Biochemical Assessment and Long-Term Monitoring in Patients with Acromegaly: Statement from a Joint Consensus Conference of The Growth Hormone Research Society and The Pituitary Society.

Abstract

In April 2003, the Growth Hormone (GH) Research Society and The Pituitary Society developed a consensus statement to address the current status of both biochemical assessment and long-term monitoring in patients with acromegaly. They also highlighted the pitfalls of current GH and Insulin-like Growth Factor-1 (IGF-1) assay methodologies and the difficulties in defining target GH and IGF-1 levels in treated acromegaly.

Consensus Statement: Biochemical Assessment of the Patient with Acromegaly

GH Assays

GH measurements are currently readily available on commercial automated platforms using non-isotopic two-site monoclonal antibody assays. These have enhanced sensitivity compared to the polyclonal radioimmunoassays available since the early 1960s, allowing more accurate quantitation of the lower detection limit of GH secretion.

Comment:

In the Royal College of Pathologists of Australasia (RCPA) Quality Assurance Programs 2003, there were 47 laboratories enrolled in the GH external quality assurance program. Of these laboratories, only two were still using RIA. The majority of the laboratories are using immunochemiluminometric assay on DPC IMMULITE. The analytical sensitivity of GH assay quoted by DPC IMMULITE is 0.01 μg/L (0.026 mU/L^*).

An Optimal GH Assay Should Have the Following:

1. The sensitivity limit of the assay should be <0.1 μg/L (<0.26 mU/L^*) with interassay coefficient of variation of <15%.

2. Assay should be validated with a normal range for suppressed GH levels after an oral glucose load (OGTT).

3. Have information on the antibody specificity to the GH isoform (the most abundant in circulation being the monomeric 22 kDa isoform).

The laboratory should have this information available to the treating clinicians to enable appropriate interpretation of the GH results. As there is lack of standardisation of GH assays, this limits comparisons of results between laboratories.

IGF Assay

Measurement of serum IGF-1 is a reliable indicator of GH status in acromegaly. There should be appropriate age and gender matched reference intervals. Serum IGF-1 is the best biochemical marker of clinical disease activity and no additional information will be gained from measuring IGF-binding protein 3.

Problems associated with IGF-1 assays:

1. Inadequate age-adjusted normative data

2. Difficulty in comparing results between laboratories due to lack of standardisation

3. Susceptibility to interference from binding proteins (e.g. IGFBPs)

4. Lack of a pure international reference preparation

The laboratory should participate in an EQAP and should be able to present individual IGF-1 results as an SD score.

Dynamic Tests

Of the many dynamic tests available to assess acromegaly, GH response to an OGTT still offers valuable information when there is a discrepancy between IGF-1 and GH levels. It does not add diagnostic value when IGF-1 level is clearly elevated.

In acromegaly, GH secretion is typically non-suppressible during an OGTT. However, false positives may occur with the following:

• Puberty

• Pregnancy

• Hepatic disease

• Renal disease

• Anorexia Nervosa

• Diabetes Mellitus

The criteria for adequate suppression need to be defined for each specific GH assay.

Comment:

Age-adjusted IGF-1 level is the best screening test for suspected acromegaly. If this is clearly elevated, one should proceed to MRI of the pituitary. If the IGF-1 result is equivocal, consider GH response to a 75g oral glucose load (OGTT) with sampling of GH every 30 minutes over 2 hours. The consensus from the Acromegaly Treatment Workshop in 2002 recommended that GH nadir during OGTT should be <1 μg/L (2.6 mU/L) in the therapeutic and diagnostic management of acromegaly.² The current consensus statement does not define diagnostic criteria for adequate suppression during an OGTT. The emphasis was that current two-site immunoradiometric or chemiluminescent assays are more sensitive than the previous RIA methods, GH levels quantified by current assays should be “several folds lower”. In a long-term, post-operative follow-up study of acromegalic patients, Ronchi et al felt that GH nadir after OGTT <1 μg/L is adequate to establish biochemical remission.³ Lowering the post-OGTT GH cutoff to that seen in healthy controls [0.19 μg/L (0.5 mU/L)] did not identify patients at risk of disease recurrence.³ In the editorial by Trainer, he felt that GH nadir after OGTT should be 0.3 μg/L (0.8 mU/L), well within the sensitivity of all major commercial assays.⁴

Random or basal GH level is not a sensitive or specific test for acromegaly given the pulsatile nature of GH secretion. Elevations of random GH levels are also seen in stress, chronic renal failure, liver failure, diabetes mellitus, and malnutrition. Interpretation of GH levels should be in conjunction with IGF-1 measurement. If a random GH level is 0.4 μg/L (<1 mU/L) and IGF-1 is in the age- and gender-matched reference interval, the diagnosis of acromegaly can be excluded.²

TRH and GnRH stimulation tests of GH secretion are of little diagnostic value in the management of acromegaly and offer no advantage over the OGTT.²

Long-Term Monitoring

The primary goal of treatment for acromegaly is to normalise both GH and IGF-1 levels. Published literature has shown that random GH level <2.0 μg/L (<5.2 mU/L) by traditional RIA is associated with reversal of increased mortality. There are currently no long-term data on the effect of different IGF-1 levels on mortality and morbidity in acromegaly. Discordant GH and IGF-1 values may be seen in 30% of patients and in these circumstances, an OGTT should be performed. It is suggested that glucose suppression of GH should be as low as <0.3 μg/L (<0.8 mU/L) as measured by current two-site assays.

Comment:

The decision to treat and frequency of monitoring rest on the clinical acumen of the clinicians, the individual patient, their disease activity and co-morbidities. The goals of therapy in acromegaly are to remove or shrink the pituitary lesion, to restore GH and IGF-1 levels to normal, and to retain normal pituitary function. The laboratory should provide robust GH and IGF-1 assays with good sensitivity and precision to improve critical evaluation of these therapeutic outcomes.

The consensus statement does not provide a biochemical definition of cure in treated acromegaly. The authors recommend that the IGF-1 level should be within the age-adjusted reference interval and glucose suppression of GH may be as low as 0.3 μg/L (0.8 mU/L). This is in contrast to another consensus statement published in 2000 addressing the criteria for cure of acromegaly.² In this consensus, biochemical control is achieved when circulating IGF-1 level is reduced to age-adjusted normal range and nadir GH after glucose load is less than 1 μg/L (2.6 mU/L).

In summary, the consensus statement

1. Highlighted the evolution of assay methodologies of GH and IGF-1 and the improved sensitivity of these assays.

2. Emphasised the importance of using age- and sex-adjusted IGF-1 reference intervals.

3. Gave an overview of currently available treatments for acromegaly.

4. There was no consensus in defining biochemical criteria or cut-offs for adequate suppression to an OGTT for diagnosis and biochemical cure in treated acromegaly.

5. Did not address the potentially increased risk of mortality associated with hypopituitarism from aggressive treatments (e.g. surgery and radiotherapy) of acromegaly.⁵

Follow-up Recommendations in Treated Acromegaly

Treatment	Biochemical Assessment
Post Surgery	Measurement of both GH and IGF-1 at 3 months. If normal GH and IGF-1 levels, then annual follow-up. Assessment of residual pituitary function at 3 months or earlier.
Medical Therapy
Dopamine Agonists e.g. cabergoline, bromocriptine, pergolide	Measurement of both GH and IGF-1 at 3 months. If normal GH and IGF-1 levels, then annual follow-up. Adequate response in a minority of patients.
Somatostatin Analogs e.g. octreotide, lanreotide	Normalisation of GH and IGF-1 occurs in 60% patients (inversely related to pre- treatment GH levels). Annual follow-up when control is stable.
GH receptor antagonist (Not currently available in Australia)	Measurement of IGF-1 only, at 6 monthly intervals after dose titration. Monthly monitoring of liver function initially for 6 months, then less frequently. Can normalise IGF-1 in >90% patients. MRI pituitary 6 monthly in the first year of treatment, annually thereafter. There is a theoretical risk of tumour enlargement in a minority of patients.
Postradiotherapy
Conventional multiple dose radiotherapy	Measurement of GH and IGF-1 after 2 years then annually. Annual assessment of residual pituitary function.
Single dose radiosurgery	Measurement of GH and IGF-1 after 1 year. Assessment of residual pituitary function at 6 monthly intervals.

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