[I tried to keep this webpage as short as possible. However, the subject is somewhat complicated.]
Hereditary Hemochromatosis (HHC or HH) refers to the genetic/inherited form of hemochromatosis (also spelled haemochromatosis). Hemochromatosis is an Iron Overload Disorder and is sometimes called Iron Overload Disease. I am going to limit my discusion to the most common type of HHC. It results from a mutation in the HFE gene that regulates iron absorption from food. The (most common) mutation is referred to as "C282Y".
"Hemochromatosis is a disorder that causes the body to absorb more iron than it needs. Since there is no way for the body to get rid of this excess iron (other than bleeding or shedding skin and other cells), people with hemochromatosis end up storing iron in cells of the liver, heart, pancreas, and other organs."
"What normally happens is that a gene (called HFE) makes a protein that regulates how much iron is taken from the food you eat. Everyone absorbs a certain amount of iron in the small intestine, most of which is used for making new red blood cells. A genetic change (called a mutation) in this HFE gene causes the protein to work incorrectly, and the body absorbs too much iron."
"It is presumed, through genetic studies, that the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60-70 generations ago. Around that time, when nutrition was less balanced than today, the presence of a mutant allele may have provided a natural selection reproductive advantage in maintaining sufficient iron levels in the blood. With our current balanced diets, this 'extra help' is unnecessary and indeed harmful." [Personally, I don't think that "mutation" is an ideal word. I prefer "variation", "change" or "trait" because "mutation" has the connotation of a mistake or error - even though it really means "a genetic change". Actually, the C282Y "mutation" is an adaptation that persists due to its success in the environment. It probably still confers more advantage than disadvantage in most people by reducing the prevalence of iron deficiency. If it is no longer beneficial, it will gradually disappear through natural selection. This is what is occuring with sickle cell trait. Similar genetic mutations/variations could be connected to many diseases like diabetes, heart disease, etc. Many of these types of mutations probably enhanced survival during famines.]
"We get most of our iron from our diet. In the United States, most people consume 10 to 20 milligrams of iron per day (1000 milligrams = 1 gram). As the body digests food, about 10 percent - 1 to 2 milligrams - of the iron is absorbed from the small intestine into the blood stream."
"Most people have 3 to 4 grams of iron stored in their bodies at any given time. People with iron overload have greater amounts of stored iron."
"Since iron accumulates gradually over time, many people with iron overload do not know about it. On average, people with hereditary hemochromatosis absorb iron from their diets at 2 to 3 times the normal rate. This equals about 0.5 to 1.0 grams of iron per year."
"People generally begin to experience signs and symptoms of hemochromatosis when their iron levels reach 15 to 20 grams of iron. If the iron stores are not lowered, iron continues to accumulate and can cause serious, irreversible damage to certain organs."
"The doctors on the Board of Directors of The American Hemochromatosis Society state that transferrin saturation percentage greater than 40% and serum ferritin greater than 150ng/mL indicates clinical iron overload/iron storage in the body and should be treated with phlebotomy (bloodletting) regardless of DNA test results. This means that patients' treatment should not be based on genetic test results alone whether positive or negative." Some doctors/guidelines allow up to 50% and 300ng/mL for males. The guidelines are not exact. My results (45 year old male) were 98% and 1500ng/mL which is way above the normal limits. My liver biopsy also showed cirrhosis and iron in the liver.
"Liver biopsy... used to be the gold standard to diagnose hemochromatosis. Today, it is rarely needed to make the diagnosis, but may be used to make a prognosis (a prediction about the course of disease). Liver biopsy is the only test that can determine if someone has scarring of the liver, or cirrhosis." [Liver biopsy carries some risk.]
"The main way that hereditary hemochromatosis is treated is by regularly giving blood, a procedure called phlebotomy (pronounced fle-bot-o-me). This is the safest, most effective treatment. It is identical to a blood donation at a blood bank."
"Phlebotomy is effective because iron is used by the body to make red blood cells. Every time your body loses blood, it needs to make new red blood cells -- and it uses the iron that your body has stored in your organs. Thus, anything that allows your body to lose blood will help lower the amount of iron it has stored, and so help prevent organ damage. By regularly giving blood, you force your body to make new red blood cells and lower its stores of iron. Each phlebotomy treatment removes 200 to 250 mg of iron."
Patients usually donate one unit (pint) of blood per week (52 units per year) until their iron levels reach normal. This may take 1 to 4 years. Then they usually have 3 or 4 phlebotomies per year for the rest of their lives to maintain normal iron levels.
By regularly giving blood, you force your body to make new red blood cells and lower its stores of iron. Each phlebotomy treatment removes 200 to 250 mg of iron. [Therefore, 2-5 phlebotomies removes all the iron an HHC patient absorbs from diet in a year. This is why diet is not as big a factor as people think. Between 50 & 200 phlebotomies (~1-4 years) should get your iron levels to normal. ]
"Some manifestations are improved by phlebotomy, including fatigue, malaise, elevated serum aminotransferase levels, and insulin requirements in diabetes. In addition, exercise tolerance and cardiac function can improve with aggressive iron depletion in patients with cardiac complications.[27,42] In such cases chelation therapy with desferrioxamine is indicated. While its progression can be slowed, diabetes is not completely reversed. Hypogonadism, arthropathy, and cirrhosis do not resolve with venesection [phlebotomy], and arthropathy may progress after complete iron removal. Treatment is symptomatic, though hip and knee replacement may be required. Hypogonadotrophic hypogonadism may be treated successfully with gonadotrophin therapy with or without parenteral testosterone therapy."
"People of Caucasian European descent are much more likely to be carriers of the C282Y, H63D, or S65C mutations in the HFE gene than any other ethnicity. Until recently, this was the only known gene to cause hereditary hemochromatosis." [I am generally limiting this discussion to the C282Y mutation for simplicity.] "Hereditary hemochromatosis is one of the most common genetic disorders in the United States. It most often affects Caucasians of Northern European descent, although other ethnic groups are also affected. About 1/200 or 0.5 percent of the U.S. Caucasian population carry two copies of the hemochromatosis gene and are susceptible to developing the disease. One person in 8 to 12 is a carrier of the abnormal gene."
"That's approximately 32 million Americans who are carriers and 1.5 million Americans have the double gene which can lead to full blown hemochromatosis. Recent studies in Ireland show a frequency of 1 in 4 as carriers of the single mutation and 1 in 64 as double gene mutation. All ethnic groups can be affected, but those with an Irish/Scottish/Celtic/British heritage have an even higher prevalence of the HH mutation." [The high numbers in Ireland may be the result of poverty & events like the Irish Potato Famine that selected for the C282Y mutation.]
"Iron overload, however, is as common in African Americans and Mexican Americans as it is among Caucasian Americans -- but it is most likely due to causes other than these three mutations. Researchers believe that hemochromatosis in these groups may be caused by mutations in a number of other genes, such as transferrin receptor-2 (TFR-2) which may be involved in regulating how cells take in iron." [The literature is contadictory & not at all clear on the prevalence of hemochromatosis in non-European populations.]
Everyone has two copies of the HFE gene on chromosome 6. One HFE gene is inherited from each parent. "Inheriting just one of the C282Y mutations (heterozygous) makes a person a carrier who can pass this mutation onward. Carriers of one HFE mutation ordinarily do not manifest with clinically relevant iron accumulation at all. (They may even be more resistant to anemia.) In the United States, most people with clinically measureable haemochromatosis (i.e., iron overload with or without end organ damage) have inherited two copies of C282Y - one from each parent - and are therefore homozygous for the trait. Mutations of the HFE gene account for 90% of the cases of clinical iron overload."
"Most people who have inherited the (two) genetic mutations for HH do not develop iron overload or any signs or symptoms of the condition. This is a phenomenon called incomplete penetrance." The penetrance may be 50% or less, but the literature is not clear on this point.
"In addition, people can have varying degrees of signs and symptoms of the condition. Someone who has HH can develop more (or less) severe complications than someone else with the same genetic mutations, even within the same family. This is known as variable expression."
Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause). Cases of iron overload have been found in young children as well.
Many of the symptoms of hemochromatosis are general & subtle. Often times, it is too late when definitive symptoms appear. Serious organ damage often has already occurred. The list of symptoms/problems is long. Iron overload may cause:
People with HHC should avoid raw seafood or exposing cuts to seawater which could lead to infection by Vibrio vulnificus, a bacterium. The infection can be fatal to people with HHC because Vibrio vulnificus thrives in an iron-rich environment. People with HHC may have increased susceptibility to other bacteria as well.
"As noted previously, early diagnosis and treatment by therapeutic phlebotomy are crucial for preventing damage to vital organs such as the liver, pancreas, heart, and pituitary gland in patients with hereditary hemochromatosis."
"Research has shown that the presence or absence of liver cirrhosis is the single most important factor affecting prognosis (predicting the course or outcome of the disease) for patients with hereditary hemochromatosis. In general, studies have demonstrated that if therapeutic phlebotomy is initiated before liver cirrhosis develops survival rates for patients with hereditary hemochromatosis are similar to age and sex-matched individuals of the general population. In the absence of liver cirrhosis, the prognosis for patients with hereditary hemochromatosis is quite good."
"In contrast, research has shown that the 10-year survival rate of patients with hereditary hemochromatosis who develop cirrhosis of the liver is about 60% even with therapeutic and maintenance phlebotomy. The lower survival rate for cirrhotic patients has been attributed to the risk of developing hepatocellular carcinoma (primary liver cancer) that occurs in about 25% to 30% of patients with liver cirrhosis. For this reason, early diagnosis and treatment of patients who develop signs and symptoms of hereditary hemochromatosis is crucial to prevent liver cirrhosis and hepatocellular carcinoma as well as other potentially serious complications such as diabetes and heart problems (e.g., congestive heart failure, irregular heart beats)."
"Early diagnosis and treatment of HHC with phlebotomy to remove excess iron is associated with a good prognosis. For those patients who progress to end-stage liver disease, liver transplantation is the only available treatment option."
[3-8-2006] I was diagnosed with HHC & cirrhosis in March 2006 at the age of 45. My transferrin saturation was 98% & my serum ferritin was 1500 ng/mL. Liver biopsy showed (micronodular) cirrhosis. The first indication was an abnormal liver function test (LFT). I never noticed any symptoms. However, this is not surprising since many of the early symptoms (fatigue, weakness, joint pain, etc.) can be attributed to normal aging.
[12-31-2007] I can guesstimate that I have accumulated somewhere between 23 & 46 grams of iron in my lifetime. As of the beginning of 2008, I have had around 80 phlebotomies. This should have removed about 20 grams of iron. (20 phlebotomies removes ~5 grams of iron.) This would leave somewhere between 3 and 26 grams of iron remaining. I have a hunch/hope that 10 grams or less remains. If this hunch is correct, then only 40 more phlebotomies (or less) will be required to reach normal levels. Worst case would require over 100 more to reach normal levels. My only symptoms to date are a slight tenderness of the liver & spleen and possibly an occasional minor incident of arrythmia.
[12-31-2007] In October, my serum ferritin measured 170ng/mL (down from 1500ng/mL). This is close to normal. I believe they want to get me near 20ng/mL to remove all iron stores. My estimation is that a few more phlebotomies will get me there, i.e. less than 10 phlebotomies. I estimate a drop of ~16.6ng/mL for each phlebotomy averaged over that time period.
[4-16-2008] In April, my serum ferritin measured 55ng/mL (down from 170ng/mL in October). The middle of the normal range is around 150ng/mL. I believe they want to get me near 20ng/mL to remove all iron stores. Therefore, (170-55) = 115ng/mL and 115/12 = 9.5 or roughly 8-10ng/mL drop for each phlebotomy during that period.
[4-30-2008] In April, I had two phlebotomies after the serum ferritin measured 55. My doctor has changed me to monthly phlebotomies (my next will be at the end of May). I believe they want to get me near 20ng/mL to remove all iron stores. Therefore, (55-20) = 35ng/mL drop required. [35/9 = 4 phlebotomies and 35/6 = 6 phlebotomies.] So, 4-6 phlebotomies should get me there, and I had two in April. This would mean I should reach 20ng/mL between late June and late August. (This estimate allows for a significant drop in the effect of each phlebotomy.)
[10-29-2008] My serum ferritin measured 58. Therefore, it appears to have leveled off at this level (55-58ng/mL), using monthly phlebotomies. This is a low level & my doctor may want to remain at this level using monthly phlebotomies (for life).
[12-7-2008] Now that my iron is under control, the main issue is the liver cirrhosis. Cirrhosis is at least as complicated as hereditary hemochromatosis (HHC). Therefore, I won't try to cover it all on this web page. Details can be found here: Cirrhosis - Signs & symptoms I am including some major complications below.
[12-15-2008] The Child-Pugh score (sometimes the Child-Turcotte-Pugh score) can be used to determine the prognosis (likely outcome) of cirrhosis. The Child-Pugh score seperates cirrhosis in to three classes: A, B, & C. Class A has the best prognosis while class C has the worst. The Child-Pugh score is based on five measurements or indications: the level of bilirubin, the level of serum albumin, the INR, the presence/degree of ascites (fluid in the abdomen), & the presence/degree of hepatic encephalopathy (brain dysfunction due to toxins in the blood). Below is an outline of the Child-Pugh score:
Points Class One year survival Two year survival[1-18-2009] Fortunately, my cirrhosis is graded as class A. When cirrhosis degrades to class C or becomes unstable, liver transplantation is the only recommended option. Per Wikipedia, "Cirrhosis and chronic liver disease were the 10th leading cause of death for men and the 12th for women in the United States in 2001... .Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis... . The risk of death due to all causes is increased twelvefold; if one excludes the direct consequences of the liver disease, there is still a fivefold increased risk of death in all disease categories."
[4-30-2009] My doctor increased phlebotomies to one every two weeks from one per month. The goal is to cause iron stores to "bottom out" by inducing mild anemia. Per the CDC, this is accomplished when the patient reaches these levels: serum ferritin between 25 and 50 ng/mL, hemoglobin (Hb) lower than 11.0 g/dL.
[7-8-2009] My hemoglobin (Hb) has been falling since april. (It would not go below 15 g/dL prior to April.) When my Hb reaches 10 g/dL, I can go on maintenance phlebotomies for life. Per the CDC, the goal of lifetime maintenance is to keep serum ferritin levels at 25–50 ng/mL. Hopefully, this will require one phlebotomy per month or less.
[11-4-2009] My iron stores have been removed (Hb = 10). After today, I will have a phlebotomy every 3 months. The lifetime maintenance rate will be adjusted from there by trial & error.
It is a good viewpoint to see the world as a dream. When you have something like
a nightmare, you will wake up and tell yourself that it was only a dream. It is
said that the world we live in is not a bit different from this.
-- Hagakure: The Book of the Samurai by Yamamoto Tsunetomo