Presentation
G.O. is a 50-year-old white man referred for help in managing his diabetes. Two years before his visit, diabetes was diagnosed during a routine exam. He was started on oral hypoglycemic agents. He initially responded to this treatment, but over the ensuing 2 years, his medication doses were slowly raised until he was on 15 mg glyburide and 2,000 mg metformin. At the time of referral, his fasting blood glucose levels were in the range of 150 mg/dl and his hemoglobin A1c (A1C) was 8%. He requested a consultation when he was advised to start on insulin therapy.
His medical history was significant for heavy alcohol intake and hepatitis B with full recovery. Family history was negative for diabetes and hemochromatosis. His review of systems was positive for joint discomfort in his hands and erectile dysfunction.
Physical exam revealed normal vital signs and no retinopathy or other signs of diabetic complications. His hand joints showed mild swelling and tenderness over the proximal interphalangeal joints, and his skin was slightly, diffusely hyperpigmented.
Lab data included a random glucose of 253 mg/dl, A1C of 7.9%, normal creatinine and electrolytes, aspartate aminotransferase (GOT) of 66 units/l (normal < 44), alanine aminotransferase (ALT) of 133 units/l (normal < 31 units/l), normal bilirubin and alkaline phosphatase levels, normal testosterone level, and negative hepatitis antigen screen. His iron level was 306 μg/dl (normal < 155) with an iron-binding capacity of 315 μg/dl (normal < 400) and percent saturation of 97% (normal < 50%). Serum ferritin was 2,920 μg/l (normal < 160). The polymerase chain restriction assay demonstrated homozygosity for the C282Y chromosome. Referral to the hepatology clinic resulted in a liver biopsy, which identified increased iron stores and early periportal fibrosis.
Following confirmation of a diagnosis of hemochromatosis, he was started on phlebotomy therapy. Family screening was encouraged and resulted in the finding of asymptomatic diabetes associated with hemochromatosis in his brother. His medication doses have not changed, nor have his fasting glucose level or A1C results after 4 months of phlebotomies.
Questions
What is the prevalence of hemochromatosis in the general and diabetic population?
What is the effect of treatment on diabetic control in patients with hemochromatosis?
Should all people with diabetes over age 30 be screened for hemochromatosis?
Commentary
Hereditary hemochromatosis is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. This mutation results in increased intestinal absorption of iron and eventually to iron overload. About 10% of the white population in the United States is heterozygote, with the frequency for homozygosity at 0.2–0.5%. Heterozygote individuals are gene carriers but are not medically affected.
Onset of symptoms is seldom apparent before age 40 because it takes years to build up enough iron to cause tissue damage. Liver function abnormalities are the most frequent finding leading to a diagnosis. Other important organ systems usually involved include the pancreas (diabetes), skin (hyper-pigmentation), joints (arthralgias and arthritis), heart (arrhythmias), and gonads (hypogonadism).
Approximately 50% of patients diagnosed with hemochromatosis will have either type 1 or type 2 diabetes. The likelihood of finding hemochromatosis in the adult population of diabetic patients is reportedly between 1–2%. Diabetes is not uncommonly the only apparent manifestation of hemochromatosis in unrecognized cases.
Early recognition of the presence of hemochromatosis is extremely important. Prompt therapy can prevent cirrhosis of the liver, development of a hepatoma, joint and gonadal damage, and the development of diabetes. In addition, as in this case, it can lead to early recognition of the disease in family members. Unrecognized, advanced hemochromatosis carries a high risk for premature death.
Development of diabetes in hemochromatosis is likely multifactorial. Selective β-cell damage, due to uptake of iron, leads to impaired insulin synthesis and release. α-Cell function is not impaired. In addition, liver fibrosis leads to insulin resistance and contributes to some patients requiring large amounts of insulin to obtain optimal blood glucose control. A family history of diabetes is observed in 25% of patients with hemochromatosis who develop diabetes. In contrast, only 4% of those with hemochromatosis who fail to develop diabetes have a positive family history. Therefore, it is likely that all three factors—β-cell damage, insulin resistance, and underlying genetic tendencies—play a causal role in patients with hemochromatosis developing diabetes.
Phlebotomy therapy has a variable impact on diabetes control. In a large study exploring the effect of therapy on diabetes control, 40% of 72 patients on insulin or oral agents showed improved glucose control following phlebotomy therapy. This same study reported that 6% of patients were able to stop insulin therapy during phlebotomy therapy, but 12% of the study group required increased medication to achieve good glycemic control. The majority of diabetic patients will experience no change or a progressive worsening in their diabetes management despite phlebotomy treatment.
The issue of screening all diabetic patients for hemochromatosis is currently debated. Screening by transferrin saturation using a level of > 50% is reasonably inexpensive. The dilemma is that some reports indicate no increased risk of hemochromatosis in an adult diabetic population. Furthermore, an elevated transferrin level is nonspecific, and a positive result will lead to many unnecessary evaluations being performed. Certainly type 2 diabetes and abnormal liver tests (as in this case), arthritis, or a family history of iron overload disease (as seen with this patient’s brother) should trigger an order for a transferrin level.
Clinical Pearls
Hemochromatosis is present in 1–2% of all diabetic patients, and diabetes is often the first clinical manifestation of the disease.
Early recognition and treatment is imperative to prevent fatal liver or heart abnormalities and can prevent the onset of diabetes or improve diabetes control.
Screening all diabetic patients for hemochromatosis may not be cost-effective. However, screening patients with a family history of iron overload disease, abnormal liver enzymes, or arthritis seems prudent.
Peter Capell, MD, is a clinical professor of medicine in the Division of Endocrinology and Metabolism at the University of Washington School of Medicine in Seattle, Wash.
