Haemochromatosis

Haemochromatosis, also spelled hemochromatosis (see spelling differences), also called hereditary haemochromatosis, siderophilia and bronze diabetes, is a hereditary disease characterized by excessive absorption of dietary iron resulting in a pathological increase in total body iron stores. Humans, like virtually all animals, have no means to excrete excess iron.^[1] Excess iron accumulates in tissues and organs disrupting their normal function. The most susceptible organs include the liver, adrenal glands, the heart and the pancreas; patients can present with cirrhosis, adrenal insufficiency, heart failure or diabetes. ^[2] The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British or Irish descent.^[3]

Haemochromatosis less often refers to the condition of iron overload as a consequence of multiple transfusions. More preferred terms in the United States include for transfusional iron overload or hemosiderosis used synonymously. Those with hereditary anemias such as beta-thalassemia major, sickle cell anemia, and Diamond-Blackfan anemia who require regular transfusions of red blood cells are all at risk for developing life-threatening iron overload. Older patients with various forms of bone marrow failure such as with myelodysplastic syndrome who become transfusion-dependent are also at risk for iron overload.

History

The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin.^[4] Trousseau did not associate diabetes with iron accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890.^[5][6]

Signs and symptoms

Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon and for most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity.^[7] The more common clinical manifestations include:^[8][9][10]

• Malaise
• Liver cirrhosis (with an increased risk of hepatocellular carcinoma Liver disease is always preceded by evidence of liver dysfunction including elevated serum enzymes specific to the liver.
• Insulin resistance (often patients have already been diagnosed with diabetes mellitus type 2) due to pancreatic damage from iron deposition
• Erectile dysfunction and hypogonadism, resulting in decreased libido
• Congestive heart failure, arrhythmias or pericarditis
• Arthritis of the hands (especially the first and second MCP joints), but also the knee and shoulder joints
• Damage to the adrenal gland, leading to adrenal insufficiency

Less common findings including:

• Deafness^[11]
• Dyskinesias, including Parkinsonian symptoms^[12][11][13]
• Dysfunction of certain endocrine organs:
  • Parathyroid gland (leading to hypocalcaemia)
  • Pituitary gland
• A darkish colour to the skin (see pigmentation, hence its name Diabetes bronze when it was first described by Armand Trousseau in 1865)
• An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:
  • Vibrio vulnificus infections from eating seafood
  • Listeria monocytogenes
  • Yersinia enterocolica
  • Salmonella enterica (serotype Typhymurium)
  • Klebsiella pneumoniae
  • Escherichia coli
  • Rhizopus arrhizus
  • Mucor species

Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation (which ceases in menopause). The severity of clinical disease in the hereditary form varies considerably. There is evidence suggesting that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Diagnosis

The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or excessive iron binding saturation of transferrin exceeding the normal value of 50%. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint. The evaluation of abnormal transferrin saturation commonly involves determining the level of ferritin, a protein found in serum made by liver that binds iron. Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis.^[14]

Imaging features

Clinically the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity in MRI scans. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand. The arthropathy can therefore be an early clue as to the diagnosis of haemochromatosis. MRI algorithms are available at research institutions to quantify the amount of iron present in the liver, therefore reducing the necessity of a liver biopsy (see below) to measure the liver iron content. As of May, 2007, this technology was only available at a few sites in the USA, but documented reports of radiographic measurements of liver iron content were becoming more common. ^[15]

Chemistry

Serum transferrin and transferrin saturation Transferrin binds iron and is responsible for iron transport in the blood.^[16] Measuring transferrin provides a crude measure of iron stores in the body. Saturation values in excess of 62% are recognized as a threshold for further evaluation of haemochromatosis. ^[14]

Serum Ferritin- Ferritin, a protein synthesized by the liver is the primary form of iron storage within cells and tissues. Measuring ferritin provides another crude estimate of whole body iron stores though many conditions notably inflammation can elevate serum ferritin. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for female, 12-150 ng/ml.^[14][17] Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).

test characteristics for detecting hemochromatosis and the sensitivity or specificity ^[18]

• serum iron > 180 mcg/dL (32 mcmol/L) has 68% sensitivity, 83% specificity, 61% positive predictive value and 87% negative predictive value
• transferrin saturation > 50% has 82% sensitivity, 88% specificity, 74% positive predictive value and 93% negative predictive value
• serum ferritin > 400 ng/mL has 88% sensitivity, 95% specificity, 88% positive predictive value and 94% negative predictive value
• elevation of transferrin saturation or serum ferritin has 94% sensitivity, 86% specificity, 73% positive predictive value and 97% negative predictive value

Functional testing

Based on the history, the doctor might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.

Histopathology

Iron accumulation demonstrated by Prussian blue staining in a patient with homozygous genetic hemochromatosis (microscopy, 10x magnified). Parts of normal pink tissue are scarcely present.

Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, it is debatable whether a liver biopsy is still necessary to quantify the amount of accumulated iron.^[14]

Screening

Screening specifically means looking for a disease in people who have no symptoms. Diagnosis, on the other hand refers to testing people who have symptoms of a disease. Standard diagnostic measures for haemochromatosis, serum transferrin saturation and serum ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms:^[14][19]

• Joint disease
• Severe fatigue
• Heart disease
• Elevated liver enzymes
• Impotence
• Diabetes

Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force (USPSTF), among other groups. The USPSTF recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than 1 in 1000. Although there is strong evidence that treatment of iron overload can saves lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit.^{[20] [21]} Recently, it has been suggested that patients be screened for iron overload using serum ferritin as a marker -- if serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.

Differential diagnosis

There exist other causes of excess iron accumulation, which have to be considered before Haemochromatosis is diagnosed.

• African iron overload, formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa. Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin which predisposes some people of African descent to iron overload.^[22]
• Transfusion hemosiderosis is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassemia).
• Dyserythropoeisis, also known as myelodysplastic syndrome is a disorder in the production of red blood cells. This leads to increased iron recycling from the bone marrow and accumulation in the liver.

Epidemiology

Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism, the most common allele being the C282Y allele in the HFE gene. The prevalence of mutations in iron metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations will not manifest clinically relevant haemochromatosis (see genetics below).^[23] Other populations have a lower prevalence of both the genetic mutation and the clinical disease. Genetic studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60-70 generations ago^[24]. At that time when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided a natural selection reproductive advantage by maintaining higher iron levels in the blood.

Genetics

Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion.

Haemochromatosis type 4 is inherited in an autosomal dominant fashion.

The regulation of dietary iron absorption is complex and our understanding is incomplete. One of the better characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6 which codes for a protein that participates in the regulation of iron absorption. The HFE gene has two common alleles, C282Y and H63D.^[25] Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. Mutations of the HFE gene account for 90% of the cases of non-transfusional iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, results in clinically evident iron overload. There is considerable debate regarding the penetrance -- the probability of clinical expression of the trait given the genotype -- is for clinical disease in HHC homozygotes. Most, if not all, males homozygous for HFE C282Y will show manifestations of liver dysfunction such as elevated liver-specific enzymes such as serum gamma glutamyltransferase (GGT) by late middle age. Homozygous females can delay the onset of iron accumulation because of iron loss through menstruation. Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the mutation and the presence of other insults to the liver such as alcohol and viral disease. As such the degree to which the liver and other organs is affected, expressivity, is highly variable and is dependent on such these other factors and co-morbidities as well as age at which they are studied for manifestations of disease.^[23] Penetrance differs between different populations.

One of the most common cause of hereditary haemochromatosis is a single point mutation at C282Y in which the cystine residue at position 282 is changed into a tyrosine residue.

Recently, a classification has been developed (with chromosome locations):

Pathophysiology

The normal distribution of body iron stores

Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available as of May, 2007. For example, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.^[26]

People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.^[27]. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".

Intestinal crypt enterocytes and iron overload

The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus. The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron. Depending on this information, the enterocyte cell can regulate the quantity of iron receptors and channel proteins. If there is little iron, the enterocyte cell will express many of these proteins. If there is a lot, the cell will turn off the expression of iron transporters. In haemochromatosis, a mutation in the HFE gene leads to a lack of the basolateral transporter that endocytoses iron from the plasma into the epithelial cell. As a consequence of being unable to detect serum iron concentrations, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption. These iron transport proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, the only known cellular iron exporter, for the basal side of the cell.

Hepcidin-ferroportin axis and iron overload

Recently, a new unifying theory for the pathogenesis of hereditary haemochromatosis has been proposed that focuses on the hepcidin-ferroportin regulatory axis. Inappropriately low levels of hepcidin, the iron regulatory hormone, can account for the clinical phenotype of iron overload. In this theory, low levels of circulating hepcidin result in higher levels of ferroportin expression in intestinal enterocytes and reticuloendothelial macrophages. As a result, this causes iron accumulation. HFE, hemojuvelin, BMP's and TFR2 are implicated in regulating hepcidin expression. In particular, mutations in hemojuvelin (HJV), also called RGMc (Repulsive Guidance Molecule c), result in a severe form of iron overload that has a juvenile onset (by the second decade of life) called juvenile haemochromatosis (JH).

End-organ damage

Iron is stored in the liver, the pancreas and the heart. Long term effects of haemochromatosis on these organs can be very serious, even fatal when untreated.^[28] For example, similar to alcoholism, haemochromatosis can cause cirrhosis of the liver. The liver is a primary storage area for iron and will naturally accumulate excess iron. Over time the liver is likely to be damaged by iron overload. Cirrhosis itself may lead to additional and more serious complications, including bleeding from dilated veins in the oesophagus and stomach (varices) and severe fluid retention in the abdomen (ascites). Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy).

Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)

Diabetes: The pancreas which also stores iron is very important in the body’s mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose). Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease.

Congestive heart failure: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur including death. The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.

Heart arrhythmias: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life threatening. This condition can often be reversed with treatment for haemochromatosis.

Pigment changes: Deposits of iron in skin cells can turn skin a bronze or gray color.

Treatment

Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.^[29] Treatment is initiated when ferritin levels reach 300 milligrams per litre (or 200 in nonpregnant premenopausal women).

Every bag of blood (450-500 ml) contains 200-250 milligrams of iron. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 20 milligrams per litre. After that, 1-4 donations per year are usually needed to maintain iron balance.

Other parts of the treatment include:

• Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy).
• Limiting intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron) and potential causes of food poisoning (shellfish, seafood).
• Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (such as spinach or collard greens, which must be consumed at the same time as the iron-containing foods in order to be effective.)

References

^[1]

See also

• Cirrhosis

External links

• Haemochromatosis at the Open Directory Project