A 45-year-old man comes to the office due to fatigue, lack of sexual desire, and inability to maintain an erection. A year ago, he was advised to lose weight with diet and exercise due to mildly elevated fasting glucose levels. The patient has smoked a pack of cigarettes daily for the past 20 years and drinks an alcoholic beverage 3-4 times per month. Blood pressure is 110/70 mm Hg and pulse is 65/min. Oxygen saturation is 99% on room air. BMI is 29 kg/m². Skin examination shows increased pigmentation over the knuckles and face. The liver is palpable 3-4 cm below the right costal margin. The remainder of the examination reveals small testes. Which of the following is most likely contributing to the development of the patient's symptoms?

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11ec160b_39a0_4a58_9249_21e6f20b48fe_MD0001_00 This patient's decreased libido, erectile dysfunction, and testicular atrophy are indicative of hypogonadism. These findings, in combination with hyperpigmentation of the skin, elevated glucose/diabetes mellitus, and hepatomegaly, are strongly suggestive of hereditary hemochromatosis (HH). HH is an autosomal recessive disorder characterized by excessive intestinal iron absorption and accumulation in various tissues. Secondary hypogonadism occurs in HH due to deposition of iron in the pituitary gland, resulting in decreased gonadotropin secretion and subsequent testicular failure. In women, HH is often not diagnosed until after menopause, as premenopausal women have ongoing menstrual blood loss that usually prevents significant iron overload and symptom development; therefore, amenorrhea is a rare finding in women with HH. (Choice A) Atherosclerotic disease is a common cause of erectile dysfunction in older men, especially those with a history of smoking, but it typically would not affect libido and would not cause hyperpigmentation or hepatomegaly. (Choice B) Autoimmune adrenalitis is a common cause of primary adrenal insufficiency (ie, Addison disease). Hyperpigmentation is common due to increased cosecretion of melanocyte-stimulating hormone with ACTH, but patients typically have orthostatic hypotension (due to loss of mineralocorticoid) and hypoglycemia (not hyperglycemia). (Choice C) Ectopic ACTH secretion causes paraneoplastic Cushing syndrome (eg, small cell lung cancer). Patients may develop hyperpigmentation and hyperglycemia but also often have hypertension and proximal muscle weakness. Small testes are not seen. (Choice D) Testicular fibrosis is a common manifestation of Klinefelter syndrome (KS). Hypogonadism due to KS is typically apparent at puberty and is often associated with a eunuchoid habitus, sparse body hair, and high-pitched voice. Hepatomegaly is not common. Educational objective: Hereditary hemochromatosis can cause secondary hypogonadism due to deposition of iron in the pituitary gland, resulting in decreased gonadotropin secretion. Patients who develop secondary hypogonadism are also at risk for deficiencies in other pituitary hormones (eg, central hypothyroidism).

A 45-Year-Old Man Comes to the Office Due to Fatigue