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New Discovery?: High Cortisol Binding Globulin as cause of Addison's?

Mike Welch, Devon,UK.

First published: 14 February 2006

Since late 2004 it has become increasingly obvious that a proportion of patients who present to their General Practitioner (GP), Primary Care Physician (PCP), or Endocrinologist, with a multitude of signs and symptoms which closely resemble or are identical to those often seen with adrenal insufficiency, or Addison's Disease per se, when tested do NOT exhibit the classical results which may have been expected with the condition.

It is well known that the body may be expected to respond to stress with an increase in the level of cortisol. When a random sample of blood plasma is analysed for cortisol, patients with adrenal insufficiency may be seen to exhibit a low, low normal, or normal level of this hormone. However, for years it has been the norm to confirm the diagnosis of Addison's Disease by means of the SynActhen (Synthetic ACTH enhancement) test, known in the USA and some other countries as the Stim (ACTH stimulation) test.
This test is traditionally performed on patients who are not on any supplementary corticosteroid therapy (i.e. hydrocortisone or prednisolone). However in an emergency patients who have been prescribed the alternative corticosteroid, dexamethasone, may have the SynActhen test performed without results being adversely affected or skewed. A baseline cortisol assay sample of blood is taken. The patient is then given the appropriate dose of ACTH, following which repeat samples of blood are taken after 30 minutes & often another at 60 minutes for further cortisol assays to determine what response has been generated by the adrenal glands.

It has been noted that a few patients who, clinically, have been judged by their physician to exhibit classic signs of Addison's disease, have reported to me personally or via the 'Yahoo' Addison's disease discussion group that they have been told by their physician that their SynActhen test results have not supported a diagnosis of Addison's disease. Where these particular patients have had access to copies of the results of these tests or the results have been explained to the patient by the physician, it has often been related that the cortisol response has either been sub-optimal from a normal or low normal baseline level, or that the result appears to be 'normal'. Several of this group of patients have subsequently had repeat SynActhen tests performed and found that the results have varied from the previous tests. Not all the patients who have initially had sub-optimal or normal results have had repeat tests carried out.
In the United States, an alternative diagnosis if 'adrenal fatigue' is often offered for example, where the ACTH stimulation test fails to provide the expected results in the face of clinical signs & symptoms highly suggestive of Addison's disease.

I am a retired Chief Biomedical Scientist with over 36 years experience in pathology and I believe these results from patients who were clinically suffering from symptoms of adrenal insufficiency suggest that something else was interfering, in those patients' blood stream, with their cortisol levels. I had already noticed that most of this group of patients were female and that many had reported they also suffered from an established diagnosis of hypothyroidism or Hashimoto's disease. One female patient in the group who also had Hashimoto's disease reported that her replacement dose of thyroxine had at one time required increasing over a period of several months from 200µg/day (often recognised as full replacement dose) to 400µg/day at the time of an apparently unrelated medical condition. This required increase had been investigated by her endocrinologist and discovered to be the result of an elevated level of thyroid binding globulin (TBG).

From research on the Internet, I discovered a paper by Wyeth Lederle, a well known drug company, in which they related the fact that patients with increased TBG levels also were often found to also have elevated levels of both sex hormone binding globulins (SHBG) and cortisol binding globulins (CBG). I also uncovered another report by the Department of Chemical Pathology at Hong Kong University Hospital in which they mentioned in a ward manual that high CBG could affect cortisol response to ACTH, 'often from a normal baseline'.

Following discussion with an endocrinologist in the United States, with patients who have encountered similar problems in establishing an adequate diagnosis by their physicians, and after further extensive research on the Internet, I submit the following theory which I confidently believe explains the previously unknown or 'atypical' form of Addison's disease, its cause, and the tests required to assist the clinician to establish the diagnosis:-

The Theory of High CBG Addison's Disease.

The cause of primary Addison's disease in the 21st century is autoimmune in approximately 70% of cases, with antibodies (where found) directed against adrenal tissue.
The SynActhen test as described currently remains the method of choice to establish if adrenal insufficency exists.

In a small proportion of patients (see below) who clinically manifest the signs and symptoms of adrenal insufficiency, the SynActhen test as currently performed fails to support the diagnosis of Addison's disease. Instead it may show either an unexpected normal result, or a sub-optimal response to ACTH from, often, a normal baseline. Furthermore, results may vary on subsequent repeated SynActhen tests from previous investigations.

It is suggested that an elevated level of Cortisol Binding Globulin, which are known to have been reported in patients with pre-existing raised Thyroid Binding Globulin levels, binds to the free cortisol in the blood plasma, thus giving false negative or variable non-responsive results when a SynActhen test is performed under current conditions.

Tests Required to Confirm or Exclude High CBG Addison's Disease.

Current methodology for SynActhen tests measures total plasma cortisol levels, i.e. free plus protein bound plasma cortisol.
Bound cortisol cannot be easily metabolised by the human body, thus the measured levels of cortisol in the SynActhen test may not truly reflect the amount of free cortisol available for use within the body.

A modification to the SynActhen test whereby free cortisol in plasma is the required measurement, together with an assay of CBG, may be required to enable the clinician
to establish a diagnosis of atypical, or high CBG, Addison's disease.

Current methodology for the assay of free cortisol in plasma is not yet established as an accredited technique. This requires urgent attention. In discussion with my own endocrinologist (who accepted that the CBG AD theory is correct) I understand that work is in progress to establish an accredited method for this test within the UK.

Criteria for Patients With Suspected High CBG Addison's Disease.

The patients who should be considered as suffering from High CBG Addison's disease and who should be tested as above fit into a fairly tight group of criteria.

They appear to satisfy most or all of the following criteria:

• Female.
• Suffer from an upset of oestrogen/progesterone balance. (Mostly related to gynaecological problems, may also include patients with or who have suffered from oestrogen dependent breast carcinoma, amongst other conditions)
• With hypothyroidism or established Hashimoto's thyroiditis, on replacement thyroxine.
• With elevated thyroid binding globulin.
• Have been shown to demonstrate non-responsive or variable SynActhen test results often from normal or low normal baseline cortisol.
• Exhibit classic symptoms of adrenal deficiency or Addison's disease (including those patients elsewhere in the world considered to suffer from 'adrenal fatigue').