May 2004 CBR 220404.qxd

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					Consensus Statement Review

Diagnosis and Complications of Cushing's Syndrome:
a Consensus Statement
J Clin Endocrinol Metab 2003;88:5593-602.

Reviewed by *Chotoo Bhagat
Clinical Biochemistry, PathCentre, Nedlands, WA 6909, Australia.
*For correspondence: Dr Chotoo Bhagat: e-mail

This is a Consensus Statement arising from a workshop held         the unextracted urine by immunoassay on Immulite 2000; the
in Ancona, Italy in October 2002. It was attended by almost        term UFC is used when cortisol is measured by HPLC.
50 leading endocrinologists with specific expertise in the
management of Cushing’s Syndrome (CS). In this review of           • 24 Hour UFC
the Consensus Statement I have only selected tests that are
commonly used in Australia. My comments and opinion are
                                                                   Twenty four hour UFC gives an integrated index of free or
in italics.
                                                                   unbound plasma cortisol. It is not affected by factors that
                                                                   influence cortisol binding globulin.
Diagnosis of CS

                                                                   I am surprised that the measurement of 24 hour urine
In the diagnosis of endogenous CS one should exclude
                                                                   creatinine to verify adequacy of urine collection is left as an
exogenous intake of oral, parenteral, inhaled or topical
                                                                   option and not as a recommendation.

In addition to these sources of exogenous                          If glomerular filtration rate is less than 30 mL/min, urine
corticosteroids, I have come across patients with Cushingoid       cortisol excretion is decreased and is a potential cause of
features who were taking either high dose medroxyproges-           false negative results. The methods for urinary cortisol are
terone for endometrial cancer or herbal medicine containing        immunoassay (IA), HPLC or mass spectrometry combined
corticosteroids. These patients were identified by taking          with gas chromatography or HPLC. The IA methods are less
history from patients with Cushingoid features and low             expensive and easily available compared with other
random serum cortisol.                                             techniques.

   First Line Screening Tests                                      We measure urinary free corticoids by IA; where the result is
                                                                   borderline or there is a strong clinical suspicion of CS and
In the Consensus Statement the first line screening tests for      the UFCo is within reference interval we measure urinary
CS are 24 hour urine free cortisol (UFC), low-dose                 cortisol by HPLC.
dexamethasone suppression test (DST) and late night
salivary cortisol.                                                 UFC may not identify patients with mild hypercortisolism
                                                                   and therefore UFC cannot be considered a universal single
In my laboratory the first line screening test is 1 mg overnight   screening test for the detection of CS.
DST, except in women who are on oral contraceptives or
oestrogens for whom we recommend 24 hour urine free                The Consensus opinion is that intermittent hypercortisolism
corticoids (UFCo). We use the term corticoids rather than          or cyclical CS is highly unlikely if three 24 hour UFC are
cortisol because cortisol metabolites are also measured in         normal.

                                                                                 Clin Biochem Rev Vol 25 May 2004            149

• Low-dose DST                                                    We use the low dose DST over 2 days as part of extended low
                                                                  dose-high dose DST to confirm the diagnosis of CS once the
The overnight low dose test consists of dexamethasone (1mg)       screening tests have been found to be positive.
taken orally between 2300 and 2400 hours, and the
measurement of fasting plasma cortisol between 0800 and           I will not comment on the DST-CRH combined test as CRH is
0900 hours the following morning. As indicated in the             not readily available in Australia.
Consensus Statement there are many causes of false positive
results     for    low     dose     DST      besides    oral      Differential Diagnosis of Cushing’s Syndrome
contraceptives and oestrogens. These include acute and
chronic illness, chronic anxiety, depression, alcoholism,         • Adrenocorticotrophic Hormone (ACTH) Measurement
malabsorption and ingestion of drugs such as barbiturates,        and High-dose DST
phenytoin and carbamezapine which enhance hepatic
dexamethasone metabolism. The original criteria for normal        Measurement of basal plasma ACTH and high dose
level of suppression was a plasma cortisol below 138 nmol/L       dexamethasone are used to determine the cause of CS. ACTH
but more recently the cut-off has been reduced to 50 nmol/L,      concentration below 2 pmol/L at 0900 hours suggest an
the latter resulting in greater sensitivity but more false        ACTH independent cause and values above 4 pmol/L suggest
positive results.                                                 an ACTH dependent cause. ACTH levels tend to be higher in
                                                                  ectopic ACTH secreting CS than in Cushing’s disease but the
The Consensus Statement does not state what                       values overlap.
cut-off level should be adopted. In my laboratory we have
adopted 100 nmol/L as the cut-off. We found that 33 of 195        High dose glucocorticoids partially suppress ACTH secretion
patients had serum cortisol between 50 and 100 nmol/L and         from most corticotroph adenomas (80-90%) whereas ectopic
39 greater than 100 nmol/L in the overnight 1 mg DST.             tumours are resistant to feedback inhibition. However, in
                                                                  some benign differentiated neuroendocrine tumours (usually
• Late Night Salivary Cortisol                                    carcinoid tumours of bronchus, thymus and pancreas)
                                                                  cortisol may be suppressed by high dose dexamethasone. In
Late night salivary cortisol is said to be a promising            adrenal CS there is lack of cortisol suppression. Suppression
screening test for CS. Larger studies are necessary before this   is defined as 50% reduction in basal cortisol.
could be considered as a first line screening test.
                                                                  However the greater the reduction the more likely that CS is
                                                                  due to pituitary adenoma.
   Second Line Screening Tests
                                                                  There are several versions of high dose DST including the
Midnight plasma cortisol, low dose DST over 2 days and
                                                                  standard 2 mg 6 hourly for 8 doses, the overnight 8 mg and
combined DST-Corticotropin-releasing hormone (CRH) have
                                                                  IV 4-7 mg test. Plasma and/or urine cortisol are evaluated
been listed as second line screening tests.
                                                                  before, during and after dexamethasone administration.
• Midnight Plasma Cortisol
                                                                  • Pituitary and Adrenal Scans

Midnight plasma cortisol requires inpatient admission for a       Pituitary MRI should be done in all patients with ACTH
period of at least 48 hours.                                      dependent CS. This will reveal a discrete adenoma in 60% of
                                                                  patients. Adrenal scans should be done in ACTH independent
In my laboratory we have found midnight cortisol                  CS. However, incidental tumours of pituitary gland (10%)
particularly useful to rule out CS in a psychiatric patient who   and adrenal gland (3-4%) may be found on MRI/CT scans.
was on phenytoin (consequently the overnight DST was
positive) and accurate collection of 24 hour urine was not        • Bilateral Inferior Petrosal Sinus Sampling
                                                                  Bilateral inferior petrosal sinus sampling for ACTH
Two cut-off values are mentioned in the Consensus                 determination should be recommended in patients with
Statement: 50 and 207 nmol/L.                                     ACTH dependent CS whose clinical, biochemical or
                                                                  radiological studies are discordant or equivocal. CT and/or
Once again they do not recommend which cut-off value to           MRI of neck, thorax and abdomen should be performed in
adopt. We have adopted a value of 200 nmol/L.                     the search for occult ectopic secreting tumours.

150 Clin Biochem Rev Vol 25 May 2004
Cushing’s Syndrome Consensus Statement

Complications of CS

Patients with CS have a mortality rate four times higher than
age- and gender-matched subjects. This is due to
complications of the syndrome. Most patients with CS
develop some manifestations of the metabolic syndrome.
These include insulin resistance, visceral adiposity,
dyslipidaemia, carbohydrate intolerance and/or type 2
diabetes mellitus, coagulopathy and hypertension. This
contributes to increased cardiovascular risk.

Growth hormone secretion is decreased but the changes in
IGF-I are minor. Reproductive function is often altered in
CS; men usually exhibit hypogonadotropic hypogonadism
whereas women of reproductive age have oligomennorhoea
or anovulation. Hypercortisolism causes suppression of TSH
and impaired conversion of thyroxine to trioiodothyronine
(T3); consequently TSH and FT3 are low.

However there is little evidence for the Consensus Statement
that FT4 is also low in CS.

Osteoporosis and pathological fractures can be a presenting
sign of CS in some patients. The prevalence of osteoporosis
in adult patients with CS has been reported at approximately

Subclinical hypercortisolism is present in about 10% of
patients with adrenal incidentalomas.


In conclusion, I found this article disappointing. It was more
of a review than a Consensus Statement. For example it
stated what different cut-offs were for low dose DST and
midnight cortisol but did not come to a consensus of which
ones to adopt. But as a review of CS, it was comprehensive.

1 Papanicolaou DA, Yanovski JA, Cutler GB, Jr, Chrousos
GP, Nieman LK. J Clin Endocrinol Metab 1998;83:1163-7.

                                                                 Clin Biochem Rev Vol 25 May 2004   151