ventilation with dilation of airways
-Decreased GI motility and secretions
-Increased blood glucose
Dx
-Often post-mortem
-Ante-mortem = signs, abdominal ultrasound, adrenal ultrasound.
-Urinary catecholamines concentrations
Tx
-Surgical resection may be possible
-Management of hypertension and arrhythmias during and before surgery
Px
-Varies
-Survival 2 mts to 3 years
Lecture 3
Who is the Great Impostor?
Describe RAAS regulation
Addison’s disease
RAAS
Stimulation of Renin Release
-Decreased extracellular fluid volume
-Decreased renal perfusion
-Hemorrhage
-Na depletion
-Increase in Serum K+ depolarizes adrenal cells to open up Ca++ channels
-Intracellular Ca++ increases to stimulate aldosterone secretions
Pathogenesis
Primary or Idiopathic Hypoadrenocorticism - Addison’s Disease
-Deficiency of both mineralocorticoid and glucocorticoid
-Immune mediated or
-Infiltrative disease or vascular thrombosis/hemorrhage
-Drugs (Mitotane, Trilostane)
ACTH is ELEVATED
Electrolytes may be normal
Pathogenesis
Secondary Hypoadrenocorticism
-Only Glucocorticoid deficiency
-Destructive pituitary lesion or
-Chronic exogenous glucocorticoid administration
-Both result in
Decreased ACTH
-Adrenocortical atrophy reversible if exogenous steroid discontinued
Addison’s disease
Signalment
-Young to middle age
Breeds with Inherited autosomal recessive suspected
-Standard poodle, Portugese, Water dog, Nova Scotia, Duck trolling Retereiver.
Others (unknown mode of inheritance)
-Great dane, Rottweiler, Berded Collie, West, Soft coated Wheaten, Leonberger
Cats
-No sex predisposition
-Young to middle aged ~6 yo average
Hypoadrenocorticism C/S and History
History
Slow mimic GI and renal disease
-Can be waxing and waning
-Slowly progressive
-Can vary from mild to severe
-Severe signs - Addisonian Crisis
High K+ cardiac arrhythmias, low Na, Impostor when electrolytes are normal
Electrolytes normal but lack cortisol, or maybe potassium is low. GI signs, diarrhea in times of stress. Do an ACTH test on them
PE
-Lethargy - collapse in severe cases
-Weakness
-Dehydration
-Hypovolemia
-Bradycardia
-Weak pulses
-Abdominal pain
Hypoadrenocorticism Diagnosis
Lab
-CBC
-Mild Anemia - non-regenerative, combined with lack of stress leukogram
-Neutrophilia
-Leukocytosis
-Eosinophilia - most common finding
Lack of stress leukogram
-Azotemia
-Increased BUN/Creatinine ration
-Pre-renal = expect high USG maybe Isothenuria
-Low Na in serum
-Elevated K+ in serum
-Low Serum Chloride
-Low Na:K ratio (<27:1)
Chemistry
-Hypoglycemia
-Hypercalcemia
-Mild low serum Albumin
-Mild low serum cholesterol
Metabolic acidosis
Chest Radiographs
-Microcardia due to hypovolemia
-Megaesophagus: focal
Abdominal Ultrasound
-Small adrenal glands
ECG - Hyperkalemia changes
-T wave gets taller
-R wave decreases in amplitude
-QRS widens
-P wave flattens then disappears
ACTH stimulation
-Baseline Cortisol (<2 ug/dl) supportive and diagnostic when ACTH is high = primary
-Baseline Cortisol (<2 ug/dl) supportive and diagnostic when ACTH is low = secondary
Treatment Hypoadrenocorticism
Acute Crisis
-0.9% Saline (NaCl): 40-80 ml/kg/24 hr
-Dexamethasone or
-Dexamethasone Na Phosphate: IV initially q 12 hr until Prednisone
-Bicarbonate: if acidic
-50% Dextrose IV if hypoglycemia
-Insulin/Glucose IV to lower extremely elevated K+
Maintenance
-Desoxycorticosterone Pivalate (DOCP)
-Injection every 25-29 days
-Monitor electrolytes to determine ideal interval
-Mineralcorticoid: FLUDROCORTISONE ACETATE, adjust dose based on electrolytes
-Glucocorticoid:
-Prednisone or Prednisolone
-“Physiological dose”
-Amount needs to increase during times of stress/illness or prior to surgery
Px
-Excellent
-Good with owner compliance
-Life-long therapy
-Follow-ups
-Can have normal life expectancy
Primary Hyperaldoesteronism - Feline
AKA “Conn Syndrome”
-Decreased Renin
-Autonomous secretion of aldosterone
-Neoplasia of Zona glomerulosa (adenoma or adenocarcinoma)
-Idiopathic hyperplasia pf zona glomerulosa
Secondary Hyperaldoesteronism - Feline
-Increased renin due to decreased effective blood volume
-Due to heart failure, kidney disease, liver disease, severe hypoproteinemia
Hyperaldosteronism
C/S
Hypokalemia, Hypernatremia
-Profound muscle weakness
-“Ventral cervical flexion”
-Difficulty walking
-Muscle damage
-Myoglobinuria (renal toxin)
-Elevated CK
-Cardiac arrhythmias
-Systemic hypertension
-Retinal detachment/bleeding
-Cardiac dysfunction
-Renal dysfunction
Dx
-C/S
-Adrenal Ultrasound, adrenal mass (unilateral) or hyperplasia (bilateral)
-Elevated Na, Low K+, +/- Azotemia
-Urine aldosterone:Creatinine Ratio
-Serum Aldosterone Concentrations
-Baseline ACTH not always diagnostic
Treatment
-Neoplasia: surgery
-Medical management of low K+, high Na
-Slow IV of KCL in 0.45% Saline
-Spironolactone: K+ sparing diuretic
-K gluconate orally
-Hypertension: Amlodipine
-Hypernatremia: usually mild
Px
-Good for hyperplasia with life-long management
-Variable for neoplasia
Lecture 4 Disorders of Thyroid Gland
Feline Hyperthyroidism
In one study, 15.3% of cats that were nonazotemic at diagnosis of hyperthyroidism became azotemic within 240 days.4 Hyperthyroidism masks azotemia; cachexia causes muscle loss and lowers creatinine levels while increased glomerular filtration rate (GFR) raises cardiac output and lowers BUN, creatinine, and SDMA levels.5
-Multisystemic disease
-Excessive circulating levels of T4 and T3
The most common endocrine disorder in cats
-10% of cats equal or >10 yo get it
T4 is the active form
Causes
-Functional thyroid adenomatous hyperplasia (adenoma) is most common
-Can affect one or both thyroid glands
-1-2% thyroid adenocarcinomas
-Hyperactive thyroid tissue exclusively in the mediastinum is 3-5% of cases
Etiology
-Don’t really know
Risks
-Siamese/Himalayans reduced risk
-Cats eating canned diet more at risk
-Genetic factors
-Cats using cat litter
Signalment
-Cats middle age to older median 13 yo
-Only 5% of cats are <8-10 yo
-Most cats have slow progression of disease, may not notice until advanced unless early screening checks
C/S
-Hypermetabolic signs
-Weight loss
-Increased appetite, polyphasic
-Mild to severe weight loss
-Vomiting, diarrhea, large fecal volume
-Increased fecal fat associated with malabsorption
-Unkept, ragged haircoat, shedding, matting
-Restlessness, frantic or aggressive behavior
-Stress intolerant
-Bad cases hypertrophic cardiomyopathy
Renal
-Mild Azotemia in 30% cases
-Elevated levels of T4
-PU/PD
-Renal damage secondary to hypertension and resultant glomerular sclerosis
Chronic renal failure may be masked by hyperthyroidism
-Recommended reversible anti-thyroid treatment trial if CRF suspected, wait 2-4 weeks and check
-Early effective treatment can prevent progressive renal disease
CV
-Thyrotoxic cardiomyopathy HCM or DCM
-Hyperthyroidism alters hemodynamics leading to volume overload and high CO
-Compensatory mechanism result in dilation and hyperthrophy
-Tachycardia, gallop rhythm, systolic murmur
-Increased R wave
Echocardiography
-LV septal hypertrophy
-LV or LA dilation
-Increased fractional shortening
PE
-Palpate the thyroid glands
-One or both enlarged in 80% of cases
-Enlargement may not always be related to clinical signs, but most cases do become hyperthyroid
Atypical hyperthyroidism C/S
-Affects <5% of cases
-Characterized by depression and weakness
-Weight loss
-Anorexia instead os polyphasic (incessant hunger)
-Ventroflexion of neck
-Most cases have concurrent disease
Hyperthyroidism Differential Diagnosis
-Diabetes mellitus
-Gastrointestinal malabsorption or maldigestion
-Neoplasia (GI lymphosarcoma)
-Chronic kidney disease
-Parasitism
AAFP FHT Groups
- Clinical disease
-Clinical FHT
-Elevated T4
=Consider and recommend Tx - Possible FHT with probable NTD
-Normal T4
=T4 and fT4 assays 2-4 weeks after initial exam
-Evaluate for non-thyroidal disease
-Consider suppression of thyroid scintigraphy - Enlarged thyroid without clinical FTH
-No clinical FHT
-Normal T4
=Monitor and repeat assay in 6 mts - Subclinical FHT
-No over clinical FHT but some PE findings suggest FHT
-Elevated T4
=Repeat T4 in 2 weeks
-If elevated, Tx
-If T4 normal, re-evaluate in 6mts - Clinical FHHT with confirmed NTD
-Elevated T4
-One or more concurrent diseases
=Treat for FHT
-Institute management of NTD - Clinically normal
-No palpable nodule
-Elevated T4
=Confirm T4
-If normal, monitor and repeat T4 in 6 mts
-If elevated, Tx for FHT
Hyperthyroidism Diagnosis
-Nothing specific in CBC and Chemistry
Clinical pathology
-Elevated ALT, SAP, AST
-BUN and Creatinine elevated in 20-40% of cases
-SDMA (symmetric dimethylarginine acid) sensitive early marker for decreasing GFR
-Elevated PCV
-Lymphopenia
-Eosinopenia
-USG <1.035 in 52% of cases
Baseline thyroid hormone testing
-T4 and T3 elevated
-Free T4 elevated (96% of cases)
Radionuclide thyroid scanning
-Technetium m99
-Identify ectopic tissue
Treatment of FHT
- Medication/diet
- Surgery: falling out of favor
- Radioactive iodine treatment
Choice depends on health, age, renal function, concurrent disease type, etc.
Goal of treatment
-Normal range 1-4 ug/dl
-Thyroid level T4 1-2.5 ug/dl if no renal insufficiency
-Creatinine may raise too much, so may need to adjust Tx
CV
-HCM: beta-blockers (propanolol, atenolol) +/- diuretics
-DCM: diuretic, vasodilator (ACE inhibitors), +/- digoxin
Treatment for hyperthyroid state usually reverses signs of HCM but not DCM
Renal
-CFR diet management (omega fatty acids, renal diets food)
-Control hypertension to decrease GFR (amlodipine, ACE-Inb)
-Titrate treatment for hyperthyroidism to evaluate
Diet
-Ultra low iodine diet
-Lower tT4 but may not resolve clinical disease in more advanced cases
Anthithyroid medications
-Methimazole (Felimazole) FDA approved
-Inhibits synthesis of thyroid hormone
-Drug of choice
-T4 usually returns to normal within 1-2 weeks
Adverse Effects
-Lethargy
-Vomiting
-Diarrhea
-Mild hematologic changes: cytopenias
-Facial pruritic and pinnae scabbing
Discontinue if facial scloration and substitute with iodine
-Hepatic toxicity in small number of cases
Radioactive Iodine
->95% resolves
-2-4% need second treatment
-2% of cases have recurrence in 1-6 years
-Side effect: hypothyroidism in only 2% of cases
-Cost, limited availability, 8-14 days isolation
Surgery
-Perform m99 scan prior if possible
-Hypocalcemia due to hypoparathyroidism is most serious complication
OVerall prognosis
-Good
-Chronic kidney disease survival up to 5.3 years
Dogs and Hyperthyroidism
XRT chemotherapy
Lecture 5
Hypothyroidism
Which hormone is protein bound? the active form? and the one that does all things inside the cell?
-Functional or structural abnormality of the thyroid gland resulting in deficient production of thyroid hormone THs.
T4 - protein bound in plasma
fT4 - not bound, goes into cell = active form
T3 - does all things inside the cell
Primary Hypothyroidism
-Most common form: direct destruction of the thyroid gland
-Lymphocytic thyroiditis: immune mediated cellular infiltration of the thyroid gland
-Idiopathic atrophy: loss of normal thyroid tissue with replacement by adipose tissue
Secondary Hypothyroidism
-Dysfunction within the pituitary thyrotropic cells
-Impaired secretion of thyroid stimulating hormone TSH
-Deficiency of thyroid hormone secondary to follicular atrophy of thyroid glands
Tertiary hypothyroidism
-Deficiency in thyrotropin releasing hormone from the hypothalamus TRH
-Deficiency of thyroid hormone associated with a decrease in TSH and follicular atrophy of thyroid glands
-Rare in dogs
Congenital
-Deficiency dietary iodine intake
-Dyshormonogenesis (iodine organification defect)
-Thyroid gland dysgenesis
-Genetic deficiency of TSH Giatn Schnauzers and Boxers
Physiological effects of THs
-Primary determinants of basal metabolism
-Affect all aspects of lipid metabolism, lipolysis
-Interaction with growth hormone is essential for normal growth and development
-Nervous and cardia systems important
-CNS development in the fetus and neonate
-THs increase HR and force of contraction
Signalment and susceptible breeds of hypothyroidism
-Middle age 2-6 yo
-Can develop earlier in predisposed breeds
-No sex predilection
-Apparent breed predilection
Clinical Signs
Metabolic
-Lethargy
-Inactivity
-Weight gain
Dermatologic
-Endocrine alopecia “RAT TAIL”
-Hyperpigmentation
-Dry, brittle haircoat
-Seborrhea, dermatitis
-Pyoderma, otitis externa
Clinical Signs
Reproductive
-Anestrus
-Weak/silent estrus
-Prolonged estrual bleeding
-Infertility
Neuromuscular
-Muscular weakness, knuckling
-Facial nerve paralysis
-Seizures, ataxia
-Megaesophagus, laryngeal paralysis
CV
-Bradicardia
-Arrhythmias
-GI: diarrhea, constipation
Ocular
-Corneal lipid deposits, ulceration
-Uveitis
Clinical signs in puppies
-Cretinism
-Stunted growth and mental development
-Disproportionate body size
Diagnosis of Hypothyroidism
What drugs can affect tT4 levels and impact test results?
-Hyperlipedemia/cholesterolemia
-Elevated AST, ALT, SAP, mild-moderate increase in LDH
-Mild normocytic, normochromic, non-regenerative anemia (33% of cases)
-Coagulopathies, decrease in vonWillebran Factor (unusual)
T4
-All serum T4 comes from the thyroid gland
-T4, fT4, and cTSH (canine TSH) assess thyroid gland function
-Combination of T4, fT4, cTSH has a sensitivity of >99% for hypothyroidism
T3
-Serum T3 and rT3 are primarily formed by deiodination outside the thyroid gland
-Poor indicators of Thyroid function
Factors that can decrease baseline Thyroid hormone
-Concurrent illness, non-thyroidal illness NTI
-Drug therapy: steroids
-Random fluctuations
NTI
-Physiologic adaptation by body during periods of illness to decrease metabolic rate
-T4 suppressed; tT4 fraction more sensitive to alterations than fT4
-In general, the more severe the disease, the more profound effect the thyroid suppression
Diagnosis - Baseline tT4, fT4
The gold standard is measurement by equilibrium dialysis (ED)
Baseline tT4
-Sum of free and protein bound fractions
-Easy and less expensive
-Check during regular yearly visits for older dogs
-Disadvantage: considerable overlap in serum tT4 in hypothyroid and normal dogs, especially with NTI
-90% sensitivity
-The higher the T4 value the more likely the dog is euthyroid - good negative predictor
Baseline fT4
-Gold standard is measurement by equilibrium dialysis (ED)
-Low fT4 diagnosed 94% of hypothyroid, sensitivity
Baseline cTSH
-High cTSH adds specificity to fT4 and tT4
-assay must be validated for canine
-Poor screening test values overlap NTI
TSH and TRH
-Labs
-Differentiate between true hypothyroidism and NTI
Diagnosis - Lymphocytic thyroiditis
-3 forms: T3, T4, and thyroglobulin autoantibodies
-Antibodies can interfere with RIA tests and produce unusual baseline thyroid hormone values
Preferred Diagnostic Plan
Groups similar to feline
-MDB
-History, PE, CBC, chemistries and urinalysis
Screening of pet dogs
-Add tT4
-No Tx indicated if inconsistent MDB and tT4 is normal
-cTSH and fT4 if tT4 normal but index of suspicion is still high
Screening breeding dogs with C/S
-MDB, tT4, fT4, cTSH, autobody test
-Tx if MDB supportive and thyroid tests abnormal, otherwise no treatment
Repeat in 2-4 weeks if inconclusive
Screening healthy breeding dogs
-Annual evaluation of thyroid function recommended
-If any test abnormal, do not use for breeding, and re-evaluate in 6 months
Hypothyroidism Treatment
-T4 supplementation of choice is
-LEVOTHYROXINE
-Namebrand: Soloxine
-Initial dose every 12 hours
-Monitor tT4 levels for 6-8 weeks post induction or
-4 weeks following dose adjustment
Monitoring
-Supplementation ideally should result in normal serum tT4, T3, and cTSH
-Measure tT4 levels pre and 4-6 hrs post pill if dosed once daily. It will tell you how long it last and if need to do q 12 hours instead
Failure to respond
-If no improvement within 8 weeks
-Re-evaluate!
Decrease dosage if tT4 >7.5 ug/dl to avoid thyrotoxicosis
Lecture 6 Disorders of the parathyroid gland
Differentials for Hypercalcemia
Things that increase total calcium, not necessarily Ionized calcium
GOSHDARNIT
Granulomatous
Osteolytic
Spurious
Hyperparathyroidism (primary)
D Hypervitaminosis
Addison’s disease
Renal secondary Hyperparathyroidism
Neoplasia
Idiopathic (most common in cats)
Temperature induced (hyperthermia)
PTHrP only positive
Humeral hypercalcemia of malignancy
-Cancer is causing the high ionized calcium
Calcium Metabolism
-Total calcium in chemistry panel does not tell you about active calcium
-Ionized calcium is what is important because hypercalcemia is high ionized calcium
Ionized calcium
-45-50% of total calcium
-Active form
Protein bound calcium
-Typically bound to albumin
-50-55% of total
Complexed calcium
-Bound to phosphorous, citrate
-Important in kidney disease
-Decreases GFR
-1-2% of total
-Can cause an increase in total calcium without affecting ionized calcium
Bone, gut, and kidney
PTH
-The major defense against fluctuations in ionized calcium
-PTH = pee out phosphorous, Ca goes up in blood, out of bone into blood.
-Calcium always does the opposite of phosphorus
-Increases Ca resorption in the kidney
-Increases Phosphorous excretion by the kidney
-Increases calcium and phosphorous mobilization from the bone
-Stimulates increased production of vitamin D
-Increases calcium and phosphorous absorption from the intestine
Granulomatous
-Histoplasmosis: fungal
-Blastomycosis
-Coccidiomycosis
-Tuberculosis
-Schistosomiasis
Increased iCa, decreased PTH
Macrophages can activate vitD
Osteolytic
-Primary and metastatic bone tumors
-Bacterial and mycotic osteomyelitis
-Mechanical destruction by infiltrating cells (as in metastatic tumors, osteosarcoma)
-Local production of oesteclast-activating factor and other bone resorbing factors (ex: multiple myeloma)
Spurious
Lipemia
-Hemoconcentration
-Hemolysis
Hyperparathyroidism (primary)
-Excessive secretion of PTH
-Adenomas»_space; Carcinomas
D Hypervitaminosis
-Increased iCa, increased PTH
-Cholecalciferol rodenticide
-Calcipotriene, people cream for psoriasis, dog licks it
Addison’s Disease
-Normal iCa
-Total Ca high because they are hemoconcentrated, volume depleted
-~30% of dogs
-Increased calcium citrate (calcium complexed)
-Increased renal resorption of calcium
-GFR is down
-Increased affinity of serum proteins for calcium
Renal secondary Hyperparathyroidism
-Chronic renal failure
-Hyperphosphotemia
-Supression of iCa, compensatory high PTH
-Total Ca is elevated NOT iCa (low to normal)
-Not physiologically important
Neoplasia
-Lymphoma
-Multiple myeloma
-Anal Sac Adenocarcinoma
-Squamous cell Carcinoma
-Thyroid carcinoma
-Any malignancy (especially those that invade/metastasize to bone)
Hypercalcemia of Malignancy = humeral hypercalcemia of Malignancy
-Increased osteoclastic bone resorption
-Increased renal tubular resorption
-Increased intestinal absorption
-PTH
-PTH-related protein
-Transforming growth factor
-1,25-dihydroxyvitamin D
-Prostaglandin E2
-Osteoclast activating factor
-Other cytokines
Idiopathic
-Cats
-Magnesium restricted, acidifying diets
-Lyphoma in cats
-Excessive dietary vitD
-PTH low to normal, PTHrP negative
-PTH independent
-Vitamin D and calcitriol levels normal
Long haired cats overrepresented
Temperature induced (hypothermia)
Did not discuss
How many parathyroid glands are present?
4
What is the normal calcium level?
What is the function of calcitonin?
What gland releases it?
10mg/dl
Calcitonin: calcium tone down
-Keep it in the bone
-Pee it out
-Not absorbed from the gut
Released by Thyroid glands
Parathyroid glands release PTH
Where is Vitamin D activated in animals?
Liver
Who antagonizes the ADH receptor?
-Ionized calcium
-PU/PD pee it out
Serum Ionized Calcium Scenerios
Normal
High
Low
Primary Hypoparathyroidism
LOW iCa
-Serum iCa = Low to normal
-Plasma PTH (parathyroid hormone) LOW
PTH independent Hypercalcemia
HIGH iCa
-Usually due to osteolysis
-PTH low
-Malignancy, vitaminD toxicity
Secondary Hyperparathyroidism
LOW iCa
-Renal or nutritional
-Serum PTH high
-Ionized calcium is not high
-iCa normal or low
Primary Hyperparathyroidism
HIGH iCa
-High PTH
Hypeparathyroidism - Primary
-Occurs most commonly as a malfunction of one of the glands, usually as a result of benign tumor (adenoma)
-Usually bilateral adenoma
Dogs
-4-16 yo
-No sex predilection
Keeshounds common
Cats
-8-20 yo
-No sex predilection
-Mixed and siamese
C/S
Dogs
-PU/PD because ionized hypercalcemia antagonizes ADH receptors
-Muscle weakness
-Decreased activity
-Lower urinary tract signs
-Decreased appetite
-Weight loss
-Muscle wasting
-Vomiting
-Shivering/trembling
Cats
-Lethargy
-Anorexia
-Vomiting
-Constipation
-PU/PD
-Weight loss
PE
-Most often normal
-Generalized muscle atrophy
-May have palpable mass cervical region
-Cystic calculi in 1/3 of dogs Calcium oxalate or mixed stones
Diagnosis
-Persistent hypercalcemia
-Normal to decreased serum phosphorous
Ddx cats and dogs hypercalcemia
-Hypercalcemia of malignancy
-Primary hyperparathyroidism
-Renal failure
-Hypervitaminosis vit D
-Hypoadrenocorticism
-Idiopathic (cats)
Diagnosis
-Minimum database (CBC, chemistry, UA)
-iCa is elevated with Primary hyperparathyroidism
-iCa typically normal in chronic kidney disease induced (total) hypercalcemia
-Thoracic radiographs looking for cancer
-Cervical exam ultrasound structural abnormalities, cancer
Specific tests
-PTH
-PTHrP can be secreted by malignant cells
-Specific tests for malignancy
Primary = high PTH, high iCa, low phosphorous and zero PTHrP
Treatment
-Surgical excision of affected parathyroid gland
-Chemical (ethanol) or heat ablation of mass
-Monitor for hypocalcemia
-May need to Tx hypocalcemia: Calcium carbonate (Tums) and calcitriol
Secondary Hyperparathyroidism
Usually Renal or Nutritional
-Occurs as a result of a metabolic abnormality
-Outside of parathyroid glands, which causes a resistance to the function of the parathyroid hormones
Chronic Kidney disease
-Phosphate retention
-Decreased iCa or normal
-Increased PTH because phosphorous asking to be excreted
-Increased Ionized phosphate excretion
Nutritional Secondary Hyperparathyroidism
-Feeding a diet with excess phosphorous or low calcium
-Ideal calcium:phosphorous is 1.2:1
-Animal fed pure meat diets
-Not retaining phosphorous, diet trigger, PTH goes up
Watch for it in reptiles
Prolonged Elevation of PTH leads to
-Growth abnormalities
-Replacement of normal bone by fibrous tissue
-Malformed and pathologic fractures due to osteopenia
Adrenal Secondary Hyperparathyroidism
-Increased PTH in dogs with hypoadrenocorticism
-Compensatory response to calcium loss and or increased phosphorous
-Resolves with successful treatment of HAC
Primary Hypoparathyroidism
-Relative or absolute deficiency of PTH
-Leads to hypocalcemia
-Hyperphosphatemia
-Uncommon in dogs and cats
-Lymphocytic infiltration and fibrous tissue scarring of parathyroid gland
-Suggest an immune mediated process
-Most classified as idiopathic
Signalment
-Age 6 weeks - 13 yo
-Average 5yo
-Sex predilection FEMALES
Breeds
-Toy poodles, miniature schnauzers, labrador retrievers, GSD, Terriers
Cats
-Any range 6 mts - 7 yo
-Mean 5 yo
-Sex predilection: MALE
-Several breeds
-Very few reports of naturally occurring
C/S Dogs and Cats
-Seizures (when iCa is low, nerves depolarize)
-Stiff gait
-Muscle tetany, cramping, pain
-Focal muscle fasciculations, twitching , tremors
-Facial rubbing (intense)
-Nervousness, anxiety, vocalizing
-Panting, hyperventilation
-Aggressive behavior
PE
-See above
-Bradycardia
-Paroxysmal tachyarrhythmias
-Weak femoral pulses
Diagnosis
-Persistent hypocalcemia
-Hyperphosphatemia
-Normal kidney function
-Rule out other causes of hypocalcemia (ex: renal, nutritional hyperparathyroidism)
-PTH levels undetectable in face of hypocalcemia. Body can’t make PTH
-Postpartum risks for eclampsia
Transient Hypoparathyroidism
-Occurs secondary to hypomagnesemia
-Suppressed PTH secretion
-Increases end organ resistance to PTH
-Impairs synthesis of calcitriol
-Results in mind hypocalcemia and hyperphosphatemia
-Reverses with magnesium supplementation
Ddx for hypocalcemia cats and dogs
-Primary hypoparathyroidism
-Puerperal tetany (eclampsia)
-Renal failure
-Secondary nutritional hyperparathyroidism
-Hypomagnesemia
-Hypovitaminosis D
Treatment
-Correct underlying cause
-Administration of calcium and vitamin D
Phase 1: Slow IV calcium gluconate, then CRI
Phase 2: Oral supplementation of calcium and vitamin D (calcitriol has fastest onset)
Goal calcium maintenance between 8-10 mg/dl
Prognosis
-Excellent
-Requires frequent checks
Pituitary Independent Hypercalcemia
-Hypercalcemia of malignancy
-Tumor producing PTHrP
-Vitamin D toxicosis, high dietary levels or accidental ingestion
Lecture 8
Endocrine Pancreas
What cells in the pancreas produce insulin and which produce glucagon?
Insulin = Beta cells
Alpha cells = Glucagon
When blood sugar levels are low, Glucagon is released so that liver breaks down glycogen and releases glucose = blood glucose raises
When blood sugar is high, insulin is released into the blood and liver takes up glucose and stores it as glycogen, blood glucose levels declines.
Enemies of insulin
epi and norepinephrine
used in an emergency situation to get Glucagon going and raising blood glucose levels
Classification of Diabetes Mellitus
Type 1
-Destruction or loss of pancreatic beta cells with progressive and eventual insulin insufficiency. Immune mediated, common in people
Type 2
-Characterized by insulin resistance and dysfunctional Beta cells
-Chronic longterm obesity association
Insulin Dependent DM
-Permanent hypoinsulinemia and requirement for exogenous insulin therapy
-Type 1 commonly
Insulin Independent DM
-Includes obesity induced down-regulation of insulin receptors, impaired receptor binding affinity and post-receptor defects in insulin action.
DM in Dogs
-Essentially all dogs have IDDM at time of presentation
-NIDDM uncommon
-Multifactorial causes: genetic, infection, insulin antagonism with drugs or disease, obesity, pancreatitis and immune mediated insulinitis
-Rapidly leads to IDDM
-Loss of beta cell function resulting in hypoinsulinemia
-Impaired intracellular glucose transport, accelerated hepatic gluconeogenesis
-Loss of beta cell function is permanent and results in lifelong requirement for insulin therapy
DM in Cats
4 Types
Type 1: immune mediated
Type 2: common, insulin resistance due to beta cell exhaustion
Other
-Endocrine pancreatic disease, other endocrinopathies that antagonize insulin
-Drug induced
Obesity and free choice feeding may predispose
Steroid therapy potentially leads to insulin resistance, clients will be angry if they are not aware of side effects
Type 2 DM - Hallmark
Insulin resistance
Beta cell dysfunction
-Leads to chronic, persistent hyperglycemia which itself is toxic to beta cells
-GLUCOSE TOXICITY: leads to abnormal protein folding and beta cell apoptosis
-Reversal of glucose toxicity increases chances for diabetic remission
-Feline patients may be reversible with rapid glycemic control
-Commonly “Brittle diabetic” = dose of insulin needed to control disease is close to dose causing hypoglycemia
-C/S may be transient
-Insulin often required in advanced cases
Risk Factors
Amylin
-aka Islet Amyloid polypeptide
-Co secreted with insulin (antagonizes insulin)
-Overproduction causes irreversible amyloid deposits
-Leads to progressive islets loss where beta cells are in the pancreas
Obesity
-Fat is the enemy of glucose regulation
-4 times more likely to develop disease
-Causes internalization of insulin receptors by fat cells
-Reduces insulin receptor affinity
-Reversible with weight loss
Physical activity
-Inactivity regardless of presence or absence of obesity
Gender - Cats
-Males
Age
-8-12 yo
Genetic
-Burmese
-Main coon
-Russian blue
-Siamese
Medications
-Glucocorticoids
-Megestrol acetate
High carbohydrate diet ?
DM in cats
-Insulin requirements fluctuate in approx 20% of cats
-Brittle diabetics (dose of insulin needed to control disease is close to dose causing hypoglycemia)
Neutered males more frequently affected
Age
->6yo, average 10yo
Genetic predisposition
-Burmese, Maine Coon, Russian Blue, Siamese
Medications
-Glucocorticoids
-Megestrol acetate
C/S
-PU/PD
-Weight loss
-Polyphagia
-Sudden blindness cataracts
-Weight loss when prolonged and untreated
-Hepatic lipidosis - hepatomegaly
Diabetic Neuropathy
-Pelvic limb ataxia: more in dogs
-Plantigrade stance: cats more common
-hyporeflexia
-No specific Tx
DM dogs
-Females twice as likely as males to be affected
-Age of onset 4-14 yo, 7-9 yo prevalence
Breeds
-Keeshound
-Cairn
-Miniature Schnauzer
-Poodle
-Daschund
-Beagle
-Miniature Pinscher
C/S
-PU/PD
-Weight loss
-Polyphagia
-Sudden blindness cataracts
-Weight loss when prolonged and untreated
-Hepatic lipidosis - hepatomegaly
Diabetic Neuropathy
-Pelvic limba ataxia
-Plantigrade stance: cats more common
-hyporeflexia
-No specific Tx
DM Diagnosis
-Suspicion based on clinical signs
-Demonstration of persistent, fasting hyperglycemia in conjunction with glucosuria
-Difficult to determine NIDDM vs. IDDM
Cats can get stress hyperglycemia, glycosuria, 300-400 mg/dl
-Ketonuria, diabetic ketoacidosis
-CBC, Chem, UA with culture.
-PLI/TLI
-Baseline fructosamine: shorter term 2-3 weeks
+/- Glycosylated hemoglobin: longer term 2-3 months
-Look closely for concurrent disease
Fructosamine
-Index of average blood glucose over 2-3 weeks
-Can help distinguish stress hyperglycemia
-Non-enzymatic, independent of glycosylation insulin serum proteins
Glycolated hemoglobin
-Index of average blood glucose over previous 4-8 weeks
-Insulin independent binding of glucose to hemoglobin in RBCs
Fructosamine and Glycosylated Hemoglobin
-Separates stress hyperglycemia
-Can not identify cause
-Clarify discrepancies in history, PE, and BG curves
-Every 3-6 months
DM Treatment
Goals
-Prevent complications: cataracts, bacterial infections, pancreatitis, ketoacidosis, hepatic lipidosis, peripheral neuropathy
-Eliminate owner observed c/s
Methods
-Proper insulin administration, dose, control
-Diet
-Exercise
-Prevention or control of concurrent disease
-Avoid potential fatal hypoglycemia due to overzealous insulin administration
Diet
Don’t start right away with insulin administration start
Dogs
-Provide increased amounts of fiber soluble to slow intestinal absorption of glucose
Cats
-Important to eliminate obesity
-High protein
-Low carbs
-Moderate fat
-Obligate carnivores
-Naturally insulin resistant
-Don’t store glycogen as well as dogs
-Maintain euglycemia naturally
Feed 66 kcal/kg/day for ideal BC
Both
-Maintain timing and calorie content in order to minimize post prandial glucose fluctuations.
Exercise
-Promotes weight loss
-Helps to increase absorption of insulin from injection site
-Daily, moderate is the goal
-Overzealous or sporadic can lead to hypoglycemia
Hypoglycemic Agents
- Inhibit intestinal glucose absorption
-Acarbose - Improve peripheral insulin sensitivity
-Troglitazone
-Vanadium
-Chromium picolinate
-Metformin - Promote insulin release from pancreas
-Sulfonylureas: type 2 diabetes in humans - NEW decrease kidney reabsorption of glucose, pee out more glucose
-They don’t substitute for insulin
-Can not reverse beta cells glucose toxicity
-Limited veterinary data
Nutrition and optimal weight control are cornerstone
SGLT2 receptor inhibitors NEW
-Bexacat: Bexagliflozin tablets
-Senvelgo: Velagliflozin oral solution
-They block receptor in kidney and increase renal excretion of glucose
DM Treatment - INSULIN mainstay
Types
- Onset of duration
-Short acting: Regular Crystalline
-Intermediate acting: NPH
-Long acting: PZY - Protein source
-Human: Pro-Zinc, NPH, Glargine
-Biosynthetic human analogues
-Bovine: bovine-porcine protamine zinc, PZI-Vet
-Porcine: Veterinary porcine zinc lente insulin, Vetsulin
Cats and cows similar structure
Pigs, puppies, people
Never switch needles and bottles, they are calibrated for IU
Which insulin do you use in hospital setting?
Regular
-IV CRI
-0.5 hrs onset
-Peak 1-5 hrs
-Duration 8hrs
Intermediate acting
-NPH
-Lente
Longer acting
-Glargine
-Determir
-PZI
All species origins are effective in cats and dogs, but every patient is individual
Immunogenicity and insulin antibodies can alter the effect and duration of the insulin
Initial Insulin therapy
Dogs
-Intermediate acting NHP
-BID
-0.5-1.0 IU/kg
Cats
-Glargine: first choice
-ProZinc or PZI
Hospitalize
-Initially for 24-48 hours to ensure that hypoglycemia is managed if occurs
BG curve
-During hospitalization
-Initial goal is to reverse metabolic abnormalities
Re-evaluate in 7-10 days
Glycemic control
-Takes 1 about month to establish
-Achieved based on
1. Resolution of clinical signs
-Pet is healthy and interactive at home
-Body weight is stable
-Owner satisfied
-Blood glucose 100-250 mg/dl dogs
-BG 100-300 mg/dl cats
Home Management
-Owner should keep a log
-Never change insulin dose without consulting with veterinarian
At home glucose curves are most useful, no stress hyperglycemia
-Sample taken every 2-4 hours
Urine testing should not be used for adjusting insulin dose
Monitoring
-Get a pre-feeding reading
-Serum BG after feeding and give insulin
-Serum every 2-4 hrs at home ideal
-Serum BG every 1-2hrs at hospital if no other option
-Jugular catheter to avoid multiple needle sticks
Blood Glucose Curves
-Pre-feeding reading
-Feed same amount and type of food before insulin injection
-Take initial blood sample
-Have owner give insulin
-Assess owner’s injection technique
-Take blood samples every 1-2 hrs intervals for 12-24 hrs
-Help determine insulin dose and frequency of administration required for control of hyperglycemia
Monitors for Glucose
-Alpha TRAK - feline calibrated
Ideal Blood Glucose Curve
Inappropriate duration of Insulin action
Insufficient Insulin Dose
Somogyi effect
InSulin Resistance Curve
Insulin Resistance causes
-Rapid insulin metabolism
-Anti-insulin antibodies
-Poor subcutaneous absorption of insulin
-Severe obesity
-Infection/inflammation: dental disease, UTI, pancreatitis
-Drugs: glucocorticoids, pro gestational agents
-Endocrine disorders: hyperthyroidism, hyperadrenocorticism, acromegaly, diestrus and progesterone excess
Monitoring
Blood Glucose Curve
-Assess the effectiveness
-Does it lower BG?
-Consider range, BG differential and nadir together
For example
-A differential of 50mg/dl is acceptable if range is 120-170mg/dl but not if 350-400 mg/dl
-Or a differential of 100 mg/dl is acceptable if dose is 0.4 IU/kg but not if dose is 2.2 IU/kg
Assess the duration
-time from injection to nadir to rise to 200-250 mg/dl
-May need extended BG 18-24 hrs
-Evaluation of duration is inaccurate if Somogyi effects is occurring
-Accurate measurement of duration can help dictate type of insulin and dosing schedule
Always Check for Owner management errors
Monitoring parameters
Tools in the tool kit
- Initial regulation
-Urine glucose monitoring
-Blood glucose monitoring - Intermediate regulation
-Serum fructosamine
-Fasting or mean blood glucose - Long term regulation
-Glycosylated hemoglobin
Routine management
-Once controlled re-examine every 2-4 months
-PE, BW, Glycosylated hemoglobin and fructosamine
-Re-evaluate BG curve in hospital if clinical signs change
Complications
Hypoglycemia
-Common and potentially life threatening
-Can occur for several reasons
-Excessive overlap of duration in BID dosing
-Prolonged inappetence
-Unusually strenuous exercise
-Insulin-treated cats reverting to NIDDM
C/S
-Lethargy
-Weakness
-Head tilt
-Ataxia
-Seizures
Tx
-PO Food
-Karo syrup on gums
-IV dextrose
-IM glucagon
-Decrease insulin dose 25-50% and re-evaluate BG curve in 2-3 days
Complications
Recurrence of C/S most common
-Usually problems with insulin type, dose, frequency or concurrent disease
-Technique factors: outdated, overheated, shaken, syringe type mismatch, faulty injection
Somogyi Effect
-Insulin overdose
-Induces hepatic glycofenolysis and secretion of diabetogenic hormones (epinephrine and glucagon)
-Results in rebound hyperglycemia and C/S
Recurrence of C/S
-Short duration on insulin effect
-Inadequate absorption
-Circulating insulin antibodies
-Concurrent disease interfering with insulin action (HAC, UTI, steroids, hypo or hyperthyroidism, acromegaly chronic inflammation, obesity, hyperlipidemia)
Algorithm for Diabetic control
Algorithm for diabetic control
Algorithm for Diabetic control and Prognosis
Prognosis
-Good to excellent with treatment
being effective and owner compliance
