Dear Lowell Physician,

I thank you for your referrals to my office. Recently, I attended the annual MGH Endocrine Review course. Below are some tidbits of information, intermixed with my personal opinion and other sources of information, which may be of utility to you.

Also, if you are ready to put an EMR into your office, take a look at www.comchart.com. ComChart is the only EMR that can file labs and radiology reports obtain from LGH & LGH PatWeb.

Finally, I am still looking for a Board Certified endocrinologist to join my practice. If you know of a Board Certified endocrinologist, please call me

Hayward




ENDOCRINE REVIEW 2005

ADRENAL INSUFFICIENCY:
A random cortisol level>18 is excludes adrenal insufficiency. This standard may not be valid in women who are on birth control pills or pregnant, as estrogen can raise cortisol binding globulin levels.
A Cortrosyn stimulation test (synthetic ACTH 250 mcg IV) followed by a cortisol level 30 - 60 minutes later is the best test to rule out adrenal insufficiency. A normal response is a cortisol > 18. The test is not useful in patients to have acute central adrenal insufficiency(ACTH deficiency), as the adrenal gland has not had a chance to atrophy and will still react to Cortrosyn.

24 hour urine free cortisol levels are not useful in diagnosing adrenal insufficiency.

Prior to treating patients will levothyroxine, it is important to exclude it adrenal insufficiency. Levothyroxine increases the metabolism of cortisol and can precipitate adrenal crisis in patients who are borderline compensated with respect to cortisol production.

At the normal replacement steroid dose, in patients who have adrenal insufficiency, is approximately equivalent to prednisone 5-7.5 mg a day for hydrocortisone 20-30 mg a day or Dexamethasone 0.5-0.75 mg a day.

CUSHING'S DISEASE:
60% of patients have a pituitary adenoma, 25% have an adrenal adenoma(s) and 15% have ectopic ACTH or CRF production.

An overnight dexamethasone suppression test (1 mg po at 11 PM) which suppress the morning cortisol <5, usually rules out Cushing's disease. False positives can occur in patients who have depression, ethanol abuse, obesity, stress, in hospitalized patient and in patients who are taking drugs which accelerate dexamethasone metabolism.

A 24 hour urine free cortisol collection is the single best test for making a diagnosis of Cushing's disease. The false negative and false positive rate is about 5%.

Salivary cortisol levels are also an excellent way of making a diagnosis of Cushing's disease, especially in the early, mild disease and with intermittent or periodic cortisol production.

ADULT GROWTH HORMONE DEFICIENCY:
Treating patients with growth hormone deficiency will have an improvement in trabecular bone density, reduced body fat and possibly improve quality of life. the diagnosis of growth hormone deficiency is difficult. It is a very likely that patient has growth hormone deficiency if they also have a deficiency of 2,3 or 4 other pituitary hormones. It is controversial whether or not growth hormone therapy reduces the risk of coronary vascular disease. Therapy is expensive and contraindicated in patients with a malignancy. I believe these patients to will be entered into academic studies, if possible.

HYPERPROLACTINEMIA:
The evaluation of hyperprolactinemia should include a TSH, creatinine, HCG (women), testosterone (men), a review of medications, and an MRI or CT of the pituitary.

Medications which raise prolactin levels include Verapamil, Reglan, cocaine, opiates, tricyclic antidepressants, SSRIs, MAOIs, phenothiazine, Haldol, Risperdal.

Parous women who have galactorrhea and a normal prolactin level do not need MRIs of the pituitary.

Women who are menstruating and have microprolactinomas, do not necessarily require medical therapy. Without therapy, 80% of these lesions remained unchanged over the years.

Women with amenorrhea and microprolactinomas, man with hypogonadotrophic hypogonadism and microprolactinoma as well as patients with macroprolactinomas, should all be treated with cabergoline as the initial therapy.

Before imaging either the pituitary or adrenal glands (for almost any reason) it is essential the one make a biochemical diagnosis which will localize the defect to the gland of interest. 10% of normal patients will have pituitary incidentalomas and 5% of normal patients will have incidental adrenalomas. Thus, small lesions in the pituitary or adrenal gland may not necessarily imply causality, and can be frankly misleading.

HYPERTHYROIDISM:
Subclinical hyperthyroidism is defined as a low TSH with a normal T4, free thyroxine index, T3. Subclinical hyperthyroidism may need to be treated at times...

HIGH RISK LOW RISK
TSH<0.1 Treat consider Rx if hot nodule
TSH=0.1-0.5 consider Rx Observer

consider beta-blocker

A "high risk" patient would include the elderly, patients at risk of fracture, current CAD, osteoporosis or (osteopenia)


HYPOTHYROIDISM:
Subclinical hypothyroidism (elevated TSH with normal T4, free thyroxine index, T3) occurs in 15% of women over 60 years old.
The risk of progression to overt hypothyroidism rises with the TSH:

Baseline TSH (normal 0.5-5) 10 year risk of overt hypothyroidism
TSH<6 0%
TSH 6-12 43%
TSH>12 77%
TSH>20 100%
All patients with TSH > 10 should be treated.
Consider treating patients with a TSH in the 5 - 10 range if they have a goiter or symptoms referable to the thyroid.
Treat patients with a TSH in the 5-10 and markedly elevated thyroid peroxidase antibodies (as a large % will progress to overt hypothyroidism.)

Levothyroxine should not be prescribed for patients to have normal thyroid tests, even if they have symptoms of hypothyroidism.

Treating patients with the combination of levothyroxine (Synthroid/Levoxyl/Unithroid) and liothyronine (Cytomel) does not result in an improvement in symptomatology when compared to treating patients with levothyroxine alone.

Although there is data to suggest that the normal range of TSH is 0.5-3, there is no data to suggest that patients feel better if their TSH is in the lower end of normal as compared to the upper end of normal.

Hypothyroidism can result in diastolic hypertension which is refractory to anti-hypertensive therapy.

Approximately 15 to 20% of patients with hypothyroidism occurring as a Hashimoto's disease may be able to come off LT4..

For patients who have very non-compliant, send a weekly nurse to their home to administer all 7 thyroid pills once a week.

Patients should be treated with a brand name levothyroxine, (Synthroid, Levoxyl, Levothroid, Unithroid) but not with the generic levothyroxine. FDA law only requires that the generics be ± 10% of the target dose.

When begin levothyroxine, young patients can begin at a full dose. There full LT4 dose is approximate proportional to the initial elevation in the TSH level. Elderly patient should begin levothyroxine at 12.5 - 25 mcg a day, and titrated up on in 25 mcg increments on a monthly basis

Minor deviations of the TSH level from normal do not necessarily mandated a change in therapy.

Medications which can decrease levothyroxine absorption include on iron, aluminum hydroxide, calcium, sucralfate, cholestyramine, raloxifene and food.

THYROID AND PREGNANCY:
Hypothyroid pregnant women, who are hypothyroid as a result of treatment Graves' disease, need to have a thyroid stimulating immunoglobulin levels measured in the second (or third) trimester. If the patient's thyroid stimulating immunoglobulin >3-4 times the upper limit of normal, the fetus is at increased risk for hyperthyroidism.

Women who are contemplating pregnancy and are on LT4, she have their LT4 dose titrate so that their TSH < 2.5 prior to conception. As soon as they conceive, they should increase their dose by 30% or they should have of there levels monitored within one month of conception. It is likely that the required dose of LT4 will rise about 50% during the first 16 weeks of pregnancy.

There is great controversy regarding whether or not we should screen for hypothyroidism during pregnancy. Personally I believe we should. During pregnancy, one wants to err on the side of over treating. There is data to suggest that a child's IQ will be slightly lower if their mother was hypothyroid during the pregnancy.

THYROID NODULES:
The evaluation for thyroid nodules should be as follows: TSH; if is normal, then refer to ENT or endo for FNA. If TSH is low, then thyroid scan to determine if it is a hot nodule.

THYROID CANCER:
Papillary thyroid cancer, the most common form of thyroid cancer, has an overall 20 year mortality of only 5% and 20 year recurrence rate of only 15%.

OBESITY:
Obesity is associated with an increased risk of GI and reproductive malignancies.

Obesity is almost never the result of undiagnosed hypothyroidism or Cushing's. Medications that contribute to obesity include Zyprexa, Clozaril, Depakote, lithium, phenothiazines, SSRIs, TCAs, MAOIs, steroids, progesterone, insulin, sulfonylureas, Actos and Avandia.

There are probably 275 genes which may effect a person's weight. Obesity is not simply the result of patient's eating too much or exercising too little, but is likely the result of a change in the slope of, or a shift in a person's energy expenditure curve (energy vs BMI) and their energy intake curve. Obesity is thus the result of a change in a person's BMI set point.

On average, women consume 335 more calories and men consume 168 more calories than in 1970.

No single diet plan (e.g., low fat vs low CHO vs...) has been shown to be more effective, in the long run.

There are multiple medication which can be used to promote weight loss including phenteramine, sibutramin, orlistat, buproprion, metformin, Zolft, Prozac, Zonagran and others. At 5 years, medical Rx will achieve a weight loss of only 2-5%.

Gastric surgery, indicated for patient's with BMI>40 or BMI>35 and with major medical complications, can result in a sustained weight loss of 50-70%, with a concomitant reduction in the incidence of DM, GERD, hyperlipidemia, edema and sleep apnea, Operative mortality is 0.5-1%, however the long term mortality is lower in obese patients who have gastric surgery vs those who do not. The cause of weight loss after gastric surgery is likely related to a CNS effect of the surgery, leading to a decrease in energy intake and an increase in energy expenditure, thus altering the body's BMI “set point.” This occurs without an increased sense of hungry or decreased sense of satiety. The weight loss is not simply the result of the physical restriction of food intake.

DIABETES:
When treating diabetics, the most common mistake physicians make is to fail to escalate therapy aggressively In my office, I go into the exam room expecting to escalate at least one therapy (DM, BP or lipids.) The only excuse I have not to escalate therapy is if the patient is at target, ie, HBA1c<7, BP<130/80 and LDL<70 or 100. I do not accept the statement “Doc, I am now going to take this seriously and begin to ....” as a reason to continue an established therapy unchanged. I tell the patient that I will happily titrate down their therapy, if/when their BP, BS or lipids are too low. As a result of this policy, the HBA1c profile of my DM-1 patient population is essentially identically to the HBA1c profile of MGH's DM-1 patient population.

Monotherapy for DM-2 Change in HBA1c with monotherapy
alpha-glycosidase inhibitor (Precose) -0.5%
TZD (Actos, Avandia) -0.5%
metformin -1.5%
sulfonylurea -1.5%
insulin -2.5% or more

When treating DM-2, consider beginning with metformin (avoid if Cr>1.5, NYHA Class ≥III) or a sulfonylurea agent. If this is not adequately effective, then either add the other agent or add insulin or switch the patient to insulin. There is no upper dose limit for insulin. Most patients will require, on average, 85 units units of insulin a day.

The TZDs (Actos and Avandia) are weak hypoglycemic agents and should not be used as monotherapy. Actos, and certainly not as first line agents. Actos appears to have a more favorable impact on lipids than Avandia.

Do not use Glucophage XR, which is no more effective than metformin.

If BS control is not at target, consider adding a long acting insulin qhs and have the patient automatically escalate the dose, maybe every 5-7 days, if the fasting CBS remains elevated. (see Diabetes Care 1995;18;843,)

Three drug oral therapy is about 3x as expensive, has more side effects and is less effective than using insulin + metformin.

Severe hypoglycemia is an uncommon complication of DM-2 Rx.

Target BP in diabetic patients is <130/80.
preferred Rx
DM-1 w/ hypertension or (normtensive DM-1 with microalbuminuria) initial Rx ACE (or ARB)
DM-2 w/ hypertension or (normtensive DM-1 with microalbuminuria) initial Rx ARB (or ACEI)
Combination ACEI + ARB, in submaximal doses, may be better than either agent alone at maximal dose.
If intolerant to ACEI and ARB, then try verapamil or diltiazem
Next, add a thiazide

HYPERLIPIDEMIA:

2004 NCEP protocol http://www.nhlbi.nih.gov/guidelines/cholesterol/
1.Determine full Lipid profile
r/o hypothyroid, poorly controlled DM, nephrotic, drugs such as HCTZ, EtOH, steroids, BCP, some beta-blockers.
2.Determine number of risk factors, see table 2
a) If ≥2 risk factors, determine 10 year risk using cardiac risk calculator
b) Diabetes is considered a “cardiac eqivalent risk factor.”

3.Determine target LDL. Patients with CAD, DM, target<100 and optional LDL<70 if very high risk.
4.Begin statin, based on target reduction/formullary. Usually fluvastatin/Lescol is the least expensive.


TABLE 1. Doses of Currently Available Statins Required to Attain an Approximate 30% to 40% Reduction of LDL*
Drug Dose, mg/d LDL Reduction, %

  • Atorvastatin 10 39%
  • Lovastatin 40 31%
  • Pravastatin 40 34%
  • Simvastatin 20–40 35–41%
  • Fluvastatin 40–80 25–35%
  • Rosuvastatin 5–10 39–45%


Triglyercides are a risk factor for CAD. The relative risk of CAD rises when the TG exceed about 150-200. Patients with TG>200 should be treated, with goal TG<200. Also, secondary treatment target is non-LDL treated to same target level as LDL goal. Hypertriglyeridemia should be treated with fibrate (gemfibrozil 600 mg BID or Tricor 160 mg qd)

Hyperlilpidemic premenopausal women without CAD need not be treated aggressively. Allow LDL up to 225 without initiating medical Rx.

The combination Zetia + fibrate is likely to be effective for hypertriglyceridemia (theoretically.)

Combination Rx's for combined hyperlipidemia (increased LDL and TG)
niacin + statin
fibrate + ezetimibe
fibrate + resin
fibrate + niacin
statin + fibrate, patient should sign informed consent because of risk of rhabdomyolysis and legal risk.

Patients with DM & h/o MI have a 45% chance of having another cardiac event within 7 years.

Anecdotally, Vytorin 40/10 (Zocor 40 + Zetia 10) is about as effective in lowering LDL as Lipitor 80 mg.

HYPOGONADISM:
In men, testosterone levels decline with age, as due due free testosterone levels. There is also in diurnal variation in testosterone level, with the highest level being in the morning. This variation is much less significant in older men. Normal men may occasionally have low testosterone levels, which, on repeat, would be normal. Thus, before making a diagnosis of hypogonadism in man, the patient should have two or three morning testosterone levels obtained.

Testosterone deficiency in men will result in decrease sexual function, decrease libido, increased fatigue, decreased muscle mass and decrease bone mineral density. All of these parameters can be improved with testosterone therapy. Adverse effects of testosterone therapy may include polycythemia, a moderate increase in prostate volume and slight increase in the PSA level. There is insufficient data to determine the effect on the development of prostate cancer.

There is no correlation between sexual function and testosterone levels within the normal range.

If a man has true hypogonadotrophic hypogonadism (T<150-200 and low/normal LH) then patient needs pituitary imaged before beginning Rx. Also, clearly establish a reason that testosterone Rx is being initiated, and if not effective in achieving that end, then discontinue the testosterone. Contraindications to beginning testosterone therapy would include prostate cancer and breast cancer with relative contraindications in sleep apnea polycythemia. One does need to monitor testosterone levels, macro and PSA in patients were treated. Although testosterone injections are more likely to cause polycythemia and a slight increase in PSA, the injections can be give weekly, thus many men prefer to give themselves weekly injections as opposed to applying the gel or patch on a daily basis. In addition, the injections are about 1/10 the cost of the gel/patch. I no longer use the patch which tend to irritate the skin.

PHEOCHROMOCYTOMA:
Imaging should not be done until a biochemical diagnosis is secure, as 5% of patients will have an incidental adrenal adenoma.

PRIMARY ALDOSTERONISM, screening:
Indications: 1)Hypertension and hypokalemia, 2) resistant hypertension, 3) adrenal incidentaloma and hypertension, 4) screening for secondary causes of hypertension.
Diagnostic test: Have patient seated and rested. Obtain plasma renin activity and plasma aldosterone concentration
Abnormal screening test results: low PRA with PAC > 15 ng/dL and PAC/PRA > 20 ng/dL/per ng/ml/hr.
Imaging of the adrenal glands should not be done until a biochemical diagnosis is secure.

ADRENAL INCIDENTALOMA:
10% are hyperfunctioning or autonomous. 3% or adrenal cortical carcinoma. 90% of the adrenal cortical carcinoma as are > 4 cm.
94% of adrenal adenomas are less than 5 cm. Over the course of 4 years, 8% of adrenal incidentalomas will enlarge and 1% will decrease in size. Baseline assessment should include 24 hour urine for metanephrines, catecholamines, a 1 mg dexamethasone suppression test and, if hypertensive, potassium, aldosterone and renin levels. On rare occasions, FNA of the adrenal gland is indicated. A small% of adrenal incidentalomas will all involved and the, hormonally active. Thus, it is probably reasonable to repeat the hormone evaluations at 1, 2 and maybe even at 4 years. Serial imaging studies should be carried out 3, 12, 24 and ?36 months.

CALCIUM:
When assessing calcium status in the out-patient setting, it is rarely usually necessary to measure the ionized calcium. (Calciumcorrected= total calcium + 0.8(4.5-albumin), this correction for hypoalbuminemia is derived from cirrhotic patients.) The ionized calcium assayed should be used in acutely ill patient. In most labs, the total corrected calcium is more accurate than the ionized calcium.

Familial hypocalcuric hypercalcemia (FHH) must be distinguished from primary hyperparathyroidism, as both may present with an elevated calcium and an elevated PTH level. FHH will have low calcium clearance/creatinine clearance ratio, usually <0.01. FHH does not respond to parathyroidectomy. One clue to the presence of FHH is a f/h of hypercalcemia (autosomal dominant) and the presence of hypercalcemia since birth. There are a few hereditary hyperparathyroid syndromes, besides the MEN syndromes.

OSTEOPOROSIS:
Obtaining a BMD will reduce the risk of fractures. Indications for bone densitometry: all women>65 and women <65 with a h/o fracture, current cigarette use, weight<57 kg, 126 lbs, glucocorticoid Rx>3 m, h/o hyperparathyroidism, hyperthyroidism, malabsorption.

Fosamax is a bit more effective than Actonel. Calcitonin is not a particularly effective therapy for osteoporosis.

Forteo is more effective than Actonel or Fosamax in increasing bone density. It is expensive and is contraindicated in hypercalcemia, hyperparathyroidism, bone marrow malignancy or h/o bone XRT. The longterm side effects are not known. It should be reserved for severe cases and those who have had a fragility fracture. Forteo does not increase BMD in cortical bone (the hip is mostly cortical.) Prior treatment with Fosamax blunts the efficacy of Forteo. Actonel may have less off an adverse impact on the subsequent use of Forteo. For increasing spine and hip BMD: Forteo > Forteo + Fosamax > Fosamax. If Forteo is used (for 1-2 years,) it should be followed by life long bisphosphonate Rx, otherwise BMD will be lost when Forteo is discontinued.

OSTEOPOROSIS, secondary etiologies (which should be assessed if the T score<2)
ENDOCRINE: Hypogonadism, hypercortisolemia/Cushings, thyrotoxicosis, anorexia,, hyperprolactinemia, porphyria, hypophoshatemia, DM-1, thalassemia, pregnancy, hyperparathyroidism (primary and secondary),acromegaly, tumors that secrete PTHrP, endometriosis, oncogenic osteomalacia (tumor induced hypophosphatemia), GH deficiency
NUTRITIONAL: malabsorption/malnutrition, Celiac disease, subtotal gastrectomy, inflammatory bowel disease, jejunoileal bypass, pancreatic insufficiency, parenteral nutrition, primary biliary cirrhosis, chronic liver disease, Vitamin D deficiency, calcium deficiency, EtOH
MARROW-RELATED:amyloid, hemochromatosis, hemophilia, leukemia, lymphoma, systemic mastocytosis, multiple myeloma, pernicious anemia, sarcoidosis, sickle cell anemia, thalassemia
DRUGS: Vitamin D toxicity, mephanytoin Rx, glucocorticoids, phenobarbital, excessive thyroid Rx, Depo-Provera, GnRH analogs, heparin, EtOH, anticonvulsants, cyclosporin, chemotherapy,
COLLAGEN METABOLISM DISORDERS: osteogenesis imperfecta, homocystinuria due to cystathionine deficiency, Elher-Danlos syndrome, Marfan's syndrome
OTHERS: RA, immobilization, RTA, Hypercalcuria, multiple sclerosis, ankylosing spondylitis, major depression

OSTEOPOROS IN MEN:
At about the age of 40-50, men begin to loose bone density, and continue to loose BMD for the rest of their lives GnRH analogs that are used to treat men with prostate cancer will result in a decrease in the BMD within 6-12 months. Consider evaluating men for osteoporosis if h/o fracture, osteopenia on CXR, ?age >75, steroid use, CHF, GnRH Rx, longterm hyperparathyroidism. If low BMD (measure in hip), then check Ca, Phos, testosterone, PTH, TSH, Vitamin D. Also consider SPEP, 24h urine for calcium, cortisol. It is controversial regarding treatment of men with low/normal or slightly low testosterone level with testosterone. There maybe an increase in BMD which is more effective in men who have more severe hypogonadism. Fosamax is effective in improving BMD, even in men who are hypogonadal. Palmidronate is also effective in men on GnRH analogs. Forteo is effective in men. Combination of Forteo + Fosamax is not more efficacious than Fosamax alone and may be inferior to Fosamax alone. Fosamax should be considered the first line therapy for men with osteoporosis.

HYPERPARATHYROIDISM:
high PTH (can be high-normal) with hypercalcemia
normocalcemic primary hyperparathyroidism: high PTH with normal calcium
possibly very early primary hyperparathyroidism...no data
?Treat or observe...no data

2002 TREATMENT GUIDELINES

Indications for surgery

  • Calcium >1 mg/dL above upper limit of normal
  • CrCl reduced by >30%
  • Any T score< -2.5 (1º HPTH effects cortical>trabecular bone)
  • Age<50 Patients who cannot be followed will normalize calcium
  • Symptomatic patients
Follow-up if patient doesn't have parathyroidectomy:
  • BMD q1y [consider Fosamax (maybe Evista)],
  • serum calcium q6m,
  • 24h urine calcium >400 mg/day,
  • serum creatinine q1y
  • In the future, Cinacalet Rx: will normalize calcium, Won't improve BMD