A 42-year-old man comes to the emergency department after a syncopal episode preceded by palpitations and lightheadedness. The patient has no significant medical history and takes no medications. He does not use tobacco, alcohol, or illicit drugs. The patient is a computer programmer and spends most of his time indoors. Vital signs are within normal limits with no orthostatic changes. Heart and lung sounds are normal. The liver span is increased with no tenderness. The skin appears darkly tanned. ECG demonstrates sinus node dysfunction, and echocardiography reveals abnormal diastolic relaxation of the left ventricle. Which of the following is the most likely cause of this patient's condition?

Question

A 42-year-old man comes to the emergency department after a syncopal episode preceded by palpitations and lightheadedness.  The patient has no significant medical history and takes no medications.  He does not use tobacco, alcohol, or illicit drugs.  The patient is a computer programmer and spends most of his time indoors.  Vital signs are within normal limits with no orthostatic changes.  Heart and lung sounds are normal.  The liver span is increased with no tenderness.  The skin appears darkly tanned.  ECG demonstrates sinus node dysfunction, and echocardiography reveals abnormal diastolic relaxation of the left ventricle.  Which of the following is the most likely cause of this patient's condition?

Quizplus · Accepted Answer

11ec160b_38d0_4f99_9249_17d8f1eecce7_MD0001_00 This patient has syncope associated with diastolic dysfunction, hepatomegaly, and skin hyperpigmentation. This presentation is suggestive of hereditary hemochromatosis (HH), an autosomal recessive disorder characterized by excessive intestinal iron absorption with accumulation of the excess iron in parenchymal tissues. Cardiac manifestations of HH include heart failure and conduction system disease. In early stages, myocardial iron overload is expressed as diastolic left ventricular (LV) dysfunction with a restrictive filling pattern. As the disease advances, progressive ventricular remodeling leads to dilated cardiomyopathy and reduced LV ejection fraction. Iron deposition can also affect the cardiac conduction system. Sinus node dysfunction (ie, sick sinus syndrome) can lead to presyncope or syncope; malignant arrhythmias with sudden cardiac death occasionally occur. On light microscopy, cardiac hemochromatosis is visible as brown, granular deposits (arrow) in myocytes that stain strongly with Prussian blue. Cardiomyopathy can be the first presenting manifestation of HH, although careful assessment can usually find evidence of iron deposition elsewhere (eg, elevated hepatic transaminases, hepatomegaly). Treatment includes therapeutic phlebotomy to remove excess iron stores, which can lead to regression of cardiomyopathy in some patients. (Choice A) Amyloidosis is caused by extracellular deposition of misfolded amyloid proteins. Multiorgan involvement (eg, cardiomyopathy, hepatomegaly) is common, but amyloidosis frequently involves the kidney (eg, nephrotic syndrome), nerves (eg, neuropathy), and muscles (eg, macroglossia). It is not associated with hyperpigmentation. (Choice B) Primary adrenal insufficiency (ie, cortisol deficiency) can cause hyperpigmentation due to cosecretion of melanocyte-stimulating hormone with ACTH (both derived from proopiomelanocortin). However, hepatomegaly is not seen, and although hypotension is common, sinus node and diastolic dysfunction are not. (Choice C) Sarcoidosis results from widespread formation of noncaseating granulomas. Cardiac infiltration can cause conduction blockade, and liver involvement may result in hepatomegaly. However, lung symptoms (eg, dyspnea, cough) are more common, and skin manifestations include papules and nodules rather than hyperpigmentation. (Choice D) HH is associated with mutations in the HFE gene; the HFE protein binds to the transferrin receptor and regulates intestinal and hepatic iron uptake. Human leukocyte antigen (HLA) mutations are associated with autoimmune disorders (eg, celiac disease, type 1 diabetes). (Choice F) Glycogen storage disease type II (ie, Pompe disease) is caused by a deficiency in alpha-glucosidase (acid maltase). It manifests shortly after birth with hypertrophic cardiomyopathy, hepatomegaly, muscle weakness, and failure to thrive. Skin hyperpigmentation is not typical. Educational objective: Hereditary hemochromatosis is characterized by excessive intestinal iron absorption with deposition of iron in parenchymal tissues. Cardiac manifestations include diastolic dysfunction (initial), dilated cardiomyopathy (later), and conduction system disease (eg, sinus node dysfunction).

A 42-Year-Old Man Comes to the Emergency Department After a Syncopal