Endocrinology I (French)

Report
ENDOCRINOLOGY I
Sarah E. French, MD
July 19, 2014
Diabetes
Lipids
Calcium disorders
MEN I and II
Medical-Content Category
Relative Percentage
Cardiovascular Disease
14%
Pulmonary Disease
10%
Gastroenterology
9%
Infectious Disease
9%
Rheumatology/Orthopedics
8%
Endocrinology
8%
Medical Oncology
7%
Hematology
6%
Nephrology/Urology
6%
Psychiatry
4%
Neurology
4%
Allergy/Immunology
3%
Dermatology
3%
Miscellaneous
3%
Obstetrics/Gynecology
2%
Ophthalmology
2%
Otorhinolaryngology
2%
Endocrinology (8%)
17–19 questions
Diabetes mellitus
5–8
Thyroid disorders
2–4
Lipid disorders
2–3
Calcium metabolism and bone
1–5
Male reproductive health
1–2
Adrenal disorders
0–2
Hypertension
0–1
Female reproductive health
0–1
Hypothalamic disorders
0–1
Anterior pituitary disorders
0–1
Posterior pituitary/water metabolism
0–1
Endocrine tumors and endocrine
manifestations of tumors
0–1
Hypoglycemia not due to insulinoma
0–1
Polyglandular disorders
0–1
Nutritional disorders
0–1
Women’s health endocrine issues
0–1
Miscellaneous endocrine disorders
0–1
DIABETES
Diagnostic criteria for diabetes
• Random glucose >200 mg/dL with symptoms
• Polyuria, polydipsia, unexplained weight loss
• Fasting glucose > 126 mg/dL on 2 different days
• 2 hour glucose >200 mg/dL during 75-gram oral glucose
tolerance test
• A1c > 6.5 (new)
Secondary causes of diabetes
• Chronic pancreatitis
• Cystic fibrosis
Pancreatic failure
• Hemochromatosis
• Polycystic ovarian syndrome
• Cushing’s syndrome
Insulin resistance
• Acromegaly
• Drugs: glucocorticoids, thyroid hormone, thiazides,
dilantin, alpha interferon
• Somatostatinoma
A1c
• Goal <7%
• Can be unreliable if
• Blood transfusion
• Decreased RBC lifespan
• Hemoglobinopathies
• Alternative is fructosamine
Oral agents in diabetes
• Need to know contraindications and most side effects of
different agents
• Metformin, TZDs and sulfonylureas are roughly equivalent
on ability to decrease A1c
• Metformin, TZDs and sulfonylureas are FDA approved for
combination with insulin
• DDP-4 inhibitors (sitagliptin, etc) are NOT FDA approved
for combination with insulin
• Metformin
• TZDs
• Only oral agent that is
• Can have fluid retention
weight loss/weight neutral
• Generally first line agent
• Contraindicated if Cr >1.5
in men, >1.4 in females
and edema
• Contrainidicated in NYC
Class III and IV heart
failure
• Sulfonylurea
• DDP-4 inhibitors
• Insulin secretagogue
• Increases insulin
• Contraindicated in renal
production and sensitivity
• Delays gastric emptying
• Can be used in CKD with
dose reduction
failure
Indications for insulin
• Significant hyperglycemia at presentation
• Acute decompensation
• Surgery
• Pregnancy
• Renal disease
• Poor control despite oral agents
Diabetic ketoacidosis
• Total body potassium is low
• Even if patient presents with hyperkalemia
• Monitor potassium and replace
• Follow bicarb and anion gap
• Generally no need to follow ketones
Diabetes is not just hyperglycemia
• Keep blood pressure <130/80
• ACE inhibitor or ARB if proteinuria
• Manage any dyslipidemia
• If age >40, start statin even if LDL at goal
• Screen for complications
• Urine microalbumin, dilated eye exam
• Smoking cessation
• Immunizations
Lipid goals in diabetes
• LDL
• < 100 for every diabetic
• < 70 if DM with CAD or CAD equivalent (PAD, AAA)
• First choice is statin
• Triglycerides
• <150
• First treatment is glycemic control
• Fenofibrate safer than gemfibrozil when in combo with statin (less
rhabdo)
• Secondary target (treat LDL first) unless >500
Complications of diabetes
• Acute complications
• DKA
• Hyperosmolar hyperglycemic nonketotic state (HHNS)
• Microvascular
• Retinopathy
• Neuropathy
• Nephropathy
• Macrovascular
• CAD
• PVD
• CVD
• Atherosclerosis is most common cause of death
Diabetes in pregnancy
• Glargine and detemir are contraindicated
• Use NPH for basal insulin
• Can use regular for prandial/bolus insulin
• A1c < 7% before conception and keep it there
• Retinopathy may worsen during pregnancy
• Remember: statins, ACEIs, and ARBs are contraindicated
ADJUSTING INSULIN
Adjusting insulin
• Basal insulin—controls fasting glucoses
• If fasting hyperglycemia—increase dose
• If fasting hypoglycemia—decrease dose
• Prandial insulin—controls post-prandial glucoses
• If post-prandial hyperglycemia—increase dose
• If post-prandial hypoglycemia—decrease dose
• Adjustments should be 10-20% of dose
A 58 yo WM with HTN and DM is followed in your clinic and
previously had good control of his diabetes with A1c of 6.9 on
Novolog 70/30, taking 35 units before breakfast and supper.
Has had recently begun complaining of highly variable blood
sugars:
Pre-breakfast FSG – 200-250
Pre-Lunch FSG – 135-160
Pre-Supper FSG – 130-150
Which of the following is the best next step in his
management?
1.
Increase Novolog 70/30 dose in the evening to 40 units.
2.
Begin acarbose therapy
3.
Increase Novolog 70/30 dose in the morning to 40 units
4.
Check blood sugar at 3 AM
5.
Change the patient’s regiment to Lantus and Regular
Insulin before each meal for better compliance.
Early morning hyperglycemia
• Dawn phenomenon
• Rise in GH and cortisol lead to morning hyperglycemia
• No associated hypoglycemia
• Somogy effect
• Nocturnal hypoglycemia leads to morning hyperglycemia
• Only way to differentiate is to check 3 AM FSG
23-year-old man with 13-year history of type 1 DM is preparing for
racquetball tournament. The first game of his tournament is at 8 AM
and he asks for advice about his insulin regimen because he has never
attempted to play racquetball so early in the day (usually plays late
afternoon).
Usual insulin dosage is 6 units NPH with 10 units insulin lispro with
breakfast at 7 AM, 4 units insulin lispro with lunch at 12 PM, and 8 units
NPH with 12 units insulin lispro with dinner at 6 PM. His last A1c was
6.4 and his fasting fingerstick readings at 7 AM ranges between 160
and 200 mg/dL.
Assuming that his 7 AM glucose concentration is in usual range, which
one of the following should he do?
A.
B.
C.
D.
E.
Not take his insulin or eat breakfast but drink 8oz of orange juice just
before the game
Take his usual insulin and eat his usual breakfast
Omit the insulin lispro but take the usual dose of NPH with breakfast
Omit the NPH but take the usual dose of insulin lispro with breakfast
Decrease the insulin lispro and NPH and eat his usual breakfast
GLUCOSE PATTERNS
250
200
150
100
50
8AM
6PM
Noon
Normal
Increased insulin requirement
Steroid Effect
250
200
150
100
50
8AM
6PM
Postprandial Hyperglycemia
Noon
250
200
150
100
50
8AM
6PM
Noon
Somogyi or Dawn Phenomena
250
200
150
100
50
8AM
6PM
Noon
Dietary/Medical noncompliance
HYPOGLYCEMIA
Definition of hypoglycemia
• Whipple’s triad
• Symptoms, signs or both consistent with hypoglycemia
• A low plasma glucose concentration
• Resolution of symptoms/signs after raising plasma glucose
• “In the absence of Whipple’s triad, the patient
may be exposed to unnecessary evaluation,
costs and potential harms, without expectation of
benefit.”
• From “Evaluation and Management of Adult Hypoglycemic
Disorders: An Endocrine Society Clinical Practice Guidelines”
Insulinoma
• Extremely rare
• Typically fasting hypoglycemia
• Whipple’s triad
• Symptoms associated with hypoglycemia
• Glucose <70 at time of symptoms
• Relief with glucose administration
• Have elevated insulin and C-peptide levels
• Negative sulfonylurea screen
• 18 yo woman evaluated for syncope. Has had 3 episodes in
•
•
•
•
past month that resolved after she drank fruit juice with sugar.
Has history of depression treated with citalopram and
occasional insomnia treated with zolpidem as needed. Her
mother has type 2 diabetes treated with NPH and glyburide.
Several minutes into presentation, patient becomes confused
and agitated with tachycardia and profuse sweating. Blood is
drawn. IV glucose given with resolution of her symptoms.
Vitals are normal and physical exam is unremarkable.
Lab studies: C peptide 0.4 (0.5-2.5), glucose 34, insulin 26 (220), sulfonylurea screen negative.
What is most appropriate next step in management?
• Abdominal CT
• Abdominal octreotide scanning
• Gastric emptying study
• Psychiatric evaluation
Interpreting laboratory data
• Remember that hypoglycemia is result of low glucose
production rather than high glucose utilization.
• Plasma insulin, C-peptide, and pro-insulin concentrations
don’t have to be high relative to normal values.
• Can be “inappropriately normal” for hypoglycemia
• Generally, only interpret results if glucose is <55 mg/dL.
• A concurrent illness can complicate interpretation of
results.
Interpreting laboratory data
Signs
Glucose
Insulin
Cpeptide
Proinsulin
β-hydroxybutyrate
Glucose
after
glucagon
(+)
sulfonylurea
screen
Abs
Dx
No
< 55
<3
< 0.2
<5
> 2.7
< 25
No
-
Normal
Yes
< 55
>> 3
< 0.2
<5
≤ 2.7
> 25
No
-
Exogenous
insulin
Yes
< 55
≥3
≥ 0.2
≥5
≤ 2.7
> 25
No
-
Insulinoma
Gastric
bypass
Yes
< 55
≥3
≥ 0.2
≥5
≤ 2.7
> 25
Yes
-
Oral
hypoglycemic
Yes
< 55
>> 3
>> 0.2
>> 5
≤ 2.7
> 25
No
+
Insulin
Antibody
LIPIDS
Lipid profile
• Ideally after 14 hour fast and no alcohol for 3 days
• LDL is calculated
• Total cholesterol – HDL – triglycerides/5
• Not accurate if triglycerides > 400
• VLDL and chylomicrons are rich in triglycerides
Hyperlipidemias
• May be primary (genetic) or secondary (meds, other
diseases).
• Hypercholesterolemia—elevated cholesterol with normal
triglycerides
• Hypertriglyceridemia—elevated triglycerides with normal
cholesterol
• Mixed hyperlipidemia—elevated cholesterol and
triglycerides
Familial hyperlipidemia
• Familial hypercholesterolemia
• Reduction or absence of LDL receptor
• Tendinous xanthomas
• Lipoprotein lipase (LPL) deficiency
• Cannot degrade chylomicrons and VLDL
• Triglycerides > 1000
Familial hyperlipidemia
• Familial combined hyperlipidemia
• Most common genetic hyperlipidemia (1%)
• Increase ApoB 100 → ↑LDL and ↑ VLDL
• Premature CAD
• No risk for xanthomas
• Familial dysbetalipoproteinemia
• Elevated IDL (total cholesterol and triglycerides)
• Associated with diabetes, obesity and alcohol abuse
• Palmar xanthomas (“yellow hands”)
Tendon xanthoma
Elevated LDL
Familial hypercholesterolemia
Eruptive xanthomas
Elevated triglycerides
Tuberous xanthomas
Elevated triglycerides
Palmar xanthomas
Elevated IDL
Familial dysbetalipoproteinemia
Normal retina
Lipemia retinalis
Elevated triglycerides
Lipid disorder scenarios
Young child with TG of 8000, pancreatitis, eruptive
xanthomas, lipemia retinalis, positive family history. Most
likely diagnosis?
Lipoprotein lipase deficiency – unable to degrade VLDL and
chylomicrons.
32 yo man with CAD, LDL 350, TG normal and tendon
xanthomas. +Familly hx of premature CAD. Diagnosis?
Familial hypercholesterolemia (LDL receptor defect; LDL >300).
Autosomal dominant with variable penetrance.
48 yo woman with premature CAD and severe PVD.
+Tuberous and palmar xanthomata. TC 380, TG 400,
LDL 50. Diagnosis?
Familial dysbetalipoproteinemia—High levels of IDL cause severe PVD and early
CAD. Treat with statins and fibrates. TC and TG roughly equal with low LDL.
Secondary hyperlipidemia
• Increased LDL
• Hypothyroidism
• Increased triglycerides
• Poorly controlled diabetes
• Oral estrogens
• Alcohol
• Increased LDL and triglycerides
• Nephrotic syndrome
• HCTZ
• Beta blockers
• Glucocorticoids
Secondary hyperlipidemia
• Treat secondary causes FIRST!
• If hypothyroid, normalize TSH and then repeat lipid profile.
• If uncontrolled diabetes, normalize A1c and repeat lipid profile.
• If oral estrogens, change to patch or change method of birth
control.
• If excessive alcohol intake, work on cessation
Treatment of hyperlipidemia
• LDL
• Statins +/- ezetimibe
• Bile acid resins
• Triglycerides
• Fibrates
• Combined hyperlipidemia
• Statin and fenofibrate (safer than gemfibrozil)
• Niacin (best for HDL)
Other points
• Unless triglycerides >500, LDL is first target.
• In patients on HAART, use pravastatin.
• Not metabolized through cytochrome P450s.
• Statins are contraindicated in pregnancy.
CALCIUM DISORDERS
Hormonal regulation of calcium
Parathyroid hormone (PTH)
• Increases serum calcium
• Bone resorption
• Renal resorption
• Decreases phosphorus
• PTH = “phosphorus trashing
hormone”
• Indirectly increases renal
hydroxylation of 25-OH
vitamin D to active form
Vitamin D
• Increases serum calcium
• Intestinal absorption
• Increases phosphorus
Clinical manifestations of hypercalcemia
• GI symptoms
• Anorexia
• Nausea
• Vomiting
• Constipation
• Cardiac arrhythmias
• Sinus bradycardia
• AV block
• Shortening QT interval
• Nephrogenic diabetes
• Nephrocalcinosis
inspidius
• Dehydration
• Myopathy
• Nephrolithiasis
• Band keratopathy
• Pruritus
• Altered mental status
• Pancreatitis
Differential diagnosis of hypercalcemia
• Hypervitaminosis A
• Primary
hyperparathyroidism
• Malignancy
• Granulomatous
diseases
• Thyrotoxicosis
• Drugs
• HCTZ
• Lithium
• Hypervitaminosis D
• Tertiary
hyperparathyroidism
• Familial hypocalciuric
hypercalcemia
• Immobilization
• Milk-alkali syndrone
Primary hyperparathyroidism
• Most frequent case of hypercalcemia as outpatient
• Usually asymptomatic
• Calcium level typically within 1 mg/dL of ULN
• Solitary adenoma (80%) >> four gland hyperplasia (15-
20%) >> carcinoma (< 1%)
• PTH > 25 with high calcium consistent with primary
hyperparathyroidism
• Remember “inappropriate normals”!!
Management—primary hyperparathyroidism
• Treatment any underlying vitamin D deficiency
• Vitamin D deficiency is secondary cause of hyperparathyroidism
• Stop any offending medications (if possible)
• Thiazides, lithium, calcium carbonate
• Treat any hyperphosphatemia
• Hyperphosphatemia is secondary cause
Indications for parathyroidectomy
• Acute parathyroid crisis
• Osteitis fibrosa cystica
• Nephrolithiasis
• Azotemia with no other explanation
• Decreased bone mineral density
• Myopathy
• Pancreatitis
• Serum calcium >1 mg/dL above ULN
• 24-hour urinary calcium >400 mg
• Age < 50
Parathyroidectomy
• Four-gland exploration
• Mandatory in familial forms of hyperparathyroidism
• Need experienced surgeon
• Minimally invasive parathyroidectomy
• Single gland involvement (adenoma)
• Pre-operative imaging should be performed
• Pre-operative localization
• Sestamibi scintigraphy
• Neck ultrasound
Malignancy-associated hypercalcemia
• Predominate symptoms are altered mental status and
dehydration.
• Tends to progress rapidly and have serum calcium >12
mg/dL
• 80% due to PTHrP production
• Hypercalcemia, hypophosphatemia, ↓PTH
• Most commonly associated malignancies:
• Squamous cell carcinoma of lung, esophagus, cervix, head/neck
• Breast cancer
• Lymphoma
• Carcinoma of kidney, bladder and ovary
Malignancy-associated hypercalcemia
• Local osteolytic hypercalcemia remaining 20%
• Lytic metastasis with extensive destruction
• Mediated by cytokines
• Multiple myeloma and breast carcinoma
• Rarely 1,25 (OH)2 vitamin D3 production
• Hodgkin, B cell lymphoma, HTLV-1
• Treatment: steroids
Familial hypocalciuric hypercalcemia
• Autosomal dominant mutation in calcium sensing receptor
• Usually asymptomatic
• PTH inappropriately normal
• Calcium clearance/creatinine clearance <0.01
• Treatment: LEAVE THEM ALONE!
Granulomatous disease
• Macrophages have 1-α-hydroxylase which produces 1,25
(OH)2 vitamin D3
• Seen in sarcoidosis, tuberculosis, histoplasmosis, leprosy,
silicone-induced granulomatosis
• Treatment: steroids
Drug-induced hypercalcemia
• Thiazide
• Increased urinary calcium reabsorption
• Lithium
• Resets calcium setpoint for PTH
• Calcium carbonate (milk-alkali syndrome)
• Generally >10 grams daily
• Becoming more common (osteoporosis, ERSD)
• 62 yo woman evaluated for 1 week history of fatigue,
lethargy, constipation and nocturnal polyuria and
polydipsia. Patient has advanced breast cancer, which
has metastasized to liver. Conventional therapy is no
longer helpful and she is scheduled to see oncologist to
discuss treatment.
• Physical exam shows pale and somnolent woman. BP
98/65 and resting pulse 103. Mucous membranes dry.
Liver edge palpated 3 cm below costal margin.
• Lab studies: BUN 37, calcium 15.7, creatinine 1.4, sodium
151.
• What is most appropriate immediate next step in
treating this patient?
• IV bisphosphonate
• IV furosemide
• IV glucocorticoids
• IV normal saline
Treatment of hypercalcemia
• Hydration, hydration, hydration!!
• Bisphosphonates: pamidronate and zoledronic acid
• Pamidronate + calcitonin if calcium >15
• Steroids only for granulomatosis disease or hematologic
malignancies
• Lasix is only for volume overload!!
Hypocalcemia
• Low vitamin D: ↓Ca ↓Phos ↑PTH
• Secondary hyperparathyroidism is compensatory mechanism
• Treatment: give vitamin D
• Hypoparathyroidism: ↓ Ca ↑Phos ↓ PTH
• Usually complication of total thyroidectomy
• Treatment: calcium and calcitriol
• Pseudohypoparathyroidism: ↓ Ca ↑Phos ↓ PTH
• Defect in PTH receptor → PTH resistance
• Characteristic phenotype: short, obese, round face, mental
retardation, short 4th and 5th metacarpals and metatarsals
Albright Hereditary Osteodystrophy
Hypocalcemia
• Give IV calcium if symptomatic
• Calcium gluconate preferred to calcium chloride
• Otherwise, give oral calcium and vitamin D
• Only treat to calcium of 8.0-8.5
• Enough to prevent symptoms
• Not enough to cause hypercalciuria
Calcium scenarios
64 yo man with Calcium 10.8, PTH 135 (10-65).
Diagnosis?
Primary Hyperparathyroidism
64 yo man with Calcium 10.8, PTH 49 (10-65). Diagnosis?
Primary Hyperparathyroidism
PTH is inappropriately normal - If >25 with hypercalcemia, then primary HPT
70 yo smoker with dysphagia to solids, then liquids;
presents with altered mental status and dehydration.
Calcium 14, Albumin 2. Diagnosis?
Hypercalcemia of Malignancy
Be alert for diabetes insipidus with hypercalcemia → hypercalcemic crisis.
Calcium scenarios
42 yo with serum calcium of 10.9, phosphate normal, PTH normal
and no kidney stones, normal bones; +Hx of hypercalcemia in the
past.
Best next test?
24 hour urine calcium/creatinine – Familial hypocalciuric
hypercalcemia. Do NOT operate!
53 yo with calcium 12.3, Phos 5.9 and mediastinal lymphadenopathy.
Best therapy?
Steroids – Sarcoidosis causes hypercalcemia
by uncontrolled activation of Vitamin D.
Calcium scenarios
65 year old health food fanatic ingests high dose vitamin A
supplements “to help with my eyes.” Calcium 11.7 with
low PTH. Diagnosis?
Vitamin A toxicity – Periosteal resorption if taking >5000 units/day
43 year old with PUD eats 15 tums BID due to dyspepsia.
Calcium 12.3, PTH low, HCO3- 32. Diagnosis?
Milk-Alkali Syndrome – metabolic alkalosis and hypercalcemia
Calcium scenarios
42 yo with osteopenia, microcytic anemia and Calcium of
7.6. PTH is 125. Next step?
Celiac Disease. Check 25-OH Vitamin D level and replace to
>32. Look for dermatitis herpetiformis, Type I Diabetes Mellitus,
Non-Hodgkins Lymphoma, Vitamin B or K deficiencies
63 yo drunkard found passed out… again… Calcium 7.3,
PTH is 23. Next step?
Check for Hypomagnesemia  causes reversible hypoparathyroidism.
Replace magnesium to >2 mg/dL.
Calcium scenarios
68 yo woman with newly diagnosed osteoporosis starts
zoledronic acid therapy 2 days before presentation and
presents to the ER with tetany and palpitations. What
happened?
Bisphosphonate Induced Hypocalcemia - Most common several days after
infusion in Vitamin D deficient patients.
Always replace Vitamin D to 30 before starting bisphosphonate therapy.
Therapy – Replace calcium and Vitamin D
72 yo woman s/p parathyroidectomy due to primary
hyperparathyroidism develops calcium 6.9 on POD #1.
Magnesium is normal pre-op. Next step?
Check phosphorus level.
Low Phosphorus – Hungry Bone Syndrome – Give calcium/D
High Phosphorus – Hypoparathyroidism – Give Calcium/Rocaltrol
20 yo with round face, short stature, mental retardation,
obesity, basal ganglia calcifications, shortened 4th & 5th
metacarpals. Calcium 6.9, Phos 5.5. Next step?
Check PTH level
Likely Pseudohypoparathyroidism (PTH resistance)
Albright’s Hereditary Osteodystrophy
Therapy is calcium and vitamin D supplementation
MULTIPLE ENDOCRINE
NEOPLASIAS (MEN I AND II)
MEN I
• Have to have 2 out of 3 P’s
• Pituitary
• Prolactinoma, acromegaly, Cushing’s disease
• Pancreas
• Gastrinoma, insulinoma, glucagonoma, VIPoma
• Parathyroid
• Primary hyperparathyroidism (multifocal)
MEN 2
• Medullary thyroid cancer (MTC) present in 100%
• Always malignant; usually bilateral
• MEN 2A: MTC + parathyroid hyperplasia
• MEN 2B: MTC + ganglioneuromas and Marfaniod habitus
• Perform genetic screening for RET mutations in all index
patients
• If mutation found, screen family members
• Rule out pheo, then total thyroidectomy and cervical exploration

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