Iron OVERLOAD

ASD and the recognition of Hemochromatosis

By Rosalba Maistoru M.A., BCBA

The dramatic rise in autism spectrum disorders (ASD) diagnoses, both in the United States and in other countries, along with the rise in other accompanying immune and chronic illnesses has led many clinicians in the field to expand the area of research and treatment. While ASD has been modeled as a brain-based strongly genetic disorder, it is defined behaviorally, as a syndrome of abnormalities involving language, social and behavioral inflexibility. To date the causes of ASD are not entirely known but are

thought to include genetics and environmental factors.

Although it is entirely probable that ASD is not caused by a single agent or can be profiled in the same way for each afflicted individual, increasing studies have demonstrated similar underlying biological mechanisms driving the problems often witnessed in those with ASD. Many individuals with ASD and other related disorders appear to be healthy, but numerous suffer gastrointestinal and immune system problems that may go undetected until symptoms become obvious and required medical attention.

Currently, a growing number of reports have documented evidence of individuals with ASD displaying impairments associated with a common medical condition called

hemochromatosis, a disorder characterized with increased intestinal absorption of iron and the deposition of excessive amounts of iron in multiple organs. If left untreated, hemochromatosis can result in the accumulation of iron in various organs leading to

potentially serious complications. The good news is that early diagnosis and treatment can effectively reduce the body’s iron overload, prevent organ damage, and enable patients to lead normal and productive lives.

Surprisingly, as one of the most common genetic disorders in America, many people have never heard about hemochromatosis. According to the Centers for Disease Control and Prevention (CDC), individuals with this iron storage disorder are misdiagnosed 67 percent of the time and usually see an average of three doctors before obtaining a successful diagnosis. This remains a critical health concern, because early detection with treatment can save lives and improve quality of life. Increasingly, however, due to increased awareness many are being diagnosed at an earlier

less symptomatic stage.

Hemochromatosis is a progressive iron overload disease caused by uninhibited iron absorption. Individuals with this condition absorb more iron (from their diet) than their body needs. As the body does not have a way to excrete excess iron, there is a progressive buildup of it. Eventually, the metal can reach toxic levels in tissues of major organs, leading to dysfunction and failure of the liver, heart, pituitary gland, thyroid, pancreas, spleen and joints. Therefore, undiagnosed and untreated hemocrhomatosis

increases the risk for diseases and conditions including cirrhosis of the liver or liver cancer, diabetes mellitus, heart problems, arthritis (osteoarthritis, osteoporosis), depression, impotence, infertility, hypothyroidism, hypogonadism, and

some forms of cancer.

The genetic form is known as primary hemochromatosis or hereditary hemochromatosis (HH) and it is an autosomal recessive disease due to mutations of HFE, a gene located on chromosome 6. There are more than 20 known mutations of HFE, but

the most important for iron loading to date are C282Y and H63D. The C282Y mutation in the HFE gene explains 80 to 90 percent of all diagnosed cases of HH in populations of northwestern European ancestry and is the most commonly inherited

liver disease in Europe. The acquired form is known as secondary hemochromatosis or transfusional iron overload. This form of hemochromatosis should be suspected in patients with chronic anemia, multiple transfusions, prolonged iron supplementation,

or chronic liver disease. Iron overload caused by HH should be distinguished from overload secondary to other entities. In secondary iron overload, iron often accumulates in Kupffer cells rather than hepatocytes, as typically occurs in HH.

While all ethnic groups can be affected, those with Celtic ancestry (Irish/Scottish/Welsh), British/Northern European origin, as well as those with Dutch, German, French, Spanish, and Italian descent have the highest prevalence of the HH mutation in Caucasian groups. Hispanics and African-Americans can also acquire secondary overload and it can affect men, women and children at any age. About 1 in 100 to 200 people has HH (double gene mutation known as a homozygote) and1 in 8 to 10 people is a carrier of hemochromatosis (single gene mutation known as a heterozygote or “het” for short). That’s approximately 36 million Americans who are carriers and 1.5 million Americans have the double gene which can lead to HH.

The signs and symptoms of HH are different from person to person. Men are more likely to display symptoms than women. The signs an individual may exhibit depends on the amount of iron in their current diet, if they are taking iron pills or consuming alcohol. People who have a very high iron level may have skin with a bronze or gray color. Other symptoms include generalized weakness and chronic fatigue (the most common complaint by patients), joint pain, and abdominal pain. Some patients may also have an enlarged liver or spleen. Appropriate diagnosis of HH is based upon a thorough medical history, physical examination, and laboratory tests to measure specifically for iron overload.

Most affected people do not know they are accumulating dangerous stores of iron or do not demonstrate symptoms (asymptomatic) and that is the best time to diagnose the patient. Many doctors have been taught to look for “indicators” of HH but by the time symptoms appear, it is often too late. Most physicians diagnose only a few cases of HH in their practice because they do not routinely test for iron overload and/or because many patients with the disorder have no manifestations.

Recently, Dr. William Walsh, of the Pfeiffer Treatment Center in Illinois, conducted a study at the request of an autism parent group to check out iron levels in the center’s population of nearly 3,000 ASD patients. The results of the investigation revealed that children with ASD exhibited higher serum iron levels than controls (typical children). However, all of the differences occurred in about 1/3 of the ASD population with the other 2/3 resembling the controls. The children with ASD testing with high iron levels were extremely high, the rest of the children with ASD levels of iron were quite normal, and there was little or no “middle ground.”

Dr. Walsh went on to state, “My data essentially confirms the findings of the M.H. article ( Med Hypotheses. 2003 Aug; 61(2):220-2). Iron free radicals (ions) represent the primary oxidative stress in the brain of most humans. ASD involves

oxidative stress during early brain development. In theory, elevated iron in the brain could result in ASD. A genetic inability to regulate iron might be causative in 1/3 of autism cases.” Thus, it appears from the research findings that a segment of the ASD

population has a very abnormal iron metabolism and abnormal ceruloplasmin.

In fact, for several years now researchers have documented a number of studies suggested alterations in the levels of major antioxidant serum proteins, namely transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein), both significantly reduced in children with ASD as compared to their developmentally normal siblings. There is a positive correlation between reduced levels of these proteins and loss of previously acquired language skills in children with ASD. The alterations in ceruloplasmin and transferrin levels may lead to abnormal iron and copper metabolism in autism. Furthermore, environmental and genetic factors may increase vulnerability to oxidative stress in ASD. Taken together, these studies suggest increased oxidative stress in autism that may contribute to the development of this disease.

Transferrin is a blood protein that carries iron through the blood to the bone marrow, spleen, and liver for either the storage of iron as ferritin or the manufacture of new red blood cells. It is a protein with a relatively short half-life that can be a marker for recent protein status, and it is used for this purpose. Low blood transferrin may be an indicator of protein or calorie malnutrition, resulting in inadequate synthesis of transferrin by the liver or it can result from excess protein loss through the kidneys (proteinuria).

A systemic infection or cancer can also lower the blood transferrin level. A high blood transferrin is a marker of iron deficiency. If an individual has a low blood transferrin level, the production of hemoglobin can be impaired and can lead to anemia,

even if there is ample iron in the body.

Ceruloplasmin is a copper-containing protein involved in handing over iron from transferrin to hemoglobin in the formation of new red blood cells, or in removing iron from old red blood cells for inclusion in new ones. A copper deficiency results in low ceruloplasmin and can result in anemia that presents much like iron-deficiency (microcytic, hypochromic) anemia, possibly leading to a misdiagnosis. A ceruloplasmin deficiency is associated with iron accumulation in the pancreas, liver, and brain, resulting in neurological disorders. Laboratory testing for iron overload/hemochromatosis begins

with two specific blood tests, Serum Iron and TIBC (total iron binding capacity), from which the Serum Transferrin Saturation is calculated. Serum Ferritin is frequently measured as well, if possible while fasting, to evaluate the body's iron stores and estimate

the degree of iron overload. Remember that while hematocrit (hct) and hemoglobin (hgb) are part of routine medical testing, they are not tests to confirm iron overload. Instead, serum transferrin saturation and serum ferritin are tests to detect iron

overload, but are not part of routine medical testing. The TIBC test measures how well your blood can transport iron, and the serum ferritin test shows the level of iron in the

liver. If either of these tests shows higher than normal levels of iron in the body, doctors can order a special blood test to detect the HFE mutation, which will confirm the diagnosis. If the mutation is not present, HH or primary hemochromatosis is not the

reason for the iron buildup and the doctor will look for other causes. In some cases, an examination of a liver biopsy specimen is warranted. Progressive liver damage associated with hemocrhomatosis is

generally attributed to increased oxidative stress. In otherwise

healthy individuals, more modest levels of iron storage may

occur if iron is provided by supplements or otherwise added to

the food supply. Increased iron intake and storage have been

linked to a variety of chronic diseases. The associations are not

firmly established but are of considerable public health importance.

In several occurrences, a liver biopsy may be necessary to

determine extent of advanced liver disease if liver function tests

(LFTs) are significantly elevated and there are signs of liver distress.

The need for this procedure should be discussed with a

physician. Those with early, asymptomatic HH with normal LFTs

probably will be able to forego this invasive and potentially risky

procedure.

In the United States, public health interventions such as fortification

and enrichment of foods with iron were undertaken to

reduce the prevalence of iron deficiency anemia and improve

health. These measures, along with iron supplementation,

remain controversial, because additional exposure to dietary iron

places some segments of the population at increased risk of iron

excess. Excess iron increases the generation of free radicals in

tissues and this is what is believed to cause disease. The health

consequences of unmistakable iron excess are exemplified by

hemochromatosis.

Before considering genetic testing for HH, the pros and cons

should be discussed carefully with a family doctor or a genetic

counselor—a health care professional who practices genetic

counseling. The risks and benefits of genetic testing should be

explained thoroughly because it is important to be fully informed

of the potential for discrimination, such as employment or insurance

denial or cancellation, after being diagnosed with the HFE

gene. That is the primary reason why HFE gene testing is not

recommended for children younger than 18 years of age. In fact,

the CDC and the U.S. Human Genome Research Project, recommend

this type of testing only for adult family members of someone

with HH.

If you decide to have the DNA test, ask for the Cys282Y and

His63D mutations for both children and adults. HLA-typing is

not the same as DNA genetic testing. HLA typing is an outdated

form of testing that does not identify the gene mutation for HH.

Make sure that you or your doctor are not ordering HLA typing,

but rather genetic testing by PCR for the HFE mutation (cys282

and his63) on the short arm of chromosome 6. A very small percentage

(about 12 to 15 percent) of patients who are clinically

iron overloaded (have high TS and serum ferritin levels) may

have a negative result on the genetic test. Scientists believe that

these individuals may have another HH mutation, which has yet

to be discovered, causing this iron storage. For this reason, it is

always wise to test using the transferrin saturation and serum ferritin

annually to be on the safe side.

Genetic testing can be done by two methods, cheek brush or

whole blood. Cheek brush collection involves scraping cells from

inside the mouth using a mascara-like wand with tiny bristles on

the end. Whole blood collection requires a needle to be inserted

into the arm and a vial of blood removed. According to John

Longshore, Ph.D, Iron Disorders Institute Scientific Advisory

Board member and expert in laboratory diagnostics, both methods

are reliable. One should take care to protect the sample

which might include using an overnight mailing service, as

extreme cold or heat may destroy tissue samples.

Early diagnosis and treatment of HH is critical in order to prevent

damage to vital organs and prevent serious complications

such as cirrhosis of the liver and diabetes. The objectives of

treatment are to remove excess iron from the body and prevent

organ damage. Treatment consists of therapeutic phelebotomy

which involves removing one unit of blood once a week until the

iron levels have returned back to the normal range. Iron chelation

therapy may be considered an option for patients who are

not appropriate candidates for therapeutic phlebotomy.

For more information on a testing lab that has easy access to

direct testing without a prescription and results sent to the patient

only, please visit www.healthcheckusa.com. For additional information

on labs which test for both mutations and offer a handy “cheek

brush” tissue collection kit, contact Kimball Genetics in Denver,

Colorado (1-800-320-1807 or 303-320-1807 in Denver or outside of

the U.S.A.) and Michigan State University (MSU) ( 517) 353-2032.

For additional sources on iron overload please visit: Iron Disorders

Institute Inc. at www.irondisorders.org or call 1-888-565-4766 and

Iron Overload Diseases Association at www.ironoverload.org or call

1-561-840-8512.

Please note: All information is for educational purposes only and

is not intended or implied to be a substitute for professional medical

advice. The reader is always advised to seek the guidance of a physician

and to discuss the information provided here with a doctor,

pharmacist, nurse, or other authorized healthcare practitioner. Any

references to treatment options, programs, or services are not

endorsements and the author and any parties associated with the

materials printed do not accept any responsibility for the accuracy of

the information or the consequences arising from the application,

use, or misuse of any of the information contained herein, including

any injury and/or damage to any person or property as a matter of

product liability, negligence, or otherwise. We hope you find the

materials mentioned helpful and as a means to begin learning more

about ASD and Hemochromatosis. For more information on HH,

please visit the American Hemochromatosis Society (AHS) at

www.americanhs.org or call 407-829-4488.