Do not miss hereditary hemochromatosis

A 58-year-old man came to see me in consultation for type 2 diabetes and dyslipidemia. He had elevated transaminases presumed to be due to nonalcoholic fatty liver disease. The question was, which oral antidiabetic and lipid-lowering agents might be options?

However, he also had experienced a fragility fracture of the right hip three years earlier. No one pursued further evaluation until he established with a new primary care physician who ordered bone mineral densitometry. T score was -3.1. Weekly alendronate was initiated but the patient had no other evaluation.

I ordered additional studies including 25-hydroxyvitamin D, total calcium, parathyroid hormone, 24-hour urine calcium, tissue transglutaminase antibodies, thyroid-stimulating hormone, prolactin, follicle-stimulating hormone, luteinizing hormone, total and free testosterone. These were normal with the exception of his testosterone which was very low.

I could have initiated testosterone therapy, stopped further evaluation and then focused on diabetes/lipid management, but I did not. His family history was informative. His father had a history of cryptogenic cirrhosis. The patient said that his father had not consumed alcohol for decades and that his father’s physicians never identified the cause of the cirrhosis before his father’s death from hepatocellular carcinoma.

Because of this patient’s family history, I ordered fasting serum transferrin saturation which was high at 60%. Ferritin was also high. After discussion and counseling, we proceeded with genetic testing which confirmed homozygote C282Y mutation. This led to counseling and screening of family members. In addition to treating the diabetes, osteoporosis and hypogonadism, we initiated therapeutic phlebotomy.

Hereditary hemochromatosis is an inherited disease of excess iron absorption. It can result in a variety of complications due to chronic iron overload including liver disease, heart failure, arthropathy, male hypogonadism and “bronze” diabetes. Therapeutic phlebotomy can prevent the end-organ complications and premature death that may occur if left untreated.

Phatak and colleagues suggested offering screening to all adult men >25 years of age of Northern European ancestry and to all first degree relatives of individuals with a diagnosis of hereditary hemochromatosis. They suggested using fasting morning serum transferring saturation (>52% in men and >50% in women) and/or fasting morning serum unsaturated iron-binding capacity (<32 mcmol/L) as the screening tests of choice. For confirmation, HFE genetic testing for C282Y, H63D, and S65C mutations may be performed.

To this I would like to add my own advice which is to never forget to ask “why?” and “what?” Why has this occurred? What might have caused it? What else should I be thinking about? What other workup should be done? Curiosity is essential to success in patient evaluation and clinical decision making.

I could have easily focused on his diabetes and neglected other issues. Because I did not, I not only identified the possible cause of diabetes, liver disease and hypogonadism but hopefully may have prevented him and other family members from experiencing the same fate as his father.

For more information:

Phatak PD, Bonvosky HL, Kowdley KV. Ann Intern Med. 2008;149:270-272.