A 55-year-old man complains of fatigue. Although he sleeps 8 hours every night, he has to push himself to perform his usual daily activities. He has also experienced loss of libido and episodic impotence, which he ascribes to the fatigue.
A 55-year-old man complains of fatigue. Although he sleeps 8 hours every night, he has to push himself to perform his usual daily activities. He has also experienced loss of libido and episodic impotence, which he ascribes to the fatigue. In addition, he has had arthralgia in his wrists, shoulders, and the small joints of his hands for several months.
He has no sleep disorders, dyspnea with exertion, orthopnea, angina, or other symptoms attributable to congestive heart failure or heart disease. He reports no cough or other symptoms of chronic obstructive pulmonary disease.
The patient was previously healthy.He does not smoke; he consumes about 3 alcoholic drinks per day.
Vital signs are normal, and there are no enlarged lymph nodes. Lungs and heart are normal, and the abdomen is not tender. A firm liver edge is palpable 1 cm below the costal margin. Results of genitourinary and neurologic examinations are normal. In both wrists, there is mild discomfort with compression and with movement through the range of motion.
Hemogram is normal. A random blood glucose measurement is 136 mg/dL. Transaminase levels are mildly elevated.
Which of the following will most likely be the key to establishing the diagnosis in this patient?A. Liver biopsy.
B. Genetic mapping for the C282Y mutation.
C. Measurement of transferrin saturation and serum ferritin level.
D. Iron chelation therapy with desferrioxamine.
CORRECT ANSWER: B
This man's symptoms, physical findings, and laboratory results suggest hemochromatosis, the most common hereditary disease in persons of northern European descent. It is associated with a single base change of the HFE gene, located on chromosome 6; this change causes a substitution of tyrosine for cysteine at position 282 on the so-called hemochromatosis HFE protein (C282Y). This genetic mutation seems to have first occurred some 2000 years ago in a single Celtic/Viking ancestor in northwestern Europe.1
The physiologic and phenotypic effects of the mutation have highly variable penetrance. However, classic hemochromatosis is a well-described clinical entity characterized by a long asymptomatic period of increased GI iron absorption that first increases the transferrin saturation and then increases the body's storage of iron in ferritin and tissues. Symptomatic organ involvement usually becomes evident in midlife. Typical findings and symptoms include:
Diagnosis. The first challenge is to suspect the presence of the disease. Initial symptoms can be nonspecific (unexplained fatigue, joint stiffness, and aching). However, when a constellation of findings that include evidence of liver and endocrine dysfunction occur simultaneously, as in this patient, hemochromatosis should be suspected.
Phenotypically, the earliest abnormal finding is an elevated transferrin saturation (choice C); a saturation of more than 45% is considered suggestive of hemochromatosis. However, in today's genomic medicine environment, patients with such transferrin saturations usually have the diagnosis confirmed by genetic mapping (choice B). A result that reveals the presence of the abnormal C282Y HFE mutation is confirmatory.
As the disease progresses, storage and tissue iron overload can be demonstrated, both by serum ferritin levels above 1000 ng/mL and by findings of marked increases in hepatocyte parenchymal iron deposition (obtained either by histology staining or by the more accurate tissue measurement index of iron content [choice A]). However, in most patients, such studies are not needed; they generally are done only when the results of previous tests are equivocal.
Therapy. The mainstay of therapy in hereditary hemochromatosis is phlebotomy. Phlebotomy is clearly indicated in symptomatic patients and in patients with more advanced clinical findings (ie, cirrhosis or liver abnormalities) or biochemical findings (ie, ferritin level of more than 1000 ng/mL). However, most clinicians institute some form of phlebotomy regimen in adults once the diagnosis has been confirmed. The initial goal of phlebotomy is to remove sufficient iron (1 unit of blood contains 200 to 250 mg of iron) to lower and then maintain the transferrin saturation at less than 30% and the ferritin level at less than 50 ng/mL. After this has been achieved, phlebotomy is continued indefinitely but less aggressively, with a goal of maintaining the transferrin saturation at less than 50% and the ferritin level at less than 100 ng/mL. Such therapy has been shown to prevent progression of morbidity and reduce mortality in patients with hemochromatosis.3 Phlebotomy is almost always effective. Thus, chelation (choice D)--a much more difficult and expensive therapy--is rarely, if ever, used.
Screening. Screening for hemochromatosis is indicated in family members of patients, but the utility of screening in the general population is less clear. The C282Y mutation elevates serum ferritin levels very slowly, and thus it may take many years for levels to rise above 200 to 250 ng/mL (periods of 17 to 25 years from genetic diagnosis have been reported).4 These data suggest that general genetic screening is problematic and not at all cost-effective. However, transferrin saturation screening in more specific populations--for example, patients with chronic liver disease, impotence, or arthritis--may be worthwhile.
Outcome of this case. Transferrin testing revealed a serum iron level of 200 ng/mL and transferrin saturation of 65%. The serum ferritin level was 330 ng/mL. A genetic test revealed homozygosity for C282Y and confirmed the diagnosis of hemochromatosis.
The patient underwent an initially aggressive phlebotomy regimen (1 to 2 units per week). After 9 months, his transferrin saturation was 38% and his serum ferritin level was 220 ng/mL. There was no progression in his symptoms during this time, and the arthralgia abated somewhat.
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Andersen RV, Tybjaerg-Hansen A, Appleyard M, et al. Hemochromatosis mutations in the general population: iron overload progression rate.
Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
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Olynyk JK, Hagan SE, Cullen DJ, et al. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study.
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