Re: Weaning off Cortef and some interesting findings! congenital adrenal hyperplasia

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Congenital adrenal hyperplasia was once considered a rare inherited

disorder with severe manifestations. Mild congenital adrenal

hyperplasia, however, is common, affecting one in 100 to 1,000 persons

in the United States and frequently eluding diagnosis. Both classic and

nonclassic forms of the disease are caused by deficiencies in the

adrenal enzymes that are used to synthesize glucocorticoids. The net

result is increased production from the adrenal gland of cortisol

precursors and androgens. Even mild congenital adrenal hyperplasia can

result in life-threatening sinus or pulmonary infections, orthostatic

syncope, shortened stature and severe acne. Women with mild congenital

adrenal hyperplasia often present with hirsutism, oligomenorrhea or

infertility. Congenital adrenal hyperplasia is diagnosed by

demonstration of excess cortisol precursors in the serum during an

adrenal corticotropic hormone challenge. Diagnosis of congenital adrenal

hyerplasia in fetuses that are at risk for congenital adrenal

hyperplasia can be determined using human leukocyte antigen haplotype or

by demonstration of excess cortisol precursors in amniotic fluid.

Treatment includes carefully monitored hormone replacement therapy.

Recognition of the problem and timely replacement therapy can reduce

morbidity and enhance quality of life in patients that are affected by

congenital adrenal hyperplasia.

http://www.aafp.org/afp/990301ap/1190.html

There's the link in case the pictures don't come through.

Ninety percent of cases of congenital adrenal hyperplasia are the result

of a deficiency of the enzyme 21-hydroxylase.

The hallmark of congenital adrenal hyperplasia is inadequate production

of glucocorticoids.^1 Patients with mild congenital adrenal hyperplasia

are frequently unable to mount sufficient stress responses to trauma and

infection. Glucocorticoid precursors accumulate in these persons and are

converted to androgenic steroids, causing shortened stature, early

puberty, severe acne, and virilization and infertility in

females.^2,3,5,6 Mineralocorticoid synthesis can also be affected,

resulting in electrolyte disturbances, hypotension and syncope.^5,6

* Enzyme Pathways and Genetics *

*21-Hydroxylase*

Ninety percent of patients with congenital adrenal hyperplasia have

21-hydroxylase deficiency.^2-4,6 Because this enzyme functions in both

glucocorticoid and mineralocorticoid synthesis, some patients with

21-hydroxylase deficiency have insufficient amounts of cortisone and

aldosterone /(Figure 2)/. These persons have the " salt-wasting " form of

congenital adrenal hyperplasia, with hyponatremia, hypovolemia,

hyperkalemia and hypotension.^1-4,6 The enzyme 21-hydroxylase is a

chromosome 6, human leukocyte antigen (HLA)­linked, cytochrome P450

enzyme that is found in the smooth endoplasmic reticulum. Its DNA

sequence can be altered by at least nine mutations, many of which leave

the enzyme impaired but not totally inactive.^2,3,6

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*Enzymatic Pathway for Cortisol and Aldosterone*

Figure 1

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*FIGURE 1. *Enzymatic pathway for biosynthesis of cortisol and

aldosterone, beginning with cholesterol. Italics denote enzymes.

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* Result of a 21-Hydroxylase Deficiency*

Figure 2

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*FIGURE 2. *Accumulation of progesterone and 17-hydroxyprogesterone as a

result of a 21-hydroxylase deficiency. Italics denote enzymes.

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* Result of an 11-ß Hydroxylase Deficiency*

Figure 3

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*FIGURE 3. *Accumulation of 11-deoxycorticosterone and 11-deoxycortisol

as a result of an 11-ß hydroxylase deficiency. Italics denote enzymes.

The incidence of classic congenital adrenal hyperplasia is especially

high in Madagascar and certain areas of Alaska. Mild congenital adrenal

hyperplasia occurs more frequently in Ashkenazi Jews, and in Hispanic,

Slavic and Italian populations.^2,3,6

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*TABLE 1*

Signs and Symptoms Suggesting Mild Congenital Adrenal Hyperplasia

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*Children*

.. Moderate to severe recurrent sinus or pulmonary infections

.. Severe acne

.. Hyperpigmentation, especially of the genitalia

.. Tall for age

.. Early onset of puberty

* Adults*

.. Childhood history as defined above

.. Syncope or near-syncope

.. Shortened stature compared with either parent

.. Hypotension (21-hydroxylase deficiency)

.. Hypertension (11-ß hydroxylase deficiency)

* Women *

.. Clitorimegaly

.. Poorly developed labia

.. Hirsutism

.. Infertility

.. Polycystic ovary syndrome

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Information from references 1, 3 and 6.

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* 11-ß hydroxylase *

Deficiency of 11-ß hydroxylase is found in 8 to 9 percent of patients

with congenital adrenal hyperplasia.^2,5 Glucocorticoid synthesis

remains impaired but, in this disorder, deoxycortisol accumulates

/(Figure 3)/. Deoxycortisol and its metabolites have mineralocorticoid

properties and may cause hypertension when they accumulate.^2,3,7 Thus,

simple blood pressure measurements may help determine the underlying

type of congenital adrenal hyperplasia. The enzyme 11-ß hydroxylase is a

chromosome 8, cytochrome P450 enzyme located in the mitochondria. Known

gene abnormalities include insertions, deletions, mis-sense/nonsense

codons, and point mutations. Some of these abnormalities result in

severe dysfunction of the enzyme while others result in only partial

impairment.^3-5

Classic 11-ß hydroxylase deficiency occurs in approximately one per

100,000 births and occurs more frequently in Moroccan Jews. Mild

congenital adrenal hyperplasia due to 11-ß hydroxylase deficiency is

more common, however, and may be responsible for 1 to 2 percent of cases

of hirsutism and oligomenorrhea in women.^3-5

* Manifestations and Recognition *

*Classical Congenital Adrenal Hyperplasia *

The classic form of congenital adrenal hyperplasia occurs when cortisol

synthesis is extremely low. The disorder usually manifests in childhood.

Hypersecretion of adrenal androgens causes masculinization of the

external genitalia of the female fetus. Affected infants can have

ambiguous genitalia or even erroneous gender assignment. Because

testicles are not present to produce müllerian inhibiting factor, the

internal female organs are intact.^1,2,4

Children with classic congenital adrenal hyperplasia may lack sufficient

amounts of cortisol to mount a stress response, and they frequently

succumb to minor illnesses. Those who survive to adulthood experience

premature puberty. Premature closure of the epiphyses results in short

stature even though these children grow at an accelerated rate when

young. Severe acne is also a frequent problem. Adult women with classic

congenital adrenal hyperplasia may have pronounced hirsutism and

amenorrhea.^1-4,6

*Mild Congenital Adrenal Hyperplasia *

Mild congenital adrenal hyperplasia is much more common than the classic

form.^2,3,5,6 Men and women with mild congenital adrenal hyperplasia may

have normal height compared with the general population, yet shortened

stature when compared with their parents. Near-syncope may be a chronic

or recurrent problem in these patients, and they frequently have a

history of severe acne and mild hyperpigmentation. Some people with mild

congenital adrenal hyperplasia can mount limited glucocorticoid stress

responses and are thus never recognized as having the disorder. Others,

however, have frequent illnesses and decompensate when challenged by

common infections or minor trauma.^1-4,6

Women with congenital adrenal hyperplasia may have clitorimegaly and

poorly developed vaginal labia. These women may also be hirsute and

frequently present with oligomenorrhea, infertility or polycystic ovary

syndrome.^1-7

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* Treatment of Mild Congenital Hyperplasia *

Figure 4

*--To perform ACTH stimulation test, draw serum to determine baseline

17-hydroxyprogesterone and deoxycortisol levels. Administer 250 µg of

ACTH intravenously. Wait one hour. Draw poststimulation serum to

determine 17-hydroxyprogesterone and deoxycortisol levels.

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*FIGURE 4. *Algorithm for the treatment of mild congenital adrenal

hyperplasia. (ACTH=adrenocorticotropic hormone)

* Diagnosis and Treatment *

* Adults and Children *

When mild congenital adrenal hyperplasia is suspected, elevated serum

levels of 17-hydroxyprogesterone suggest 21-hydroxylase deficiency, and

elevated deoxycorticosterone/11-deoxycortisol levels suggest 11-ß

hydroxylase deficiency /(Table 1; Figures 4 and 5)/. In patients who

have few or no symptoms of mild congenital hyperplasia, the risks of

treatment may outweigh the benefits. Patients who require treatment

should be given glucocorticoid replacement therapy at the lowest dosage

that achieves adrenal suppression; higher dosages can cause Cushingoid

features and growth retardation.

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Mild congenital adrenal hyperplasia should be considered in a patient

presenting with near-syncope, severe acne, mild hyperpigmentation and a

poor response to stress or infections. It should also be considered in

female patients with signs of virilism, such as clitorimegaly and

hirsutism.

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Maintenance therapy is generally achieved with hydrocortisone, in a

dosage of 6 to 25 mg per m^2 per day given in two to three divided

doses.^1,3,4,8 Hydrocortisone is preferred over other glucocorticoids

because it is short acting and can be given in pulses that mimic natural

cortisol secretion. Equivalent dosages of prednisone or dexamethasone

can be used to simplify dosing regimens in noncompliant patients;

however, hydrocortisone is more physiologically similar to cortisol and

has a lower potential for growth suppression in children.^3,4 Periods of

physiologic stress, such as severe illness or surgery, require transient

dosages of three to 10 times that used for maintenance therapy.^1,3,4,8

Stress dosages are usually not needed in mild illnesses such as colds or

otitis media.^2-4

Corticosteroid replacement therapy must be approached carefully.

Hydrocortisone dosages that return

17-hydroxyprogesterone/11-deoxycortisol levels to normal frequently

induce Cushingoid features, whereas lower dosages may leave the effects

of excess androgen production unchecked. Consultation with an

endocrinologist is recommended for patients who require complex hormone

regimens.

Many patients benefit from multidrug therapy. Even normotensive patients

with 21-hydroxylase deficiency /(Figure 2)/ may have improved adrenal

suppression with the addition of the aldosterone analog fludrocortisone

(Florinef) at dosages of 0.05 to 0.2 mg per day to their regimen.

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*Analysis of 17-Hydroxyprogesterone Levels*

Figure 5

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*FIGURE 5. *Nomogram for analysis of 17-hydroxyprogesterone levels

during an adrenocorticotropic hormone challenge in patients with

suspected congenital adrenal hyperplasia. Note logarithmic scales.

(CAH=congenital adrenal hyperplasia; OHP=hydroxyprogesterone;

ACTH=adrenocorticotropic hormone). Data from references 2, 3 and 4.

NOTE: Boxes as drawn are arbitrary delineations between various forms of

the disease.

The use of flutamide (Eulexin), an androgen inhibitor, in a dosage of

approximately 10 mg per kg per day in three divided doses, in patients

with all types of congenital adrenal hyperplasia may permit

hydrocortisone to be given at lower dosages.^8,9 Aromatase inhibitors

that prevent conversion of androgens to estrogen (such as testolactone

[Teslac], in a dosage of 40 mg per kg per day), may help children with

mild congenital adrenal hyperplasia to achieve their height

potential.^1,8,9

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Hydrocortisone is preferred in the treatment of symptomatic patients

with mild congenital adrenal hyperplasia because it is short acting and

can be given in pulses that mimic natural cortisol secretion.

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*Prenatal Therapy*

If one child in a family is already affected by congenital adrenal

hyperplasia, the HLA haplotypes of the parents and the affected child

should be determined. Subsequent pregnancies can then be accurately

evaluated for congenital adrenal hyperplasia by HLA haplotype analysis

of chorionic villus or amniotic cells.^2,3 In families at risk (e.g.,

one or both parents affected by some form of congenital adrenal

hyperplasia) but with no affected children, congenital adrenal

hyperplasia can be diagnosed during pregnancy by DNA analysis of

chorionic villus or amniotic fluid cells or by measuring 17-hydroxy

steroids in the amniotic fluid.^10 All women with fetuses at risk for

congenital adrenal hyperplasia should receive dexamethasone in a dosage

of 0.02 mg per kg per day, divided into two or three daily doses.

Treatment should be initiated immediately on confirmation of

pregnancy.^4,10 Dexamethasone readily crosses the placenta and

suppresses the fetal adrenal gland. If the fetus is male, dexamethasone

therapy can be stopped until after the infant is born. Affected female

fetuses, however, require treatment throughout pregnancy.

Treatment of affected fetuses with maternal dexamethasone reduces the

incidence and severity of virilization of female fetuses. Birth weight,

length, head circumference and congenital anomalies of affected infants

whose mothers are treated with dexamethasone during pregnancy are

comparable to those of infants who do not have congenital adrenal

hyperplasia.^10 Maternal complications from treatment with dexamethasone

can be expected and include excess weight gain, mood swings and

hypertension.^10,11

The authors thank Kopp, M.D., and Fred Pfalzgraf, M.D., for

their thoughtful reviews of the manuscript.

The opinions and assertions contained herein are the private views

of the authors and are not to be construed as official positions of

the Department of Defense, the Department of the Army or the

Department of the Navy.

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* The Authors *

MICHAEL A. DEATON, M.D, PH.D.,

is currently Chief of Primary Care and Community Medicine at General

Leonard Wood Army Community Hospital, Fort Leonard Wood, Mo. He received

a doctorate in anatomy from Vanderbilt University School of Medicine,

Nashville, Tenn., and a medical degree from the Uniformed Services

University of the Health Sciences F. Hébert School of Medicine,

Bethesda, Md. Dr. Deaton completed a residency in family practice at

Tripler Medical Center, Honolulu, Hawaii.

JOHN E. GLORIOSO, M.D.,

is currently Chief of Family Practice and Aviation Medicine at Yuma

Proving Grounds, Yuma, Ariz. He graduated from the University of

land School of Medicine, Baltimore, and completed a residency in

family practice at Tripler Medical Center. He is a graduate of the Army

Aviation Medicine Course.

DAVID B. MCLEAN, M.D.,

is currently a family physician on staff at Makalapa Clinic, Pearl

Harbor, Hawaii. He received a medical degree from Virginia Commonwealth

University Medical College of Virginia School of Medicine, Richmond, and

completed a residency in family practice at Tripler Medical Center.

Address correspondence to A. Deaton, M.D., Ph.D., Division

of Primary Care and Community Medicine, USA MEDDAC, General Leonard

Wood Army Community Hospital, 126 Missouri Ave., Fort Leonard Wood,

MO 65473. Reprints are not available from the authors.

REFERENCES

1. Cutler GB Jr, Laue L. Congenital adrenal hyperplasia due to

21-hydroxylase deficiency. N Engl J Med 1990;323:1806-13.

2. New MI. Genetic disorders of adrenal hormone synthesis. Horm Res

1992;37(suppl 3):22-33.

3. WL. Congenital adrenal hyperplasias. Endocrinol Metab Clin

North Am 1991;20:721-49.

4. New MI. Congenital adrenal hyperplasia. In:

DeGroot LJ, ed. Endocrinology. 3d ed. Philadelphia: Saunders,

1995:1813-35.

5. White PC, Speiser PW. Steroid 11 beta-hydroxylase deficiency and

related disorders. Endocrinol Metab Clin North Am 1994;23:325-39.

6. Migeon CJ, Donohoue PA. Congenital adrenal hyperplasia caused by

21-hydroxylase deficiency. Endocrinol Metab Clin North Am

1991;20:277-96.

7. Baskin HJ. Screening for late-onset congenital adrenal hyperplasia

in hirsutism or amenorrhea. Arch Intern Med 1987;147:847-8.

8. Merke DP, Cutler GB Jr. New approaches to the treatment of

congenital adrenal hyperplasia. JAMA 1997;277:1073-6.

9. Laue L, Merke DP, JV, KM, Hill S, Cutler GB Jr. A

preliminary study of flutamide, testolactone, and reduced

hydrocortisone dose in the treatment of congenital adrenal

hyperplasia. J Clin Endocrinol Metab 1996;81:3535-9.

10. Karaviti LP, Mercado AB, Mercado MB, Speiser PW, Buegeleisen M,

Crawford C, et al. Prenatal diagnosis/treatment in families at

risk for infants with steroid 21-hydroxylase deficiency

(congenital adrenal hyperplasia). J Steroid Biochem Mol Biol

1992;41:445-51.

11. Seckl JR, WL. How safe is long-term prenatal glucocorticoid

treatment? JAMA 1997;277:1077-9.

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> By the way, I found out from the path report that my thyroid gland

> lesion was also hyperplastic, is that basically the same as

> hyperplasia? Or am I presuming something here? My Endo said it was

> a bunch of condensed cells producing too much? <--- Or did I

> misunderstand him...? Anyone?

>

> Hugs,

> Canasa

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