Hayward Zwerling, M.D.

MGH Endocrine Review course: ENDOCRINE REVIEW 2001

In diabetic patents, proteinuria is a risk factor for coronary heart disease. Have a very low threshold to do a treadmill test on this patient population.

The goal in treating hypertension in diabetics is a BP<120-130/80-85. Do not try dietary Rx as a first step; begin medical Rx as soon as it is determined that the BP exceeds these goals.

A diagnosis of hypopituitarism can not be made by measuring TSH, ACTH or FSH.

TSH can not be used to monitor LT4 Rx in patients with central hypothyroidism.

A random cortisol>18 indicates an intact hypothalmic-pituitary-adrenal axis, except if the patient is on estrogen Rx.

An AM cortisol<3 is presumptive evidence of adrenal insufficiency.

A cortisol<13, drawn during severe physiologic stress, is presumptive evidence of adrenal insufficiency.

The best way to exclude Cushing’s syndrome is the 1 mg overnight dexamethasone suppression test, in which dexamethasone 1 mg at 11 PM with a cortisol at 8-9 AM, a normal response is an AM cortisol<5 mcg/dL.

Patients with acromegaly typically have the disease for10-20 years before they are diagnosed.

IGF-1 (insulin like growth hormone-1, Somatomedin-C) is the best screening test for acromegaly as it presents an integrated average of the growth hormone levels. The normal range must be adjusted for age and gender. Surgery is the preferred Rx, although there are some options for medical therapy.

Growth hormone treatment, in adult patients with growth hormone deficiency, results in an increase in bone density and decreased body fat.

The most common cause of hyperprolactinemia includes pregnancy, hypothyroidism and drug induced. Also; pituitary adenoma, empty sella syndrome, pituitary/hypothalmic lesions, chest wall lesions, Zoster, breast stimulation, phenothiazines, TCA, metoclopropramide, cimetidine, methyldopa, reserpine, Ca channel blockers, renal dz, liver dz,

The size of a prolactinoma usually correlates with the prolactin level. Most microprolactinomas (ie<1 cm diameter) will not grow with time.

Aquaporin are a peptide, located in the epithelial cells of the renal collecting duct, which allow H2O to be reabsorbed by the kidney. It is made in response to ADH. In central diabetes insipidus, the number of aquaporins are low because there is insufficient ADH to stimulate the formation of an adequate number of aquaporins. In nephrogenic DI, the aquaporins structurally abnormal and thus do not work properly. The net effect, in either case, is an excessive lost of H20, polyuria, polydypsia and, possibly, hypernatremia.

Out patients should be screened for thyroid disease using only a TSH. If the TSH is low, then order a total T4, T3U and total T3. If the TSH is high, order a total T4 and T3U. The TSH is not useful in assessing thyroid status in patients with pituitary dysfunction. For in-patients, screen with the simultaneous measurement of TSH, total T4 and T3U.

Sick euthyroid syndrome (also referred to as non-thyroidal illness) may represent (transient) central hypothyroidism occurring as results of a physiologic stress. It can present with a low T4, low T3 and slightly low/nl/slightly high TSH. The free T4 by equilibrium dialysis is usually normal. In most situations, a detectable TSH (3rd generation assay) excludes a diagnosis of hyperthyroidism.

TSH measurements are not useful in assessing a patient’s response to the treatment of acute hyperthyroidism or in patients who have pituitary disease.

The efficacy of suppressive LT4 therapy to reduce the size of goiters and thyroid nodules is controversial. If LT4 is used for this purpose, the goal should be a TSH in the range of 0.05 to 0.1 or 0.4.

Subclinical hyperthyroidism is defined as a TSH<0.5 with a normal T4 and T3. About 4% will progress to overt hyperthyroidism within 4 years. There is no data that this disease is associated with an increase risk of fracture however there is an increased risk of atrial fibrillation, osteoporosis, diastolic dysfunction, reduced exercise tolerance, impaired quality of life measurements and increased LFTs. Treatment should not be initiated until repeated TSH measurements are documented to be low. High risk patients (elderly, osteoporosis) should be Rx’ed if TSH<0.1. Also rx if TSH=0.1-0.5 with a scan that shows autonomous thyroid function In low risk patients, consider Rx if TSH<0.1 and follow serially if TSH is 0.1-0.5 range.

The optimum goal in treating patients hypothyroidism may be a TSH in the lower half of the normal range.

Post-partum thyroiditis occurs in 5-9% of all pregnancies and 25% of women with DM-1.

Subclinical hypothyroidism (TSH=5-10, with normal T4 and normal T3) occurs in about 10-20 % of patients >65. The TSH may ‘regress to the mean” with time. The clinical implications of subclinical hypothyroidism are unclear.
The risk of women progressing to overt hypothyroidism is:
Baseline TSH thyroid antibodies %/year
normal (0.5-5) positive 2.1 %
Slightly high (5-10) negative 2.6 %
Slightly high (5-10) positive 4.3 %

One should consider LT4 Rx for subclinical hypothyroidism in younger patients, TSH>10, thyroid antibody are positive, symptoms are present or patient has CHD. Use lowest possible dose to normalize TSH. Serial, daily measurements of TSH have shown that the level frequently rises and occasionally fall below the normal range, as TSH is secreted in a pulsatile manner.

TSH should be monitored once during each trimester of pregnancy. LT4 Rx should not be given concomitantly with prenatal vitamins, as calcium and iron will reduce the absorption
of LT4. In women who are hypothyroid at the time of conception, it is very likely that the dose necessary to maintain euthyroidism will increase significantly (45%) during the first trimester. Post-partum thyroiditis occurs in 5-10% of pregnancies and in 28% of Type 1 diabetics with a peak prevalence at 6-7 months.

When treating patients with Graves’ disease, use methimazole (once a day dose) for 1-2 years. The likelihood of inducing a remission is about 30% and the likelihood of a relapse, after methimazole is withdrawn, is about 50-60%. If baseline ophthalmopathy is minor, it is unlikely the patient will suffer a permanent worsening. The risk of developing cancer from 131-I is less than the risk of a severe adverse event from the anti-thyroid drugs, the risk of surgery induced hypoparathyroidism and the risk of surgery induced damage to the recurrent laryngeal nerve. Thus, encourage use of 131-I ablation when appropriate. Also check for pregnancy before 131-I ablation.

Graves’ disease occurs in 1/500 pregnancies.

Thyroid nodules are very common, occurring in 2-6% (PE), 20% (u/s) and 50-60% (autopsy) About 5-8% are malignant. In most situations, the evaluation is handled most cost-effectively by having the PCP obtain a TSH and referring the patient to an endocrinologist or otolaryngologist for FNA. Routine imaging is not indicated.

The use of LT4 suppressive therapy for benign thyroid nodules and goiters is controversial and should only be used after an individualized assessment of the patients risk (complications resulting from subclinical hyperthyroidism) /benefits (the possibility of obviating the need for future surgery.)

Prior to initiating therapy for osteoporosis, one should r/o 2nd causes of osteoporosis in those patients who present with severe osteoporosis. The differential dx includes: genetics, low peak BMD, hypogonadal states, (hyperprolactinemia, hypothalamic amenorrhea, anorexia nervosa, premature ovarian failure, primary testicular failure,) hyperthyroidism, hyperparathyroidism, GH deficiency, hypercortisolemia, malabsorption syndromes, hematologic malignancies, drugs (EtOH, heparin, steroids, LT4, anticonvulsants, chemoRx), major depression, RA, immobilization, Vitamin D deficiency, cirrhosis.

Therapy for osteoporosis should always include, at least, calcium 500 mg BID-TID and Vitamin D 400-800 iu qd.

For prevention of osteoporosis, consider raloxifene (Evista 60 mg qd, decr risk of breast cancer but incr risk of DVT) or HRT or Fosamax 5 mg qd/Actonel 5 mg qd, in that order.

For established osteoporosis in early post-menopausal women, use raloxifene (Evista 60 mg qd) as first line Rx.

For established osteoporosis in late post-menopausal women, consider Fosamax 70 mg qwk or Fosamax 10 mg qd or Actonel 5 mg qd or Evista or etidronate (not FDA approved or HRT, in that order.

Patients who are going to be Rx’ed with chronic steroids should be Rx’ed with Fosamax 5-10 mg qd, from the onset of steroid Rx. Nasal calcitonin is not very effective.

The best screening test for a pheochromocytoma is a 24h urine for metanephrines, epinephrine, norepinephrine and creatinine. (abnl if >2x upper limit of normal). Do not image until a biochemical diagnosis is made.

Primary hyperaldosteronism may occur in 5-10% of patients with essential hypertension. Screen all pts if hypokalemic (even if on a diuretic) or treatment resistant hypertension. Screen with a concurrent, seated, AM plasma aldosterone and plasma renin activity levels. Consider abnl of PAC/PRA>20 and PAC>15 ng/dL One can screen on any drug except spironolactone.

DM-2: defined as FBS>126 and a random CBS>200 x 2. The new definition is based on the fact that the risk of retinopathy starts to increase rapidly as the FBS rises above 126.

“Hyperglycemia is an established risk factor for cardiovascular disease whereas hyperinsulinemia is not. It is likely that the reduction of glycemia to “non-diabetic” levels as a single therapeutic intervention would have little impact on overall or cardiovascular mortality”

Screening all patients>45 yo, every 3 years for DM-2 (as recommended) has not been shown to reduce long-term morbidity or mortality and is very expensive. Patients at high risk (h/o GDM, IGT, hypertriglyceridemia, hypertension, HDL<35, + f/h of DM-2. obesity, african-american, hispanic-american, asian-american, american-indians) should be screened periodically.

“Insulin remains the most effective drug to treat Type 2 diabetes, assuming that the patients and care providers are willing to use the large doses that are necessary to achieve near normoglycemia.” There is no maximum dose of insulin and there is no “optimum” treatment protocol. Whatever method is chosen to control BS, the patient will require a continual increase in Rx over time. The UKPDS has shown that better control will reduce retinopathy and aggregate diabetic complications but not diabetic deaths, all cause mortality, fatal or non-fatal MI or renal failure. In the obese subset, metformin reduced all cause mortality but it did not reduce the need for laser Rx.

The rate of decline of GFR is slower if BP is tightly (<120-130/80-85) controlled.

All patient with DM and ASCVD or DM + 1 risk factor of ASCVD should be on an ACE-I.

Neurontin (100 mg qhs, titrated to 300 mg TID) should be first line rx for diabetic neuropathy. Nortriptyline (10 mg qhs and titrated upward) is also effective. The SSRI have not been shown to be effective.

“Although one uncontrolled study has suggested that (external) pumps are capable of achieving target HBA1c levels with fewer hypoglycemic episodes than multiple daily injections, the DCCT experience…demonstrated a comparable rate of hypoglycemia with trivial differences in HBA1c achieved…Implantable insulin pumps have not been approved for clinical use.” The insulin pumps require a highly motivated pump, data indicates a high percentage of patients ultimately abandon the use of the pumps.

Evaluation for an incidental adrenal nodule:
1)r/o pheo, cushings, primary aldo (10% will be hormonally active)
2)Biopsy if suspicious for malignancy or infection. If very vascular, consider excision after r/o pheo. (3% are adrenocortical carcinomas-very poor prognosis)
3)If <4 cm, repeat imaging in 3-12 m then again in 12 months.
4)If >4 cm or increase in size >1 cm then excise.