A 46-year-old Caucasian female with a history of epilepsy came into our family medicine center complaining of weakness, fatigue, and arthralgia that made it difficult for her to walk. She’d had these symptoms for 6 months and reported having amenorrhea and hot flashes for the past 2 years.
The patient’s blood pressure was 133/72 mm Hg, heart rate was 82 beats per min, and respiratory rate was 20 breaths per min. Her skin was dry without hyperpigmentation, and her sclerae were anicteric. A musculoskeletal examination revealed tenderness of the metacarpophalangeal and metatarsophalangeal joints without edema, deformity, or evidence of synovitis.
She had no history of skin bronzing, jaundice, transfusions, hepatitis, abdominal pain, or diabetes and denied using tobacco, alcohol, or illicit drugs. Her medications included lamotrigine (250 mg BID) and over-the-counter iron supplementation. She had no family history of rheumatoid arthritis, lupus, cirrhosis, hemochromatosis, or other liver disease. Her mother died from colorectal cancer and her father’s cause of death was unknown; her sisters did not have any medical issues. The patient’s lab tests were normal, except for the following: aspartate aminotransferase, 89 U/L (normal, 13-45 U/L); alanine aminotransferase, 80 U/L (normal, 5-57 U/L); and alkaline phosphatase, 132 U/L (normal, 39-117 U/L). Her coagulation panel revealed a prothrombin time of 13.1 seconds, and an international normalized ratio of 1.3. Serology was negative for hepatitis A, B, and C. Additional testing revealed the following: ferritin, 4014.1 ng/dL (normal, 7-282 ng/dL); iron, 210 mg/dL (normal, 40-170 mg/dL); total iron binding capacity, 258 mg/dL (normal, 260-445 mg/dL); and transferrin saturation, 81% (normal, 20%-55%).
Abdominal ultrasonography revealed gallstones, an enlarged spleen, a dilated portal vein, and a fatty liver consistent with cirrhosis. X-rays showed soft-tissue swelling and demineralization in her hands consistent with osteopenia and degenerative arthritis in both feet.
Based on our patient’s complaints of fatigue, weakness, arthralgia, and amenorrhea, as well as her abnormal iron levels, we suspected hereditary hemochromatosis (HH). We ordered HFE genotyping, and the results indicated that the patient was homozygous for the C282Y mutation, confirming our diagnosis.
HH is an autosomal recessive disorder of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue deposition of iron. It is caused by mutations in the HFE gene (C282Y or H63D) located on chromosome 6 (locus 6p21) and commonly seen in Northern European Caucasians.1 Approximately 85% of patients with HH are homozygous for C282Y; the H63D mutation can cause HH when in the presence of a single C282Y mutation.1 Men manifest HH symptoms usually between the ages of 40 and 60 years,2 although women may be affected at a later age than men because physiologic blood loss from menstruation and parturition limit the rate at which excess iron is accumulated.2
Signs and symptoms of HH include depression, fatigue, restless legs syndrome, weakness, and weight loss.3 In advanced HH, patients may develop progressive skin pigmentation or bronzing, and hypogonadism. Advanced HH can affect the patient’s organs, including the pancreas (diabetes), liver (hepatomegaly, abnormal liver function tests), pituitary gland (amenorrhea, decreased libido, erectile dysfunction), and heart (arrhythmias, congestive heart failure), as well as the musculoskeletal system (joint pain).3,4 The spleen can also be affected after cirrhosis develops. Cirrhosis, hepatocellular carcinoma, and cardiomyopathy can reduce life expectancy.4
Testing for HH
Because symptoms of HH are common and nonspecific, a high degree of clinical suspicion is required for early diagnosis. The differential diagnosis includes conditions related to chronic liver disease or iron overload (TABLE).5 If the diagnosis goes undetected until complications arise, the risk of morbidity and mortality are greatly increased.5
If HH is suspected, serum ferritin concentration and fasting serum transferrin saturation (the ratio of serum iron level to total iron-binding capacity × 100) are recommended as initial tests.5 The normal range of transferrin saturation for males is 15% to 50% and the normal range for females is 12% to 45%. If the transferrin saturation exceeds 50% in women or 60% in men, further evaluation is warranted (FIGURE 1).6,7 The sensitivity and specificity of elevated transferrin saturation for HH are 92% and 93%, respectively.5 These transferrin saturation cutoffs don’t apply to patients with a history of frequent blood transfusion (ie, patients with sickle cell disease or thalassemia).