IM Board Review

Big heart, small ring

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Release date: December 1, 2017
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A 58-year-old man presents with a 1-year history of chronic daytime fatigue, low libido, and difficulty achieving erections. He is upset: his wife suspects him of having an extramarital affair because, in addition to problems with his sexual performance, he has not been wearing his wedding ring. The patient explains that the ring has become too small for his finger and that he has never cheated on his wife. His wife has also been complaining that he snores loudly at night.

The patient works as an accountant. He has no known allergies to medications and takes no medications or supplements. He has no surgical history. He has never smoked tobacco or abused illicit drugs. He drinks a glass of wine once a week.

His father died at age 78 of a myocardial infarction; his 86-year-old mother has hypertension. He has no siblings. His 28-year-old biological son is healthy.

Physical examination

His temperature is 97.9°F (36.6°C), blood pressure 150/90 mm Hg, heart rate 80 per minute, respiratory rate 12 per minute, and oxygen saturation 98% on room air. His height is 5 feet 11 inches (180 cm), weight 250 lb (113 kg), and body mass index 35 kg/m2.

His forehead is wide with deep creases, his jaw, nose, and lower lip are prominent, and his tongue, hands, and feet are large. He has mild thyromegaly with no palpable nodules.

On cardiac examination, his point of maximal impulse is 3 cm lateral to the left midclavicular line in the fifth intercostal space; he has normal S1 and S2 with no murmurs, rubs, or gallops. The lungs are clear on auscultation. His abdomen is soft, nontender, and nondistended; the liver is palpated 2 cm below the costal margin. His extremities are not edematous.

LABORATORY TESTING

1. In addition to a complete blood cell count and comprehensive metabolic panel, which is the most appropriate test to order?

  • Growth hormone (GH) level
  • Insulin-like growth factor 1 (IGF-1) level
  • GH and IGF-1 levels
  • IGF-2 level

Acromegaly, an overview

The patient’s history of snoring and daytime fatigue suggests obstructive sleep apnea, which together with his enlarging ring finger size, wide forehead with deep creases, prominent jaw, nose, and lower lip, and enlarged thyroid, heart, and liver suggests acromegaly.

Clinical manifestations of acromegaly
This chronic progressive disease is characterized by excessive secretion of GH leading to increased synthesis of IGF-1, the main mediator of GH’s effects. The end result is disproportionate growth of skeletal, soft, and organ tissue.1 A list of acromegaly’s clinical manifestations is shown in Table 1.2,3 The disease is often associated with insulin resistance.4

In most cases, acromegaly is caused by a GH-secreting pituitary adenoma. Rare causes include hypothalamic tumors that secrete GH-releasing hormone (GHRH) and ectopic secretion of GHRH or GH.1 Pseudoacromegaly, a mimic, is characterized by acromegalic features without hypersecretion of GH and with normal IGF-1 levels.4

The prevalence of acromegaly is 36 to 60 cases per million, and its annual incidence is 3 to 4 per million.5

With this patient’s presentation, the most appropriate next step is to order an IGF-1 level to screen for acromegaly.

GH secretion is pulsatile, IGF-1 secretion is not

GH is synthesized and stored in somatotroph cells, which account for more than 50% of pituitary hormone-secreting cells.6 Three hormones regulate synthesis and secretion of GH: GHRH, ghrelin, and somatostatin.7 GH secretion is pulsatile, with minimal basal secretion dependent on sex, age, neurotransmitters, exercise, and stress.7 It exerts its physiologic effects through an interaction with the GH receptor, a single-chain transmembrane glycoprotein.8,9

A GH-secreting adenoma develops when pituitary somatotroph cells undergo a monoclonal expansion. Mutations of various genes such as GNAS, PRKAR1A, and AIP are suspected of triggering such expansion. Disruption of the MENIN gene leads to multiple endocrine neoplasia syndrome 1, a combination of pituitary adenoma, pancreatic tumor, and primary hyperparathyroidism.9 The pattern of cytoplasmic keratin in somatotroph cells defines 2 histologic subtypes: densely granulated and sparsely granulated. The latter subtype is associated with more-invasive lesions that are seen more often in younger patients and are less responsive to somatostatin ligand therapy.10

GH induces transcription of IGF-1, mostly in the liver. In contrast to GH, IGF-1 secretion is not pulsatile, and therefore IGF-1 can be measured more reliably in serum, and the results can be interpreted according to age- and sex-adjusted reference ranges.

The IGF-1 level is a very sensitive test, but it is not very specific. It can be falsely elevated in pregnancy, in patients on estrogen replacement therapy, and in late adolescence.11 In addition, it may be difficult to interpret the IGF-1 level in the setting of malnutrition, severe hyperglycemia, renal or hepatic failure, and hypothyroidism.11,12

Nonpulsatile secretion and high sensitivity make the IGF-1 level the screening test of choice for acromegaly.9,12 In contrast, because of the pulsatile nature of GH synthesis, one cannot rely on a random GH level alone to detect the hormone’s hypersecretion.

IGF-2 has no role in acromegaly

IGF-2, produced mainly by the liver, plays an important role in promoting fetal growth. IGF-2 may induce hypoglycemia when secreted by some mesenchymal tumors.13 This hormone has no role in the pathogenesis of acromegaly and should not be measured in this patient.

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