Supercalafragilistichemochromatosis
“. . . . . . . Even though the sound of it is something quite atrocious, occurring in the virile sex it is more precocious, supercalafragilistichemochromatosis.” In this, the Hemochromatosis Screening Awareness Month, that little ditty seems all the more apropos. I can assure you, however, that for 0.5 percent, or one million plus, of the U.S. population, it is no laughing matter. Even the treatment of hemochromatosis would make Bram Stoker’s Count Dracula proud, as phlebotomy (bloodletting), to reduce and maintain body iron at normal or near-normal levels, is the treatment of choice.
But let’s not put the cart before the horse. Hemochromatosis, like any other hematologic disorder, must be affronted in an orderly, systematic manner. It is currently the most common cause of iron overload in the United States, with as much as 10 percent of the population heterozygous for this condition, and subject to a 25 percent risk of developing minor, apparently harmless increases in body iron stores. For the 0.5 percent of the population homozygous for hemochromatosis, the genetic defect results in an abnormality in the control of iron absorption that causes an inappropriate increase in iron uptake and a progressive buildup of body iron.
And if that were not bad enough . . . . . . ., the iron accumulates as hemosiderin in liver prenchymal cells (hepatocytes), and subsequently in the pancreas, heart, adrenal glands, testes, pituitary gland, and kidneys, leading eventually to hepatic, pancreatic, and cardiac dysfunction and insufficiency and hypogonadism. Women, take heart, however (and please excuse the pun), as the disease usually occurs in males and is rarely recognized before the fifth decade. Ten to twenty years postmenopause is the time-frame for targeted women.
Now, let’s get down to the nitty-gritty, and some of the “gorier” aspects of hemochromatosis. The classic tetrad of clinical signs is hepatomegaly and liver disease, diabetes mellitus, skin pigmentation (combination of slate gray due to iron and brown due to melanin, sometimes resulting in bronze color), and gonadal failure (impotence). Cardiac failure develops in about 10 to 15 percent of untreated patients, with arthropathy and bleeding esophageal varices bringing up the rear. Furthermore, in patients who develop cirrhosis due to hemochromatosis, there is a 15 to 20 percent incidence of hepatocellular carcinoma. So, the picture isn’t pretty!
Body iron stores have usually increased from the normal amount of 1 gram or less to 15 to 20 grams or more by the time symptoms of organ damage appear. Environmental factors, including dietary iron content and alcohol use, as well as the coexistence of other hereditary hematologic disorders, may also greatly influence the rate and severity of organ damage.
So, how do we screen for this polymorphic intruder, who bides its time and lies in wait at our very doorsteps, ready to spring when the genetic equinox is favorable? Screening, after all, is the point of this article.
Needless to say, a high degree of clinical suspicion must be maintained in patients with a family history of hemochromatosis or otherwise unexplained mild liver test abnormalities. For screening purposes, liver function tests (including enzyme assays) and measurements of the plasma iron, transferrin (iron-carrier protein) saturation, and plasma ferritin (storage form of iron) provide the best indirect means of screening. If any of these measurements is abnormal, further evaluation is indicated. Computed tomography (CT) and magnetic resonance imaging (MRI), however, are not sensitive enough for screening asymptomatic persons. Liver biopsy, on the other hand, which characteristically shows extensive iron deposition in hepatocytes and usually in bile ducts, vessel walls, and supporting structures, permits a definitive diagnosis. Further confirmation derives from determination of the hepatic iron index on a liver biopsy specimen (hepatic iron content per gram of liver converted to micromoles and divided by the patient’s age). A hepatic iron index greater than 1.9 suggests hemochromatosis.
However the diagnosis of hemochromatosis is established, screening of family members at risk for the disease is obligatory. Screening should include not only siblings, but also parents and children because of the possibility of homozygous-heterozygous matings.
Which brings us now to the matter of treatment, both in the cirrhotic patient and, more importantly, in the precirrhotic phase of hemochromatosis. Weekly phlebotomies of 500 milliliters of blood (about 250 milligrams of iron), continued for up to 2 to 3 years, achieve depletion of iron stores. When that is achieved, maintenance phlebotomies (every 2 to 4 months) are continued. Now, although the chelating (binding) agent, deferoxamine, administered intramuscularly, has been shown to produce urinary excretion of 5 to 18 grams of iron per year (comparing favorably with the rate of 10 to 20 grams of iron removed annually by weekly or biweekly phlebotomies), the treatment is painful and requires a constant infusion pump. Furthermore, active treatment of the complications of hemochromatosis - arthropathy, diabetes mellitus, heart disease, portal hypertension, and hypopituitarism - may be necessary. A multifaceted approach is the name of the game.
So, what is the “silver lining,” if, indeed, there is one? In precirrhotic patients, phlebotomy therapy can prevent the onset of cirrhosis, while at the same time reducing cardiac conduction defects and lowering insulin requirements. In patients with cirrhosis, bleeding esophageal varices may be reversed, but, unfortunately, the risk of hepatocellular carcinoma still lurks in the shadows.Vigilance and aggressive therapy are the only options available to turn down the volume on our “Supercalafragilistic-hemochromatosis.”
But let’s not put the cart before the horse. Hemochromatosis, like any other hematologic disorder, must be affronted in an orderly, systematic manner. It is currently the most common cause of iron overload in the United States, with as much as 10 percent of the population heterozygous for this condition, and subject to a 25 percent risk of developing minor, apparently harmless increases in body iron stores. For the 0.5 percent of the population homozygous for hemochromatosis, the genetic defect results in an abnormality in the control of iron absorption that causes an inappropriate increase in iron uptake and a progressive buildup of body iron.
And if that were not bad enough . . . . . . ., the iron accumulates as hemosiderin in liver prenchymal cells (hepatocytes), and subsequently in the pancreas, heart, adrenal glands, testes, pituitary gland, and kidneys, leading eventually to hepatic, pancreatic, and cardiac dysfunction and insufficiency and hypogonadism. Women, take heart, however (and please excuse the pun), as the disease usually occurs in males and is rarely recognized before the fifth decade. Ten to twenty years postmenopause is the time-frame for targeted women.
Now, let’s get down to the nitty-gritty, and some of the “gorier” aspects of hemochromatosis. The classic tetrad of clinical signs is hepatomegaly and liver disease, diabetes mellitus, skin pigmentation (combination of slate gray due to iron and brown due to melanin, sometimes resulting in bronze color), and gonadal failure (impotence). Cardiac failure develops in about 10 to 15 percent of untreated patients, with arthropathy and bleeding esophageal varices bringing up the rear. Furthermore, in patients who develop cirrhosis due to hemochromatosis, there is a 15 to 20 percent incidence of hepatocellular carcinoma. So, the picture isn’t pretty!
Body iron stores have usually increased from the normal amount of 1 gram or less to 15 to 20 grams or more by the time symptoms of organ damage appear. Environmental factors, including dietary iron content and alcohol use, as well as the coexistence of other hereditary hematologic disorders, may also greatly influence the rate and severity of organ damage.
So, how do we screen for this polymorphic intruder, who bides its time and lies in wait at our very doorsteps, ready to spring when the genetic equinox is favorable? Screening, after all, is the point of this article.
Needless to say, a high degree of clinical suspicion must be maintained in patients with a family history of hemochromatosis or otherwise unexplained mild liver test abnormalities. For screening purposes, liver function tests (including enzyme assays) and measurements of the plasma iron, transferrin (iron-carrier protein) saturation, and plasma ferritin (storage form of iron) provide the best indirect means of screening. If any of these measurements is abnormal, further evaluation is indicated. Computed tomography (CT) and magnetic resonance imaging (MRI), however, are not sensitive enough for screening asymptomatic persons. Liver biopsy, on the other hand, which characteristically shows extensive iron deposition in hepatocytes and usually in bile ducts, vessel walls, and supporting structures, permits a definitive diagnosis. Further confirmation derives from determination of the hepatic iron index on a liver biopsy specimen (hepatic iron content per gram of liver converted to micromoles and divided by the patient’s age). A hepatic iron index greater than 1.9 suggests hemochromatosis.
However the diagnosis of hemochromatosis is established, screening of family members at risk for the disease is obligatory. Screening should include not only siblings, but also parents and children because of the possibility of homozygous-heterozygous matings.
Which brings us now to the matter of treatment, both in the cirrhotic patient and, more importantly, in the precirrhotic phase of hemochromatosis. Weekly phlebotomies of 500 milliliters of blood (about 250 milligrams of iron), continued for up to 2 to 3 years, achieve depletion of iron stores. When that is achieved, maintenance phlebotomies (every 2 to 4 months) are continued. Now, although the chelating (binding) agent, deferoxamine, administered intramuscularly, has been shown to produce urinary excretion of 5 to 18 grams of iron per year (comparing favorably with the rate of 10 to 20 grams of iron removed annually by weekly or biweekly phlebotomies), the treatment is painful and requires a constant infusion pump. Furthermore, active treatment of the complications of hemochromatosis - arthropathy, diabetes mellitus, heart disease, portal hypertension, and hypopituitarism - may be necessary. A multifaceted approach is the name of the game.
So, what is the “silver lining,” if, indeed, there is one? In precirrhotic patients, phlebotomy therapy can prevent the onset of cirrhosis, while at the same time reducing cardiac conduction defects and lowering insulin requirements. In patients with cirrhosis, bleeding esophageal varices may be reversed, but, unfortunately, the risk of hepatocellular carcinoma still lurks in the shadows.Vigilance and aggressive therapy are the only options available to turn down the volume on our “Supercalafragilistic-hemochromatosis.”
Copyright 2003, Albert M. Balesh, M.D. All rights reserved.
posted by Dr. Al at
7/19/2006 10:52:00 AM
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