Iron out a serious problem with your diabetic patients

Don’t ignore the risk of hemochromatosis

Hemochromatosis experts urge caregivers to consider whether iron disorders can be at the root of the problems their diabetic patients face. Often, the condition can go unrecognized, even though it’s the most common potentially fatal disorder people in North America can inherit.

"Not too long ago, a physician might not expect to see more than one case of hemochromatosis in an entire career. Now we need to re-think that," says Vincent Felitti , MD, FACP, an internist in the department of preventive medicine at Kaiser-Permanente in San Diego.

Hemochromatosis is a genetic metabolic disorder where an individual absorbs too much iron in the gastrointestinal tract, resulting in serious health problems including arthritis, cirrhosis, diabetes, impotence, heart failure, and death.

It’s a disease frequently underdiagnosed, says Mary Cogswell , DrPH, an epidemiologist at the Centers for Disease Control and Prevention in Atlanta. But once it gets a foothold, diabetes can develop when iron accumulations cripple islet cells in the pancreas. Today, diabetes ranks fourth as a common comorbidity of hemochromatosis after arthritis, severe fatigue, and elevated concentration of liver enzymes. But if it can be recognized early enough in its development, the problems it causes can be reversed, says Felitti, who notes that depending on the age of the patient, hemochromatosis-induced diabetes may be diagnosed as Type 1 or Type 2.

Iron disorder often goes undetected

Earlier this year in the American Journal of Preventive Medicine, Cogswell reported that doctors look for a traditional presentation of the disease, a triad of skin pigmentation, diabetes mellitus, and cirrhosis or liver disease. But the condition appears this way only in a minority of cases. Furthermore, Cogswell adds when those classic symptoms are present, the disease is already at the end stage and it’s too late to try to reverse the diabetes.

Cogswell says statistics based on diagnostic data are probably underreported because hemochromatosis is rarely listed as the primary reason for a visit to the doctor when diabetes, arthritis, or other more symptomatic diseases are present.

The same holds true for death certificates, she says. For example, only 1.8 in a million deaths in 1992 were directly attributed to hemochromatosis, she says. The low death rate is perhaps partially attributable to effective treatment, she says, but more likely the disease has never been diagnosed in some patients at all. Doctors continue to treat patients as though they have diabetes alone, when in fact, the diabetes is secondary to a life-threatening iron disorder that could have been treated before it caused such complications.

Cogswell says studies show hemochromatosis is unlikely to be detected in patients with diabetes and liver diseases, unless doctors look for it specifically. And if conventional diabetic medications are started, the patient’s condition usually doesn’t respond to it.

The disease is like a "big bully" because it can bring such dire side effects, says Eugene Weinberg , PhD, professor emeritus of microbiology at Indiana University in Bloomington. But it is easily treated. And as it’s becoming more common, more clinicians are learning to recognize it more often in the United States, he says.

Felitti says he strongly advocates testing the general population for iron loading disorders at least once in a lifetime. The test should come early in life for those who have a family history of the disorder.

"At the very least," he says, "All Type 2 diabetics should be tested as part of the standard work-up when blood sugars are found to be elevated enough to warrant a diagnosis of diabetes."

A random transferrin saturation test is as simple as any other blood test and is both accurate and inexpensive, says Felitti. In fact, he says, the idea of adding transferrin saturation and serum ferrin screenings to other types of blood panels has been considered by several health care organizations.

"Anyone with a serum iron saturation level over 50% is suspect for the disease, so a repeat test is warranted, with the patient fasting and abstaining from any vitamin or mineral supplements for at least 24 hours.

"If the serum iron saturation test is still over 50% and the ferritin level is elevated, I recommend proceeding directly to phlebotomy [the nearly universally successful therapy for hemochromatosis]," he says.

Cogswell notes that cutoff values should be lower for women than for men because their distribution of transferrin is lower than men’s.

Weinberg adds that men usually begin showing signs of hemochromatosis in their 20s or 30s, but women frequently show no signs until they reach menopause, when they no longer shed iron through normal menstruation.

But, he says, "It varies all over the map how much damage is done and when. It’s extraordinarily variable which organs are going to be affected."

Cogswell stops short of recommending universal hemochromatosis screening, at least in terms of her role at the CDC, because she says there have not been enough detailed studies on the issue. However, "from a practical standpoint, it would make sense to screen," she says.

She says the disease is "common in comparison with many genetic disorders" and it meets many of the criteria for population screening, but the statistics on its incidence need further verification with more studies. But she acknowledges "the potential for preventing hemochromatosis-associated illness and death through screening and treatment may be great."

Prevalence of hemochromatosis in the general population is "borderline," adds Michael Engelgau , MD, a medical epidemiologist at the CDC. However, he says, the prevalence of the disease in people with diabetes is "probably high enough to warrant special screening."

Deterrents to testing

The cost of an across-the-board screening of Type 2 diabetic patients, could be prohibitive, notes Richard Dickey , MD, president of the American Association of Clinical Endocrinology and a practicing endocrinologist in Hickory, NC.

"Medicare will not pay for it, precluding the test in most patients, since it costs $54 from my lab and they would have to pay for it themselves," Dickey says. He also says some labs include ferritin levels in some panels, thereby getting around that obstacle.

He also said that generalized testing could get the prices down to as little as $20 per member of a large HMO or other large health care organization. But for individual patients seeing doctors in small practices, the price is not likely to drop.

Felitti also says hemochromatosis is hard to recognize, since patients frequently exhibit no symptoms. "There are people who have hemochromatosis that do not manifest it in any way except in death," Dickey says.

Felitti agrees, but encourages practitioners to look for hints of the disease. "An overloaded person can go for months of even years with no problem, and then suddenly flare up. It can be quite dramatic to see," he says.

The key is early diagnosis, says Felitti. "Com-plications are 100% preventable if it is caught early enough." Even later stage diagnoses are 99% reversible through phlebotomy, he says.

"I had an 82-year-old man in my office this morning who has had 120 pints of blood removed. His ferritin levels are now normal and he’s feeling fine,"says Felitti. A typical patient with hemochromatosis may require the gradual removal of as much as 80 pints of blood or more. If a patient is seriously overloaded with iron, phlebotomies could take place as often as twice a week, taking about a pint each time.

The goal is to return iron saturation to a normal level. Then maintenance phlebotomies at regular intervals will keep the patient stable and prevent iron buildup and the subsequent complications. Those diagnosed as a result of familial screening who present no symptoms may be de-ironed with the removal of only 10 or 15 pints of blood.

When the patient’s ferritin levels have dropped below 1,000 ng/mL, treatment may be needed on a weekly or biweekly basis. Then, when ferritin levels are at 300 ng/mL for men and 200 ng/mL for women, treatment frequency drops to once or twice a month. At the maintenance level (25-75 ng/mL), drawing blood depends on the patient’s condition. Phlebotomies are usually performed from once a month to quarterly.

Felitti also warns clinicians against expecting to see the typical darkened skin of "bronze diabetes," which is fairly uncommon. (See box, p. 103.) "But I did see a man at 7:15 this morning who had remarkably dark skin, equally tan all over, even in the underarms. That was clearly bronze diabetes," Felitti says, who is a scientific advisor to the Iron Disorders Institute in Greenville, SC. "If you wait for bronze diabetes, you’ll make only end-stage diagnoses in people who you are going to autopsy soon."

"Family practitioners are overwhelmingly unfamiliar with the disease. Even many hematologists have no familiarity with it at all," says Felitti.

He gives every patient who needs to be tested a printed letter of instruction explaining what tests they need. "We will even interpret the lab results at no charge because so many doctors are resistant to direction on this issue," he explains.

Dickey adds, "It’s certainly not something we pick up as often as we should. Any patient with endocrine disorder or evidence of liver disease should be tested."

[For more information, contact Eugene Weinberg at (812) 855-4842, Vincent Felitti at (858) 573-5454, Mary Cogswell at (770) 488-6053, and Richard Dickey at (828) 322-7338.]