Diagnosis of acromegaly

INTRODUCTION — Acromegaly results from persistent hypersecretion of growth hormone (GH). Excess GH stimulates hepatic secretion of insulin-like growth factor-1 (IGF-1), which causes most of the clinical manifestations of acromegaly.

The clinical diagnosis is often delayed because of the slow progression of the signs of acromegaly over a period of many years. GH excess that occurs before fusion of the epiphyseal growth plates in a child or adolescent is called pituitary gigantism and is discussed separately.

The diagnostic approach to acromegaly will be reviewed here. GH excess in children and adolescents and the causes, clinical manifestations, and treatment of acromegaly are discussed separately. (See "Pituitary gigantism" and "Causes and clinical manifestations of acromegaly" and "Treatment of acromegaly".)

EPIDEMIOLOGY — Acromegaly has been considered to be a rare disease, with an estimated prevalence in Europe of 30 to 70 individuals per million [1,2]. However, current estimates are considerably higher [2-4]. In one report, seven new cases of acromegaly were identified among 6773 unselected adults in a primary care population who underwent plasma insulin-like growth factor-1 (IGF-1) screening; this suggests a population prevalence as high as 1000 per million individuals [5]. A similar uncontrolled IGF-1 screening study in over 2000 individuals with type 2 diabetes found a prevalence of approximately 480 per million individuals [6].

WHO SHOULD BE TESTED FOR ACROMEGALY?

●The diagnosis of acromegaly should be suspected in individuals who present with the typical clinical features of growth hormone (GH) excess, which include the enlargement during adulthood of the jaw (macrognathia), hands, and feet, which result in increasing shoe and glove size and the need to enlarge finger rings. (See "Causes and clinical manifestations of acromegaly", section on 'Effects of GH/IGF-1 excess'.)

The facial features become coarse, with enlargement of the nose and frontal bones as well as the jaw, and the upper incisors may become spread apart. Despite the prominence of these findings at the time of diagnosis, the rate of change is so slow that few patients seek care because their appearance had changed.

●Other features include cardiovascular disease, sleep apnea, type 2 diabetes, arthropathies, carpal tunnel syndrome, and problems directly related to the pituitary tumor size (headache, visual loss).

However, because acromegaly is rare, we suggest against screening patients with isolated sleep apnea, uncontrolled diabetes, arthropathy, or carpal tunnel syndrome (unless there is a clinical suspicion of the disorder).

●We do suggest testing in patients who present with a cluster of the following conditions, even if they do not have the typical manifestations of acromegaly (eg, acral and facial features) [7]:

•Sleep apnea, uncontrolled diabetes, carpal tunnel syndrome, colon polyps, cardiac failure with hypertension.

•Jaw prognathism or new-onset severe snoring or sleep apnea in a person without obesity.

•Pituitary macroadenoma.

•The diagnosis should also be considered when a pituitary mass is identified on an imaging study; 75 to 80 percent of somatotroph adenomas are macroadenomas at the time of diagnosis. Some patients may be asymptomatic in spite of raised GH and insulin-like growth factor-1 (IGF-1) levels.

In the past, most patients had pituitary adenomas that caused visual field defects, but this is less common now, presumably because of increased awareness of the disease and earlier diagnosis. The percentage of patients with visual defects at presentation is now estimated to be approximately 6 percent, down from 15 to 25 percent in 1975 [2].

DIAGNOSTIC EVALUATION — Once a patient is suspected to have acromegaly, the first step is biochemical testing to confirm the clinical diagnosis, followed by imaging to determine the cause of the excess growth hormone (GH) secretion. (algorithm 1)The cause is a somatotroph adenoma of the pituitary in over 95 percent of cases (table 1) [8]. (See 'Determining the source of excess GH' below.)

Biochemical testing — The diagnosis of acromegaly is a biochemical one and does not require the presence of typical phenotypic features or the presence of a pituitary tumor on magnetic resonance imaging (MRI). Therefore, biochemical testing of anyone with a clinical picture suggestive of acromegaly (eg, pituitary tumor of any size or signs and symptoms of acromegaly) is essential. (See 'Who should be tested for acromegaly?' above.)

Serum IGF-1 concentration — The best single test for the diagnosis of acromegaly is measurement of serum insulin-like growth factor-1 (IGF-1) (algorithm 1) [7,9,10]. Unlike GH, serum IGF-1 concentrations do not vary from hour to hour according to food intake, exercise, or sleep, but instead they reflect integrated GH secretion during the preceding day or longer. Serum IGF-1 concentrations are elevated in virtually all patients with acromegaly and provide excellent discrimination from normal individuals [11,12].

Our approach, which is similar to that of the Endocrine Society [7], includes measurement of a serum insulin-like growth factor-1 (IGF-1) concentration as the first step (algorithm 1).

●An unequivocally elevated serum IGF-1 concentration in a patient with typical clinical manifestations of acromegaly confirms the diagnosis of acromegaly.

●A normal serum IGF-1 concentration is strong evidence that the patient does not have acromegaly.

●If the serum IGF-1 concentration is equivocal, serum GH should be measured after oral glucose administration. Inadequate suppression of GH after a glucose load confirms the diagnosis of acromegaly. (See 'Determining the source of excess GH' below.)

Both serum GH concentrations and IGF-1 concentrations are increased in virtually all patients with acromegaly. The increase in serum IGF-1 is often disproportionately greater than that in GH for two reasons: GH secretion fluctuates more, and GH stimulates the secretion of IGF-1-binding protein-3 (IGFBP-3), the major IGF-1 binding protein in serum.

The results must be interpreted, however, according to the patient's age. In normal subjects, serum IGF-1 concentrations are highest during puberty and decline gradually thereafter. Values are significantly lower in adults over the age of 60 years than in younger subjects. Thus, an apparently "normal" value in a patient aged 70 years may in fact be elevated.

In addition, there are a number of conditions that are associated with lower serum IGF-1 concentrations, including hypothyroidism, malnutrition, poorly controlled type 1 diabetes, liver failure, renal failure, and oral estrogen use. In these situations, it is possible that the diagnosis of acromegaly could be missed, and an oral glucose tolerance test (OGTT) should also be performed if the disorder is suspected [2].

A further caution is that values from one laboratory may not be comparable with those from another laboratory. A major cause of this finding is a difference in the calibration standards for the assay [13].

All patients with elevated age-adjusted IGF-1 levels should undergo testing for GH hypersecretion (eg, measurement of serum GH after oral glucose administration).

Oral glucose tolerance test — The most specific dynamic test for establishing the diagnosis of acromegaly is an OGTT. When performing the test, we measure serum GH before and two hours after glucose administration; the criterion for the diagnosis of acromegaly is a GH concentration greater than 1 ng/mL. In normal subjects, serum GH concentrations fall to 1 ng/mL or less within two hours after ingestion of 75 g glucose. In contrast, the post-glucose values are greater than 2 ng/mL in over 85 percent of patients with acromegaly.

OGTT is the gold standard for determining control of GH secretion after surgical treatment, but it does not appear to be useful in assessing biochemical control in patients receiving medical therapy with somatostatin analogs. In these patients, both basal and post-glucose GH levels are highly discordant with serum IGF-1 concentrations [14]. (See "Treatment of acromegaly", section on 'Monitoring'.)

These results were obtained mainly with a radioimmunoassay method for the measurement of GH. If one of the newer, highly sensitive immunoradiometric or immunochemiluminescent GH assays is used, the serum GH concentration falls to less than 0.3 ng/mL after oral glucose administration in normal subjects [15]. Thus, the diagnosis of acromegaly can be made when the serum GH concentration remains above 1 ng/mL using standard assays. More importantly, these more sensitive assays may give better discrimination between those with and without acromegaly [15].

Limitations of random serum GH measurements — Random serum growth hormone (GH) measurements are not useful for the diagnosis of acromegaly. GH secretion in normal subjects is pulsatile, diurnal, and stimulated by a variety of factors, including short-term fasting, exercise, stress, and sleep; in addition, GH clearance is rapid (plasma half-life of approximately 20 minutes) [16]. As a result, serum GH concentrations fluctuate widely, ranging from less than 0.5 to 1 ng/mL (less than 0.1 ng/mL using very sensitive assays [17]) during most of the day, to 2 to 5 ng/mL before the next meal or after exercise, to as high as 20 or 30 ng/mL at night or after vigorous exercise [2]. Serum GH concentrations also may be high in patients with uncontrolled diabetes mellitus, liver disease, and malnutrition.

All patients with acromegaly have increased GH secretion. However, the random serum GH concentration is often in the range of 2 to 10 ng/mL during much of the day, values that can be found in normal subjects. Unlike normal subjects, the patient's serum GH concentrations change little during the day or night and, in most patients, do not change in response to stimuli such as food or exercise. Nevertheless, because of the variations in serum GH that occur in normal subjects and in patients with other disorders, a high value cannot be interpreted without knowing when the blood sample was obtained and something about the patient. To obviate these problems, it is best not to obtain random measurements of serum GH.

Other dynamic tests — Although rarely necessary, other dynamic tests can be done. An example of when these might be performed would be a patient in whom acromegaly is suspected clinically but whose IGF-1 and OGTT results are normal.

Thyrotropin-releasing hormone (TRH), in a dose of 500 mcg intravenously, raises serum GH concentrations by 50 percent or more in approximately one-half of patients with acromegaly, with peak values occurring at 20 to 30 minutes; serum GH does not rise in normal subjects [18]. Conversely, L-DOPA (500 mg orally) reduces serum GH concentrations by 50 percent or more in approximately one-half of patients with acromegaly, while it raises the GH concentration in normal subjects [2]. TRH is unavailable in the United States.

Serum IGFBP-3 concentration — Because IGF-1-binding protein-3 (IGFBP-3) secretion is GH-dependent (as is IGF-1), serum IGFBP-3 concentrations are elevated in patients with acromegaly [19]. There is, however, considerable overlap of these values with those in normal persons, thereby limiting the utility of this measurement [20].

Determining the source of excess GH

Pituitary MRI — Once GH hypersecretion has been confirmed, the next step is magnetic resonance imaging (MRI) of the pituitary because a somatotroph adenoma of the pituitary is by far the most common cause of acromegaly (table 1). In one report of 39 patients undergoing pituitary MRI for suspected acromegaly, a mass was identified in 27 of the 39 (69 percent) [21].

Pituitary tumors as small as 2 mm in diameter can be detected with this technique, and the dimensions and anatomic extent of the tumor can be accurately identified (image 1); computed tomography is less sensitive. In approximately 75 percent of patients with somatotroph adenomas, the tumor is a macroadenoma (tumor diameter 10 mm or more), and the tumor may extend to the parasellar or suprasellar region. An occasional patient has an empty sella with the tumor situated within the normal pituitary tissue lining the sella turcica.

It is important to remember that MRI does not distinguish between functioning and nonfunctioning tumors; this distinction must be based upon biochemical studies. This is an important concern because approximately 10 to 20 percent of normal subjects have MRI or autopsy evidence of a pituitary microadenoma. (See "Causes, presentation, and evaluation of sellar masses".)

When no clear mass is seen on a dedicated sella MRI, we consider additional imaging, including chest and abdominal CT scans, and DOTATATE PET scan. However, most of these patients have a somatotroph adenoma, just too small to be detected by routine imaging.

Other studies — Other rare causes of acromegaly include pituitary somatotroph carcinoma, a hypothalamic tumor secreting growth hormone-releasing hormone (GHRH), a nonendocrine tumor secreting GHRH, ectopic secretion of GH by a nonendocrine tumor, and excess growth factor activity (acromegaloidism) [22].

MRI of the head and pituitary should identify some of these other tumors. If the MRI is normal, abdominal and chest imaging should be performed to look for an ectopic source of hormone secretion, followed by catheterization studies in an attempt to demonstrate an arteriovenous gradient of either GH or GHRH in the region of the tumor [8].

Ectopic GHRH secretion accounts for only 0.5 percent of cases of acromegaly [22]. Serum GHRH is the only specific marker for this disorder, and concentrations are usually quite elevated; special arrangements with a reliable laboratory must be made for this assay. Pituitary MRI often reveals a normal-sized or enlarged gland, but other patients appear to have an adenoma. GHRH should not be measured routinely but should be if a clear-cut pituitary adenoma is not seen on MRI or postoperatively if histologic and immunocytochemical examination of the excised pituitary tissue reveals somatotroph hyperplasia rather than a somatotroph adenoma.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acromegaly (The Basics)")

●Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Acromegaly has been considered to be a rare disease, with an estimated prevalence in Europe of 30 to 70 individuals per million [1,2]. However, current prevalence estimates are considerably higher. (See 'Epidemiology' above.)

●The diagnosis of acromegaly should be suspected in individuals who present with the typical clinical features of growth hormone (GH) excess, which include an enlarged jaw (macrognathia) and enlarged hands and feet, which result in increasing shoe and glove size and the need to enlarge rings. The facial features become coarse, with enlargement of the nose and frontal bones as well as the jaw, and the teeth become spread apart.

We also suggest testing in patients who present with a cluster of the following conditions, even if they do not have the typical manifestations of acromegaly (eg, acral and facial features): sleep apnea, uncontrolled diabetes, carpal tunnel syndrome, colon polyps, and cardiac failure with hypertension. (See 'Who should be tested for acromegaly?' above.)

●The diagnosis should also be considered when a pituitary mass is identified on an imaging study; 75 to 80 percent of somatotroph adenomas are macroadenomas at the time of diagnosis. (See 'Who should be tested for acromegaly?' above.)

●The first step in the diagnosis is measurement of a serum insulin-like growth factor-1 (IGF-1) concentration (algorithm 1). An unequivocally elevated serum IGF-1 concentration in a patient with typical clinical manifestations of acromegaly confirms the diagnosis of acromegaly. A normal serum IGF-1 concentration is strong evidence that the patient does not have acromegaly.

If the serum IGF-1 concentration is equivocal, serum GH should be measured after oral glucose administration. Inadequate suppression of serum GH after a glucose load confirms the diagnosis of acromegaly. (See 'Diagnostic evaluation' above.)

●Once the biochemical diagnosis is made, pituitary magnetic resonance imaging (MRI) should be performed (algorithm 1); a pituitary adenoma is found in the majority of cases. If the MRI is normal, then studies to identify a growth hormone-releasing hormone (GHRH)- or GH-secreting tumor should be undertaken. (See 'Other studies' above and 'Pituitary MRI' above.)