Hereditary haemochromatosis

Hemochromatosis is a disease in which too much iron builds up in your body. Your body needs iron but too much of it is toxic. If you have hemochromatosis, you absorb more iron than you need. Your body has no natural way to get rid of the extra iron. It stores it in body tissues, especially the liver, heart, and pancreas. The extra iron can damage your organs. Without treatment, it can cause your organs to fail.

There are two types of hemochromatosis. Primary hemochromatosis is an inherited disease. Secondary hemochromatosis is usually the result of something else, such as anemia, thalassemia, liver disease, or blood transfusions.

Many symptoms of hemochromatosis are similar to those of other diseases. Not everyone has symptoms. If you do, you may have joint pain, fatigue, general weakness, weight loss, and stomach pain.

Your doctor will diagnose hemochromatosis based on your medical and family histories, a physical exam, and the results from tests and procedures. Treatments include removing blood (and iron) from your body, medicines, and changes in your diet.

NIH: National Heart, Lung, and Blood Institute

Source: MedlinePlus, U.S. National Library of Medicine

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 most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy.

Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.

The more common clinical manifestations include:

Bronze or gray skin color (for this the illness was named "bronze diabetes" when it was first described by Armand Trousseau in 1865)

Liver fibrosis or 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, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema, and spider naevi. Cirrhosis can also present with jaundice (yellowing of the skin) and ascites.

Diabetes mellitus type 2: HH patients have insulin resistance for liver disease, and poor insulin secretion due to pancreatic damage from iron deposition.

Erectile dysfunction and hypogonadism, resulting in decreased libido, amenorrhea

Congestive heart failure, abnormal heart rhythms, or pericarditis

Arthritis of the hands (especially the second and third metacarpophalangeal joints), but also the knee and shoulder joints

Dyskinesias, including Parkinsonian symptoms

Parathyroid gland (leading to hypocalcaemia)

Pituitary gland: secondary hypothyroidism, secondary hypogonadism

An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:

Vibrio vulnificus infections from eating seafood or wound infection

Salmonella enterica (serotype Typhymurium)

In the hereditary hemochromatosis (HH or HHC), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause. The severity of clinical disease varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone. Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.

End-organ damage

Iron is stored in the liver, pancreas and heart.

Long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated.

Since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload.

Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy.

Together, they can increase the risk of liver cancer to one in three persons.

If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. Arrhythmia or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. This condition can often be reversed with treatment.

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), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure.

Haemochromatosis may lead to cirrhosis and its complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites).

Severity of periodontal disease is associated with high transferrin saturation in haemochromatosis patients.

Diagnosis

The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation or elevated serum ferritin. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.

Blood tests

Serum ferritin and fasting transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood. Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis. Other source says that the normal values for males are 30-400 ng/mL and for female, 13-150 ng/mL. Fasting transferrin saturation is a better test to detect HH. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.

Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues. Measuring ferritin provides a crude estimate of whole-body iron stores, though is raised in many conditions, particularly inflammatory conditions. Examples of causes for raised serum ferritin include but are not limited to: infection, chronic alcohol consumption (mainly >20g/day), liver disease, cancer, porphyria, Hemophagocytic lymphohistiocytosis, hyperthyroidism, obesity, metabolic syndrome, diabetes, several blood transfusions, too many iron supplements, aceruloplasminemia, atransferrinemia, hyperferritinemia cataract syndrome and others. Proinflammatory states account for up to 90% of raised ferritin. Serum ferritin in excess of 1000 ng/mL of blood is almost always attributable to haemochromatosis.

Liver biopsy

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, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis. Risks of biopsy include bruising, bleeding, and infection. Now, when a history, measures of transferrin saturation and ferritin, and MRI (R2*/T2*) point to haemochromatosis, a liver biopsy is not necessary to quantify the amount of accumulated iron. Liver biopsy is the gold standard for detecting and quantifying hepatic fibrosis.

MRI

MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations (LIC) and hepatic fibrosis.

Other imaging

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, but it is not good for detecting tissue iron. 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 a clue as to the diagnosis of haemochromatosis.

Functional testing

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

Stages

The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):

Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.

Iron overload but no organ or tissue damage.

Organ or tissue damage as a result of iron deposition.

Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.

Differential diagnosis

Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 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 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.

Secondary hemochromatosis: its main cause is the Transfusional haemosiderosis. It is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassaemia). Other causes are: sideroblastic anemia, congenital dyserythropoietic anemia, pyruvate kinase deficiency, chronic hemolytic anemia, chronic liver disease (hepatitis B, hepatitis C, cirrhosis, alcoholic fatty liver disease), overdose of oral iron pills or iron injections, long-time kidney dialysis, and dyserythropoeisis, also known as myelodysplastic syndrome. It is a disorder in the production of red blood cells that leads to increased iron recycling from the bone marrow and accumulation in the liver.

Other causes of secondary iron overload: Aceruloplasminemia, Atransferrinemia, Neonatal hemochromatosis (GALD-NH), GRACILE syndrome, Dysmetabolic iron overload syndrome (DIOS)

Hyperferritinemia without iron overload caused by infections (eg. COVID-19), cancer, inflammation, hyperferritinemia dysmetabolic

Phlebotomy

Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.

Phlebotomy (or bloodletting) is usually done at a weekly or each two weeks interval until ferritin levels are 50-100 μg/L. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females to keep the serum ferritin between 50 and 100 μg/L. This treatment can have the side effect of altering trace element metabolism, including changes in the blood concentrations of potentially toxic elements such as cadmium and lead.

Iron chelation therapy

Where venesection is not possible, long-term administration of an iron chelator as Deferoxamine (or Desferrioxamine), Deferasirox and Deferiprone is useful. Deferoxamine is an iron-chelating compound, and excretion induced by deferoxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.

Organ damage

Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy). Hepatic transplantation in patients with liver failure.

Diet

Limiting intake of alcoholic beverages, high iron fortified foods such as certain cereals and supplements, vitamin C (increases iron absorption in the gut), heme iron animal products (high in iron), and potential causes of food poisoning (shellfish, raw seafood)

Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, black or green teas, and foods containing oxalic and phytic acids (such as collard greens, which must be consumed at the same time as the iron-containing foods to be effective)

Chelating polymers

A novel experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators. These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting the uptake of these ions and their long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects in sub-chronic studies. Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.

Prognosis

Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.

Epidemiology

Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe, with a prevalence of 1:200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism. In the U.S., the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele. 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 do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population, It is 2–3 times more common in males.

Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.

The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece.

Source: Wikipedia, The Free Encyclopedia · CC BY-SA 4.0