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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
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Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

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ADRENAL CORTICAL DISEASES

Cushing's syndrome: increased cortisol

increased glucose, decreased K, decreased lymphs, decreased eos may be noted

Cushing's disease (pituitary adenoma or microadenoma): increased ACTH

Adrenal cortical adenoma or carcinoma: decreased ACTH (maybe....)

Ectopic ACTH production (i.e., oat cell carcinoma, carcinoid, thymoma, pheochromocytoma) or CRF production (oat cell, rarely others)

Iatrogenic (glucocorticoid therapy)

Addison's disease: decreased cortisol (or decreased ability to produce cortisol)

decreased glucose, increased K, increased BUN (prerenal azotemia) may be noted

Primary addisonism (autoimmune, TB, after steroid Rx, etc.): increased ACTH

Secondary addisonism (hypopituitarism): decreased ACTH (maybe....)

*Isolated deficiency of ACTH is very rare, but can be congenital. See Am. J. Dis. Child. 137: 1202, 1983.

Hyperaldosteronism: increased aldosterone (maybe); increased aldosterone/renin ratio (i.e., >250 or >980 or whatever's your cutoff)

Primary (Conn's syndrome, adrenal cortical adenoma or hyperplasia)

decreased K, increased BP, decreased renin

Secondary (congestive heart failure, cirrhosis, etc.)

"Congenital adrenal hyperplasia" (virilization syndromes, etc. Once considered rare, mild forms are now recognized as among the most common illnesses.

PLASMA ACTH BY RADIOIMMUNOASSAY (normal 60 pg/mL at 9 AM)

This test could tell us a great deal, but is fraught with problems.

In health, ACTH is largely secreted by the anterior pituitary in several short bursts (half life five minutes) each day in the early morning. (The rhythm is lost in Cushingism from all the common causes.)

ACTH is very susceptible to plasma proteases after the specimen is drawn, and tends to stick to glassware. The assay is expensive, not very sensitive, the plasma must be drawn into an iced purple-top tube and frozen rapidly, etc. etc.

One time when you probably should order a serum ACTH is when your patient has proved Cushingism, and you have ruled out Cushing's disease (see below), though you will not want to delay the workup if the test needs to be sent out.

High ACTH indicates ectopic production, and the need for a cancer workup.

Low ACTH indicates adrenal cortical adenoma or hyperplasia. Nice algorithm: Mayo. Clin. 61: 49, 1988.

ACTH levels are also quite helpful after hypophysectomy for Cushing's disease (return of circadian rhythm following adequate treatment), and in the diagnosis of ectopic ACTH syndrome (very high levels).

Checking the ACTH level in each interior petrosal venous sinus is now standard as a means of establishing the diagnosis and tells on which side the pituitary microadenoma is located. CRF may be administered beforehand.

PLASMA CORTISOL BY RADIOIMMUNOASSAY

This measures the most important glucocorticoid (bound and unbound). Normal 5-25 mg/dL at 8 AM, 2-13 mg/dL at 4 PM)

In plasma, around 75% or total cortisol is bound to transcortin ("cortisol binding globulin", a minor α-1 globulin), around 15% is bound to albumin, and 10% is the unbound ("free") hormone.

Estrogens (oral contraceptive pill, pregnancy, etc.) increase transcortin levels and thus "total cortisol".

*This commonly-performed assay is replacing three obsolete tests.

Serum 17-OHCS (17-hydroxycorticosteroids, "Porter-Silber chromogens"; these are C21 steroids with dihydroxyacetone on C17.)

Phenylhydrazine and sulfuric acid give color to those steroids with a dihydroxyacetone side chain. In serum these are:

• cortisol ("hydrocortisone")
• cortisone (exogenous, probably)
• 11-deoxycortisol

Cortisol is normally the most abundant of these three, and for practical purposes, serum 17-OHCS measures total serum cortisol.

Serum cortisol by fluorimetric assay ("Mattingly")

Sulfuric acid and ethanol cause cortisol (and corticosterone and other less abundant steroids) to fluoresce.

Competitive protein binding: an old-fashioned radioassay.

Plasma cortisol is generally increased in Cushing's syndrome, and loss of diurnal variation (* 4 PM cortisol more than half 8 AM value) suggests Cushingism.

These findings are not specific to Cushingism, and may be seen in "stress" from most any cause.

If your patient's "spot" cortisol at 6-8 AM is less than 80 nonamoles/L, it's either addisonism or binding protein deficiency. However, a "spot" plasma cortisol may be normal in all but the worst cases of adrenal insufficiency (addisonism). Therefore, it should not be used alone as a screening test for adrenal insufficiency!

A patient with marginal adrenal cortical function is likely to have a normal plasma cortisol but suffer "Addisonian crisis" under stress (illness, surgery, endocrine testing....) Such a person may even pass the ACTH stimulation test, and some surgeons give post-surgical patients with high-output, low-peripheral-resistance shock a bolus of glucocorticoids (Arch. Surg. 128: 673, 1993).

URINARY FREE CORTISOL (normal 24-108 micrograms/24 hr)

This radioimmunoassay measures the unconjugated ("free") cortisol present in the urine.

At plasma cortisol concentrations above about 25 mcg/dL, transcortin becomes saturated and unbound, unconjugated cortisol spills into the glomerular filtrate.

Normal urinary free cortisol ranges around 20-90 mcg/24 hr. Of course, urinary free cortisol, unlike plasma cortisol, gives an integrated value over time.

The 24 hour urinary free cortisol (per gram of creatinine) seems to be the best way to screen hospital patients for Cushingism (Arch. Pathol. Lab. Med. 109: 222, 1985; little has changed.) Depressed, stressed, and hard-drinking patients are the only false-positives.

This test is worthless for the detection or differential diagnosis of adrenal insufficiency.

* URINARY 17-OHCS (17-HYDROXYCORTICOSTEROIDS, PORTER-SILBER CHROMOGENS)

See serum 17-OHCS above. In urine, the chromogens are reduced and conjugated.

• tetrahydro-cortisol glucuronide
• tetrahydro-cortisone glucuronide
• tetrahydro-11-deoxycortisol (may be removed with CCl₄)

The first two are the principal cortisol metabolites.

Normal range is around 4-15 mg/24 hr or (better) 3-7 mg/gm creatinine.

URINARY 17-KS (17-KETOSTEROIDS)

Metabolites of male sex hormones, etc.; * the major species are derived from α-ketosteroids:

• *dehydroepiandrosterone (DHEA)
• *androsterone sulfate
• *etiocholanolone sulfate

Notice that testosterone is NOT a 17-KS.

*These substances react with meta-dinitrobenzene to produce colored compounds (the "Zimmermann reaction").

*Normal range is around 7-20 mg/24 hr or (better) 4-10 mg/gm creatinine. We do not measure these in serum.

*Fractionation may aid in the diagnosis of adrenal cortical carcinoma (increased dehydroepiandrosterone, a beta-ketosteroid), and of inborn errors of metabolism.

* URINARY 17-KGS (17-KETOGENIC STEROIDS)

These are steroids oxidized by sodium bismuthate (NaBiO₃) to yield a 17-ketosteroid. They include all 17-OHCS, pregnanetriol, and a few obscure molecules with glycerol side chains (cortol, cortolone).

This test is not specific for much of anything, and not in widespread use any more.

ACTH STIMULATION TEST (detecting adrenal insufficiency using the lab: Ann. Int. Med. 139: 194, 2003)

This important test monitors the response of the adrenal cortex to a dose of exogenous ACTH. These are several variations.

One rapid test to screen for Addison's disease requires synthetic ACTH ("Cortrosyn", "tetracosactrin", "cosyntropin" etc., 250 mcg I.M. or IV), with plasma cortisol measured just before and one hour after.

A serum cortisol peak over 415 nmol/L rules out Addisonism. (In the old days, we were told that the serum cortisol level "should double"; this is no longer standard).

In full-blown Addison's disease, there is little or no response. Your may then with the confirm this with a prolonged infusion test.

One prolonged infusion test requires synthetic ACTH 500 mcg to be given over 8 hrs each day for one to five days, with plasma cortisol measured before, during, and after each infusion, and urinary hormones measured daily.

In a healthy person, this will result in an increase in hormone production of 3-5 fold on the first day. (If the test is repeated the next day, the response is likely to be still greater.)

In a patient with primary adrenal insufficiency, there is little or no response on the first day. There may be a slight response on the second and third days, but this is likely to taper off on the fourth and fifth days. (Why?)

In a patient with adrenal insufficiency secondary to pituitary insufficiency (low ACTH), adrenal atrophy will usually prevent a normal response. There will be a greater response on each successive day the test is run ("staircase"). (Remember to check these patients for deficiencies in other anterior pituitary hormones!)

Alternatively, in suspected central adrenal insufficiency, consider trying 1 mcg of ACTH; this is plenty to get a normal person to raise the cortisol level above 500 nmol/L. (J. Clin. Endo. Metab. 83: 2726, 1998; by an old student who became a personal friend).

*The test is also occasionally used in suspected Cushingism, though this is much less useful.

In Cushing's disease (with adrenal cortical hyperplasia due to increased ACTH production), there is characteristically a demonstrable response (often exaggerated) to ACTH infusion.

In Cushing's syndrome caused by an autonomously secreting adrenal cortical adenoma, there may or may not be a response to ACTH infusion. (Carcinomas will almost never respond.)

* Since maybe 1% of people have an adrenal "incidentaloma", you may wish to determine whether the one you've just discovered is autonomous and hence suppressing the remainder of the adrenal tissue. A radioactive cholesterol uptake test is a good way to do this. Can you figure out how?

In hypokalemic alkalosis (rarely overt Cushingism) caused by ectopic ACTH secretion by a lung cancer, etc., there may or may not be a response to ACTH infusion.

*The old (but interesting) Thorn Test involved giving an injection of ACTH and observing its effect on the absolute eosinophil count. Failure of the "eo" count to drop by over 50% indicated Addison's disease.

For the use of an ACTH stimulation test to diagnose congenital adrenal hyperplasia, see below.

Warnings:

You can see that the ACTH stimulation test is not much help in the differential diagnosis of Cushing's syndrome, though it has been used for that purpose. (* And there are hazards, notably adrenal hemorrhages during the procedure.)

When you suspect adrenal insufficiency, administer dexamethasone 2 mg before the procedure begins. This will prevent Addisonian crisis. (* It also prevented the frequent allergic responses to the bovine ACTH that was once used for the test.)

METYRAPONE TEST

This important test measures the pituitary gland's ability to produce ACTH when cortisol production is temporarily halted.

Metyrapone ("Metopirone") is a potent inhibitor of 11-hydroxylation (* etc.).

When administered to a healthy subject, cortisol synthesis becomes much more difficult, ACTH production soon increases greatly, and 11-deoxycortisol ("compound S", the immediate precursor of cortisol) is synthesized in great quantity.

This results in a substantial increase in urinary 17-OHCS, plasma 11-deoxycortisol, and ACTH.

One of the newer versions requires metyrapone 30 mg/kg at bedtime, and morning plasma for 11-deoxycortisol and ACTH.

This test is used to screen outpatients for secondary adrenal insufficiency.

The standard oral test for an adult requires metyrapone 750 mg q 4 hr x 6 doses. (Contraindicated in renal failure!)

Normal people will increase urinary 17-OHCS 2-4 fold over baseline, and plasma 11-deoxycortisol will be over 7 mcg/dL.

In patients with adrenal insufficiency with some adrenal reserve, this test can demonstrate a component of pituitary insufficiency.

In Cushing's disease (i.e., a demonstrable or presumed pituitary adenoma making ACTH), there is usually an exaggerated response (3-6 fold increase in urinary 17-OHCS, etc.)

In Cushing's syndrome caused by an autonomously secreting adrenal cortical adenoma or carcinoma, response is usually diminished or absent (i.e., the ACTH-producing cells of the anterior pituitary have been chronically suppressed.)

In the syndrome of ectopic ACTH production, there may or may not be a response to metyrapone.

The main use of the metyrapone test nowadays is to distinguish Cushing's disease from other Cushing syndromes.

This test is probably as sensitive, as specific, and easier to perform than the high-dose dexamethasone suppression test (the other main test for the differential diagnosis of Cushing's syndrome.) It's probably best to do both if you really think Cushingism is present and you must know why (Ann. Int. Med. 121: 318, 1994).

OTHER WAYS OF TESTING PITUITARY ACTH PRODUCTION

*The insulin tolerance test measures the ability of the pituitary gland to respond to hypoglycemia. Serum cortisol is measured before and after an injection of insulin. It is obsolete.

The corticotropin-releasing factor stimulation test measures the response to a dose of this substance by patients with Cushing's syndrome.

Patients with Cushing's disease show a further increase in plasma ACTH and cortisol after receiving sheep CRF (CRH), a much greater response than showed by normal people. Following successful removal of the adenoma, the response returns to normal within a week.

Patients with the ectopic ACTH syndrome or adrenal cortical tumors show no response to CRF (NEJM 310: 622, 1984; still good).

The CRF stimulation test is sometimes used as a complement to the high-dose dexamethasone test (see below) to determine whether this is Cushing's disease rather than just the syndrome. ACTH-omas are quite responsive to CRF, while other causes of Cushingism are not. Review JAMA 269: 2232, 1993; a new version that adds a bit of dexamethasone during the test.

DEXAMETHASONE SUPPRESSION TESTS

These extremely important tests measure the response to various doses of the potent synthetic glucocorticoid, dexamethasone.

A healthy patient given even a low dose of dexamethasone will temporarily stop making ACTH and hence cortisol, and drop the serum level below 50 nmol/L.

In Cushing's disease, the pituitary gland loses some of its sensitivity to feedback inhibition, so there will be little or no decrease in ACTH or cortisol unless the dose of dexamethasone is very high.

Adrenal cortical tumors that overproduce glucocorticoids are not under the control of ACTH (which is suppressed anyway!) and there will be no response to any dose of dexamethasone.

Low dose dexamethasone suppression tests are used to rule out Cushing's syndrome.

The patient is given dexamethasone 1 mg at midnight, and serum cortisol is measured at 8 AM. (Other variants take two days, with 0.5 mg of dexamethasone given every six hours.)

If serum cortisol is below 50 nmol/dL, the patient does not have Cushing's syndrome from any cause (assuming, of course, the patient is not taking exogenous steroids.)

* The one thankfully rare exception: Cushingism due to overexpression of cortisol receptors (J. Clin. Endo. Metab. 85: 14, 2000). By now, you've referred your patient.

Ten percent of patients without Cushing's syndrome will still flunk this test ("pseudo-Cushingism"). This includes patients who:

• are obese (at least the books say this, though some writers disagre. Fat people are often worked up for "glands".)
• are depressed (especially if it's so bad they aren't eating or sleeping. Ask a psychiatrist about the usefulness of this test in the diagnosis of various types of depression. Its use by general internists is discouraged. This test cannot distinguish very depressed patients from those with Cushing's disease.)
• are alcoholics who are still drinking, perhaps secretly
• are taking estrogens, or are pregnant (increased serum transcortin)
• are taking phenytoin, which speeds the metabolism of dexamethasone (and metyrapone too....)

High dose dexamethasone suppression tests are used to distinguish Cushing's disease from other causes of Cushing's syndrome.

After a baseline 8 AM serum cortisol, the patient is given dexamethasone 2 mg q 6 hr x 2-6 days (see, for example, NEJM 324: 822, 1991; * some give 8 mg overnight instead/in addition to J. Clin. End. Metab. 78: 418, 1994), and if there's doubt, go up to 32 mg). The basic high-dose test uses four times as much as the corresponding low-dose protocol.

As noted, Cushing's disease patients usually show at least 50% suppression of cortisol production at this dose. Adrenal tumors and the rare "idiopathic primary hyperplasia" are not suppressed.

PRIMARY ALDOSTERONISM (update Endocrinology 144: 2208, 2003).

Patients with high blood pressure who have low (at least <4.0 mEq/L) serum potassium after ten days off medications, or whose hypertension does not respond well to the usual medications, should be suspected of having primary aldosteronism (i.e., renin-independent, inappropriate over-production of aldosterone).

At least 1% of hypertensives are so affected.

Today's screening test is the plasma aldosterone-renin ratio.

• Aldosterone/Renin > 920: primary aldosteronism or severe chronic renal failure


• Aldosterone/Renin normal, high aldosterone: secondary hyperaldosteronism


• Aldosterone/Renin normal, low aldosterone: hyporeninemic hypoaldosteronism


• Aldosterone/Renin < 28: Addisonism


• All others: "none of the above"



You may want to draw this at 8 AM after a two-hour walk.

The anatomic pathology is either an adrenal adenoma ("aldosteronoma"), which nowadays is usually easy to remove with a laparoscope, or "bilateral idiopathic hyperplasia", which you'll treat with anti-aldosterone medications. These are now simple to distinguish on imaging studies.

TESTING FOR 21-HYDROXYLASE DEFICIENCY ("congenital adrenal hyperplasia")

This common annoying-to-lethal problem virilizes girls, turns boys into "infant Hercules", makes women grow moustaches, and wastes sodium.

The most obvious cases have preposterous elevations of 17-hydroxyprogesterone, and even mild cases will have an exaggerated 17-hydroxyprogesterone response to ACTH stimulation.

Mass screening: the Hungarian (Arch. Dis. Child. 64: 338, 1989) and Swedish (Horm. Res. 30: 235, 1988) experiences.

For the diagnosis of other congenital adrenal hyperplasia enzyme deficiencies, check with your endocrinologist.

ADRENAL MEDULLARY TUMORS

A variety of approaches have been used for the laboratory diagnosis of pheochromocytoma and neuroblastoma

Remember to screen MEN II patients and von Hippel-Lindau patients frequently for "pheo" (NEJM 329: 1531, 1993).

You will detect 98% or more of pheochromocytomas if you get a 24 hr urine specimen (use strong acid as the preservative for this assay) and order urinary catecholamines, metanephrines, and vanylmandelic acid (VMA).

If you suspect neuroblastoma (i.e., the patient is under age 20), order a homovanilic acid (HVA) too.

*Trying to make sense of the literature on neuroblastoma screening and prognostication will drive you nuts. I have some other references if you're interested.

Be sure to order a total creatinine on the sample to be sure it is complete.

Many drugs and possibly some foods interfere with the old colorimetric determination of various catecholamine metabolites. (Interferences with the newer HPLC techniques are much less of a problem.)

L-Dopa, methyldopa, aspirin, coffee, tea, vanilla, bananas, and walnuts are frequently cited.

It is probably best for the patient to remain off all drugs and to avoid the foods listed above for the week prior to the test.

During the past 20 years, a host of tests have been offered to help rule "pheo" in or out. Only three have proved to be of much value.

The clonidine suppression test is based on the fact that pheos are not innervated, so clonidine cannot suppress the production of catecholamines. This is especially helpful in distinguishing "pheo" from "white jacket syndrome" or "nerves". Measure the plasma catecholamines after a dose of clonidine; they'll drop by 80% or so in most folks, but stay up in "pheo" patients. As a general physician, you won't be doing this test.

*The glucagon stimulation test is based on the fact that glucagon somehow releases catecholamines from pheos. It's hazardout.

The isotope scan (I¹³¹metaiodobenzylguanidine) is now well-established to light up adrenal medullary tumors. Of course, CT scans are helpful in finding all but the smallest tumors.

Angiography is hazardous as it can release catecholamines. Fine needle aspiration is absolutely contraindicated if there is suspicion of a pheo.

Carcinoid tumors at many sites may be detected and monitored by measuring 5-hydroxyindoleacetic acid (5-HIAA), the principal metabolite of serotonin. (Review: Endo. Metab. Clin. N.A. 17(2).

Patients must avoid acetaminophen, caffeine, bananas, walnuts, eggplant, avocados, pineapples, plums, and tomatoes.

ADRENAL INCIDENTALOMAS: If you find a benign-looking adrenal nodule on CT scan, and it is >3 cm across, you should perhaps at least follow it with endocrine tests and repeat scans. ("And a chance to cut is a chance to cure": Am. Surg. 55: 516, 1989.)

(Clinical Pathology students: Learn the concepts, don't memorize the numbers.)

Drop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science Trivia Quiz -- have a chuckle!
Rudolf Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Part I
Part II