Overview
Hemochromatosis is an inherited metabolic disorder that causes the body to absorb too much iron. The overload of iron accumulates in the heart, the pancreas, and the liver, where it can cause life-threatening conditions, including cirrhosis, liver cancer, diabetes, and heart failure. Early symptoms are nonspecific and sometimes not present, which means that the disease may go undiagnosed. With early diagnosis and treatment, however, people with hemochromatosis can expect a normal life span.
The body gets iron primarily from food, with the greatest amount of dietary iron coming from red meat as well as iron-fortified bread and cereal. Normally, the body absorbs about 10 percent of the iron in the food it eats. But people with hemochromatosis may absorb five times that amount. The iron becomes part of the hemoglobin in blood and is transported to all body tissues. It builds up in the heart, the pancreas, and particularly in the liver, because of the liver's large blood supply. The extra iron causes an overproduction of free radicals, which leads to organ injury.
The body has no natural way to rid itself of the excess iron. Once absorbed, the iron is not lost until blood is lost. Therefore, removal of blood remains the first treatment.
Hemochromatosis was first identified in the 1800s, and by 1935 it was understood to be a hereditary disorder caused by a gene mutation. People who inherit the genetic mutation from both parents generally develop the disease. About 1 in 300 people in the United States has the genetic defect from both parents and is at extremely high risk of developing the disease. Those who inherit the defective gene from only one parent-about 1 in 9 people in the United States-usually do not develop hemochromatosis but may still have higher than average iron absorption. The prevalence of these genetic abnormalities makes hemochromatosis the most common hereditary disorder in the United States.
While the inherited trait leading to hemochromatosis is present at birth, symptoms of the disease rarely appear before adulthood. It is primarily seen in middle-aged men of Northern European descent and in postmenopausal women. Despite its widespread occurrence among Caucasians, hereditary hemochromatosis is underdiagnosed.
Need-to-know anatomy
The liver is the organ most severely affected by hemochromatosis. It is an organ essential to life. It stores vitamins, sugar, and iron. It controls the production and removal of cholesterol. It clears the body of wastes, detoxifies potentially harmful chemicals, and removes bacteria from the bloodstream to combat infection. It releases bile acids necessary for the digestion and absorption of key nutrients. And it converts nutrients into clotting factors and immune factors, to stop excessive bleeding and to fight foreign invaders.
The liver is located between the ribs and extends horizontally from the middle of the body to the right side. About the size of a football, it is the largest organ in the body. It weighs about 3 pounds in women and 4 pounds in men, and it receives a tremendous volume of blood, more than 3 pints per minute on average. In an individual with hemochromatosis, the large volume of blood pumped through the liver results in high levels of iron deposits that can lead to liver injury, cancer, or liver failure.
If the liver fails, a person can live only a day or two without it. But the liver has a wondrous ability to regenerate itself. Even if as much as 75 percent of it is diseased or destroyed, the liver will still grow new, healthy liver cells and continue to perform its essential functions.
The liver, however, is susceptible to cirrhosis, a hardening of the tissues that reduces function and ultimately causes death. Cirrhosis is one of the complications resulting from untreated hemochromatosis.
Causes
Hemochromatosis is a hereditary condition. It is mainly caused by a defect in a gene called HFE, which is key to regulating the amount of iron absorbed from food. There are two known mutations of this gene, designated as C282Y and H63D. Of these two mutations, C282Y is the most significant. It alters a protein in a way that distorts the body's iron sensing system. Like a defective thermostat that continues to increase the heat in an overheated room, the mutation tells the body to keep absorbing iron, even though it already has enough. Over time, this extra iron becomes toxic to the liver and other organs.
Individuals with clinical hemochromatosis generally have inherited the C282Y mutation from both parents. People who inherit the defective gene from only one parent usually do not develop hemochromatosis, but they may still have higher than average iron absorption.
Neither juvenile hemochromatosis nor neonatal hemochromatosis is caused by an HFE defect. Juvenile and neonatal hemochromatosis result from a mutation in a gene called hemojuvelin.
There is a small group of patients who have clinical hemochromatosis but do not have mutations in the HFE gene. Their disease is believed to be hereditary, but the genetic cause has not been found.
Risk Factors
Genetics: The main risk factor for development of hemochromatosis is having two parents with the disease. An individual with one parent with hemochromatosis is at risk of increased iron absorption and should be screened.
Race and nationality: Hemochromatosis is the most common genetic disorder affecting Caucasians of Northern European descent. The disease is less common in African-Americans, Asian-Americans, Hispanics, and American Indians.
Age and sex: Although both men and women inherit the gene defect, men tend to be diagnosed with hereditary hemochromatosis at a younger age than women. On average, men develop symptoms and are diagnosed between 30 to 50 years of age. For women, the average age of diagnosis is about 50.
Juvenile and Neonatal Hemochromatosis
Juvenile hemochromatosis and neonatal hemochromatosis are two additional forms of the disease. Juvenile hemochromatosis leads to severe iron overload and liver, and heart disease in adolescents and young adults between the ages of 15 and 30. The neonatal form causes rapid iron buildup in a baby's liver that can lead to death.
Juvenile and neonatal hemochromatosis result from a mutation in a gene called hemojuvelin.
Secondary iron overload
Hemochromatosis is distinct from secondary iron overload, which also causes increased iron absorption and iron deposition in organs. Cases of secondary iron overload may result from too many blood transfusions, Hepatitis C, alcoholism, chronic liver disease, some types of anemia, and other illnesses.
Complications
Patients with hemochromatosis must also be aware of the severe complications of untreated hemochromatosis. Rates of cirrhosis and liver cancer are high. There is no evidence that iron depletion by phlebotomy decreases the high incidence of liver cancer in patients with cirrhosis due to hemochromatosis, and no reversal of cirrhosis has been documented. People with complications of hemochromatosis may want to receive treatment from a specialized hemochromatosis center. These centers are located throughout the country.
Liver cancer
The incidence of liver cancer in patients with hemochromatosis can be as high as 45 percent, and often the tumor is multifocal.
Hepatocellular carcinoma is responsible for over 12,000 deaths per year in the United States. Worldwide, it causes over a million deaths per year, making it one of the most common malignancies in adults. It is more common in men than women, and in blacks than whites. It is especially prevalent in parts of Asia and Africa. In the United States, primary liver cancer is most prevalent in people of East Asian origin.
Most people with liver cancer have no symptoms until the disease is advanced. Later stages of liver cancer, when the cancer is very large or when it impairs the functions of the liver, can produce symptoms such as abdominal pain, weight loss, lack of appetite, and finally the development of jaundice and abdominal swelling.
Most liver cancers are first diagnosed with CAT scans, magnetic resonance imaging, or ultrasound scans. These tests range from 60 to 100 percent accuracy, with larger tumors being more detectable. About 70 percent of patients with liver cancer have elevated blood concentrations of a tumor marker called alpha-fetoprotein. If there is doubt about the presence of liver cancer, the definitive diagnosis is made by liver biopsy.
Treatment of liver cancer is based on the size of the tumor, its location, and its spread to blood vessels and nearby or distant organs. "Resection" surgery, where a portion of the liver is removed, offers the only cure for the disease and the best long-term chance of survival. Patients with smaller tumors and without cirrhosis or metastases to other organs are the best candidates for liver resection. New surgical techniques such as cryosurgery-freezing the tumor and tissue around it-or radio frequency ablation-destroying the tumor with a heat probe-may work for some patients who are not good candidates for liver resection.
For patients who have small tumors, confined to the liver, but advanced cirrhosis, liver transplantation is the treatment of choice. Liver transplant is the only treatment option for patients with tumors that cannot be surgically or medically removed. However, larger or more extensive tumors have a high risk for early recurrence after liver transplantation.
Traditional chemotherapy and radiation have not been effective for treating liver cancer. The five-year survival rate for patients with liver cancer who have one or two small tumors is now about 50 to 60 percent.
Cirrhosis
Cirrhosis is the hardening of the liver, which results in loss of liver function. Cirrhosis is also a risk factor for liver cancer. Liver cancer develops in 30 percent of patients with cirrhosis due to hemochromatosis, and the incidence of hepatocellular carcinoma increases with age, reaching almost 50 percent in patients over age 60.
Liver transplantation is an appropriate therapy for people with advanced cirrhosis due to hemochromatosis. However, survival is low compared with other cirrhosis patients receiving transplants. It is recommended that patients be iron depleted by phlebotomies before liver trasplanatation. One study showed a median survival of 2.8 years after liver transplantation with the longest survival being 5.5 years.
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