Are You Confident of the Diagnosis?
Hemochromatosis is a condition in which the absorption of iron from the intestinal mucosa is in excess of the loss of iron or of an individual’s need. It is a progressive disease, usually affecting adults, which leads to retention and damage in parenchymal tissues including the liver, heart, pancreas and skin.
What you should be alert for in the history?
Early symptoms are often nonspecific, so it is important to consider hemochromatosis as a diagnostic consideration for nondescript symptoms like chronic fatigue, features of diabetes mellitus, arthralgia and loss of libido. The most common presenting symptoms for hereditary hemochromatosis are weakness, abdominal pain, or joint pains. Many cases are asymptomatic. Northern European ancestry is important, and the frequency for hereditary hemochromatosis is highest in Northern European populations or descendents.
Look for disease or symptoms in other family members, history of alcohol abuse or ingestion, increased iron ingestion or increased ascorbic acid digestion. Although ingestion/supplementation is a rare cause of iron overdose in normal individuals, in those with hemochromatosis, symptoms may be related to reports of increased iron ingestion. All patients with porphyria cutanea tarda should be tested for hemochromatosis, as the allele frequency is higher within this group. Persistent iron overload in those presenting with porphyria cutanea tarda may be due to underlying hemochromatosis.
Characteristic findings on physical examination
Presence of increased skin pigmentation, hepatomegaly, diabetes mellitus, splenomegaly, arthropathy, congestive heart failure, arrhythmias, arthritis and hypogonadism would be ideal for suggesting hemochromatosis. However, one or few in combination must be regarded with suspicion in order to make an early diagnosis. The stereotypical bronze color is a very late sign and is seldom observed in the earlier stages. In addition, the reported observed hues are usually closer to a brown or dark grey. Hyperpigmentation may be generalized but is often more apparent in sun-exposed areas (Figure 1) .
The skin over the external genitalia, knee and elbow creases, areolae of the nipples, lid margin, and scars may also darken. Skin may be thin and velvety with sparse, delicate hair in facial, pubic, and axillary regions. Other cutaneous manifestations include xerosis/ichthyosis, atrophy, koilonychia and any skin symptoms that may suggest damage to the liver, such as palmar erythema, sparse pubic hair, spider angiomas and jaundice.
It is important to note that skin symptoms may not present until toxic concentrations of iron have accumulated, which usually takes decades. By the time a patient reports with skin complaints, it is likely that they have acquired irreversible organ damage. At this stage, the storage iron concentrations in the liver and pancreas may be as much as 50-100 times the normal figures and about five times normal in the skin Thus, skin pigmentation is usually a late manifestation of disease.
Prior to the discovery of the HFE gene, bronze diabetes was present in the majority of patients at the time of diagnosis. However, emphasis on earlier diagnosis and screening of family members has decreased the frequency of skin findings. Increased awareness about the disease and its earlier symptoms has led to more prompt diagnosis and treatment, which prevents damage from long-term iron overloading.
Expected results of diagnostic studies
Since hemochromatosis potentially involves more than one organ system, it is important to refer a suspected case to a family physician or general internist who can then coordinate examinations, testing, and results from various specialties, as well as genetic testing. Liver, pancreatic, cardiac, and joint disease should be confirmed by physical examination, radiography, and standard functional tests for these organs. It is probable that a patient with hemochromatosis may need care from rheumatology, endocrinology, cardiology, gynecology, pathology and hematology in addition to dermatology due to the potential for iron build-up in parenchymal tissues.
If the dermatologist would like to begin investigating before referrals are possible, then iron stores can be assessed by measurement of serum iron, the percent saturation of transferrin, and measurement of serum ferritin concentration (for normal values, see below). The percent transferrin saturation and serum ferritin level provide a simple and reliable screening test for hemochromatosis, including the pre-cirrhotic phase of the disease. If either test is abnormal two or more times, the patient should be referred for genetic testing.
Biopsy and Magnetic Resonance Elastography: Today, magnetic resonance elastography is used to assess fibrosis instead of liver biopsy. However, if this imaging method is unavailable, liver biopsy will show surplus iron visible on histologic examination of hepatic tissue, particularly after staining with potassium ferrocyanide. Skin biopsies also show characteristic changes. Increased melanin and hemosiderin is most often found in sweat glands, but blood vessels and dermal tissue may also contain deposits. Establishing or excluding the presence of hepatic cirrhosis is critical in determining prognosis and the risk of developing hepatocellular carcinoma. Results of liver biopsy do not alter treatment strategy.
Fasting Transferrin Saturation: A fasting transferrin saturation persistently greater than 45-50% (reference is 15-50% for men and 12-45% for women) is the earliest marker of iron overload. Patients with elevated transferrin saturation on two or more occasions should have the HFE gene test.
Serum Ferritin: The reference range is 12-150ng/mL for women and 12-300ng/mL for men. Ferritin reflects increased iron stores, but it may also increase with alcohol consumption, liver disease, and acute illness. If ferritin is elevated, it is recommended to take another sample, ensuring the patient has been fasting, to assess levels a second time. If they are still elevated on repeat, then referral for HFE gene testing is recommended, particularly if transferrin saturation is also high or borderline.
Genetic Testing: Polymerase chain reaction-based methods can be used to diagnose a hereditary form of hemochromatosis. DNA may be obtained from blood or from buccal cells. Hereditary hemochromatosis is diagnosed in patients with iron overload if the HFE gene test shows either C282Y homozygosity or C282Y/H63D compound heterozygosity. A negative genetic test does not disprove the diagnosis.
All adult first-degree relatives of patients with hereditary hemochromatosis should be tested for the C282Y and H63D mutations. Homozygosity at the C282Y position of the HFE gene accounts for the majority of hemochromatosis cases. Genetic testing should be performed with informed consent and appropriate counseling.
Phlebotomy or Venesection: Patients should be referred to hematology for phlebotomy if diagnosis has been confirmed by testing. Phlebotomy measures the extent of iron overload while treating the disease at a low cost and low risk. Hematologists can also recommend further testing to exclude iron deposition due to hematologic disease.
Phlebotomies are usually performed until serum ferritin falls to levels indicative of iron deficiency and can then be continued once every few months or as needed. The iron that was removed can be calculated by assuming 500ml blood contains about 250mg iron. The amount of iron removed by phlebotomy is an excellent marker of iron burden; this is based on blood volume and time limit between phlebotomies.
Porphyria cutanea tarda. Porphyria cutanea tarda (PCT) involves a defect and reduced activity in the fifth enzyme of heme synthesis in the liver uroporphyrinogen decarboxylase (URO-D). Decreased activity of URO-D leads to accumulation of porphyrins circulating in blood. The circulation and deposition of porphyrins in the skin lead to reactivity with light producing reactive oxygen species that account for the photosensitive, blistering skin seen on sun-exposed areas in most patients.
Other cutaneous findings include increased skin fragility, facial hypertrichosis, atrophic scarring and milia. The condition is often sporadic but can be due to a deficiency of the enzyme uroporphyrinogen decarboxylase caused by autosomal dominant mutation in the gene. In type 2 familial PCT, URO-D activity is decreased in all tissues, but in types 1 (sporadic) and 3 (familial), the enzyme is decreased only in hepatocytes.
The exact mechanism for iron overload in PCT patients is unknown. However, the frequency of the 845A (C282Y) mutation is significantly increased in patients with porphyria cutanea tarda (PCT), so porphyria cutanea tarda can be an important cutaneous marker for HFE mutations or homozygosity. Vice versa, the inheritance of one or more HFE gene mutations can increase susceptibility for PCT. About 80% of patients with PCT have a degree of hepatic hemosiderosis, ranging from mild to severe, and use of phlebotomy to decrease iron stores and decrease porphyrin production improves clinical outcome.
HFE gene testing should be performed in all patients presenting with porphyria cutanea tarda. Other risk factors for sporadic PCT are exposure to antimalarials, ingestion of alcohol or exogenous estrogens, and infection with human immunodeficiency virus or hepatitis viruses. Chloroquine therapy has been shown to be safe and effective in the treatment of patients with familial or sporadic PCT with absence of related hemochromatosis. If a patient with PCT is heterozygous or homozygous for an HFE gene mutation, then phlebotomy should be first-line therapy because chloroquine does not decrease serum iron markers as effectively in these patients.
Addison’s disease. Addison’s disease (Figure 2) is very rare and results from insufficient glucocorticoid and mineralocorticoid production by the adrenal glands. Patients may have darkening of the skin that includes areas not exposed to the sun, particularly in hand creases, old scars, nipple area and buccal mucosa. Patients usually also have electrolyte abnormalities and low blood pressure.
Wilson’s disease. Wilson’s disease is a seldom encountered genetic disorder causing defective copper metabolism, which leads to deposition of copper in liver and other organs. Unlike hemochromatosis, it usually presents in childhood or adolescence and includes central nervous system (CNS) clinical signs such as drooling, speech changes, incoordination, and abnormalities in gait and fine motor skills. Some patients may also have compulsive behavior, aggression or other psychiatric findings.
In addition to hyperpigmentation, some have azure lunulae, a bluish hue at the base of the fingernail. Jaundice, spider angiomas, palmar erythema and hypermelanotic pigmentation may develop from copper deposition within the liver. Kayser-Fleischer rings are pathognomonic for Wilson’s disease. They appear as a rusty brown-green ring around the cornea and may be viewed more easily using an ophthalmologist’s slit lamp (Figure 3).
Who is at Risk for Developing this Disease?
Hereditary hemochromatosis is most common in those of Northern European descent. The inherited disorder most often requires homozygosity at the C282Y (845A) locus of the HFE gene, although compound heterozygosity at C282Y and H63D, and rare mutations, may also lead to excessive iron absorption. One in 200 Northern, Western and Central Europeans are homozygous at the C282Y locus of the HFE gene. Italians, Greeks and Ashkenazi Jews are at lower risk as these populations have a lower allele frequency.
Although penetrance is more commonly an issue with autosomal dominant disorders, it appears to be an issue in hereditary hemochromatosis. Thirty to fifty percent of those with homozygous genotypes do not have clinical evidence of hemochromatosis. Many factors, including alcohol consumption, dietary iron intake, blood loss associated with menstruation and pregnancy and blood donation, influence the expression. Age and gender are major modifiers due to the following reasons:
The first symptoms usually develop between ages 40-60 due to the length of time needed for accumulation of toxic iron concentrations.
Clinical symptoms are more commonly seen in men than in women, since women menstruate monthly and often experience blood loss during pregnancies. In addition, men 50 or older have higher risk for developing liver cirrhosis.
Iron burden can have compounding effects in older individuals who are already subject to aging/dying cells. Iron burden is rare before the second decade of life due to higher iron needs in children and adolescents. Juvenile hemochromatosis carries a genetic defect unique from other forms of the disease. Males and females may be affected with equal probability, and symptoms usually present before the age of 30.
The course of the disease is more rapid and severe and may include hypogonadotropic hypogonadism and heart failure. Neonatal hemochromatosis is characterized by hepatic insufficiency and can quickly lead to death in a newborn. Newborns with this disease usually have a strong family history.
Lifestyle and environmental factors may also further exacerbate or prevent iron overload. Alcohol consumption and hepatitis C virus infection are both risk factors for cirrhosis. Increased alcohol intake may lead to earlier onset of symptomatic hereditary hemochromatosis even though alcohol is not the direct cause of increased iron absorption. The association of alcoholic cirrhosis with increased quantities of hepatic hemosiderin has been observed.
Blood donation reduces progression of the iron burden. Vitamin C aids iron uptake from the diet. Tannins in tea inhibit iron uptake from diet. Proton pump inhibitors alter the acidity of the gut and so suppress the absorption of dietary non-heme iron in hereditary haemochromatosis.
Some South Africans brew fermented beverages in vessels made of iron, and consumption of large quantities of this type of alcohol over many years can lead to acquired hemochromatosis. The iron content rises during fermentation, and since the alcohol content is often low, large quantities may be regularly consumed, particularly by men. Daily indulgence can lead up to 50-100mg of iron supplementation, which is much greater than the normal requirement. The ferric iron ingested is readily absorbed.
Patients who repeatedly receive blood transfusions for thalassemia major, sideroblastic anemia, or other hematologic conditions may also acquire iron overload.
What is the Cause of the Disease?
Most instances of hereditary hemochromatosis demonstrate autosomal recessive inheritance. That is, two copies of the altered gene, one from each parent, are required for a person to develop severe complications and iron overload.
Although there have been some cases of iron overload for which no genetic abnormality could be sequenced, there are two mutations in the HFE gene that are most common in the adult hereditary type. In the first, adenine is inserted instead of guanine at position 845, which codes for tyrosine (Y) instead of cysteine (C) (C282Y). The second is a weaker mutation and involves substitution of guanine for cytosine at position 187, which leads to insertion of the amino acid aspartate (D) instead of histidine (H) (H63D) during protein synthesis.
Compound heterozygotes have one recessive gene for C282Y and one for H63D and can also have increases in iron stores. The slight increase in hepatic iron resulting from heterozygosity can act as a cofactor that modifies the expression of other diseases like porphyria cutanea tarda (PCT) and nonalcoholic steatohepatitis. The other genes involved with iron metabolism may also acquire mutations, but these mutations are more rare.
Infrequently, inheritance of mutations in four other genes (hepcidin (HAMP), transferrin receptor 2 (TFR2), ferroportin (SLC40A1), and hemojuvelin (HFE2, formerly HJV)) may cause disease. Mutations in the proteins HFE2 and HAMP are seen in juvenile hemochromatosis, which often presents in adolescents and young adults approximately between 15-30 years of age.
Pathogenesis: how genetic defects lead to increased iron absorption
Iron absorption is adjusted in the intestinal mucosa according to the amount within body iron stores and the level of erythropoiesis. In hereditary hemochromatosis, mucosal absorption is greater than body requirements. Although uptake of iron may be regulated by one’s need for iron, the body has not acquired sufficient methods for eliminating surplus.
In iron overload, the amount of iron present is too great for the body to manage. Transferrin must assume the burden of safely securing iron as levels rise early in the disease process. With further elevation, iron binds to other plasma circulatory proteins, and these iron complexes may more readily release iron and create the most damage through deposition and oxidation to parenchymal organs. The risk for hepatic cirrhosis and onset of symptoms increase when serum ferritin rises above 1,000µg/L.
The exact function of the HFE protein has not been fully elucidated. It is a membrane protein that resembles MHC Class-1 proteins and interacts with ß-2-microglobulin. Its effect on iron absorption is thought to be through association with the transferrin receptor, and through inhibition of the receptor’s interaction with plasma transferrin. The 845A mutation results in the replacement of a cysteine that usually forms a disulfide bond within the molecule. This substitution prevents binding of the protein to ß-2-microglobulin and hence the transport of the HFE protein to the cell surface.
To complicate things further, there are other genes and proteins involved in iron homeostasis. Most of the pathways are not completely understood, and current knowledge is composed of fragments of the complete picture. Hepcidin, coded by the HAMP gene, has been found to be important in iron homeostatis due to its role as a negative regulator of iron uptake from the gut. It binds to ferroportin and prevents iron entry into the plasma from the enterocyte. In hemochromatosis, hepcidin is thought to be deficient, which means passage of iron from enterocytes into plasma occurs freely and amassment continues unregulated. The exact mechanisms regulating hepcidin synthesis are still unexplained.
Our iron balance remains slightly positive due to daily absorption of iron from the diet, usually a few milligrams per day. Since daily absorption occurs in small increments, the accumulation of levels needed for symptoms or long-term organ damage could take many years. Therefore, most hereditary hemochromatosis subjects are 40-60 years old at the time symptoms present. This buildup of iron occurs in stages. Early or nondescript symptoms like fatigue, arthralgia, loss of libido usually present before iron stores are measurably increased.
At this point in the disease process, more iron is being delivered to plasma than is needed, and plasma iron concentrations may be affected by iron supplements and other environmental factors. Therefore, plasma iron concentrations and plasma transferrin saturation will increase. Plasma transferrin is thus the most useful test to check for hemochromatosis during the earlier stages. Over the years, more iron will be stored by liver hepatocytes as ferritin and by macrophages in other tissues as hepcidin. The most useful test for assessing the degree of iron storage loading in later stages of the disease is the serum ferritin concentration (for reference values, see Diagnostic Testing).
Iron loading in parenchymal tissues other than the liver causes damage to the respective organs including the heart, joints, pancreas, spleen and endocrine organs although the exact mechanisms have not fully been elucidated. It has been postulated that excess iron may lead to destruction by free radical reaction within the body and through formation of the hydroxyl radical, which damages polysaccharides, DNA, and enzymes.
It is important to note that not all C282Y homozygotes develop symptomatic hemochromatosis. Though the majority suffering from hemochromatosis are homozygotes at the C282Y gene, homozygosity does not lead to disease manifestation in everyone. Environmental factors such as alcohol consumption, blood transfusion and iron supplementation may precipitate onset.
Heavy alcohol consumption has been shown to decrease survival due to alcoholic liver damage or cirrhosis and may also lead to earlier onset of symptomatic hereditary hemochromatosis even though alcohol is not the direct cause of increased iron absorption. The association of alcoholic cirrhosis with increased quantities of hepatic hemosiderin has been observed.
Anemias and Blood Transfusions
Patients suffering from a chronic anemia may present with features similar to those found in hereditary hemochromatosis. Thalassemia major is complicated by hemochromatosis more commonly than any other type of anemia. Congenital dyserythropoietic anemias are characterized by defective synthesis of both mature red cells and often precede iron overload. Patients who repeatedly receive blood transfusions for thalassemia major, sideroblastic anemia, or other hematologic conditions may also acquire iron overload.
Systemic Implications and Complications
Deposition of iron within parenchymal cells leads to irreversible organ damage over time if the disease is left untreated. Cirrhosis of the liver, bronze diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism are clinical findings indicating greater severity and later stage.
The liver is usually the first organ to be affected since ferritin is the major iron storage protein found in hepatocytes, and many symptomatic patients present with hepatomegaly. Excess iron can cause collagen formation and scarring leading to cirrhosis. Portal hypertension and esophageal varices are not as common in hemochromatosis as in alcoholic or viral cirrhosis, although presence of spider angiomas and gynecomastia may point toward alcohol abuse. Hepatic fibrosis can decrease with venesection treatments, but long-standing cirrhosis is irreversible.
Hepatocellular carcinoma is an important late complication as there is increased probability in adult hemochromatosis patients with cirrhosis. Even after venesection therapy is implemented and iron is removed, hepatocellular carcinoma may develop in those with irreversible hepatic damage.
Excessive skin pigmentation is present in patients with advanced disease. The characteristic bronze color is not often observed. Usually, a metallic or slate gray hue results from increased melanin and iron in the dermis. Pigmentation is usually generalized, but it can sometimes be more noticeable on extensor surfaces, dorsa of hands, lower legs, genital regions, face, neck and in scars. In most patients, skin color improves with phlebotomy treatments and removal of iron.
Diabetes mellitus is more likely to develop in patients with a family history of diabetes. Impaired glucose tolerance may develop in the absence of diabetes or cirrhosis because of impaired insulin secretion. Iron deposition occurs in beta cells only within the islets and is not usually found in the alpha cells. Although exocrine cells within the pancreas have the heaviest iron overload, most cases do not describe symptoms relating to impaired exocrine function. Impaired glucose tolerance is reversed by phlebotomy. However, once diabetes becomes severe, cirrhosis is usually present, and phlebotomy can no longer reverse the insulin resistance.
Loss of libido, impotence, amenorrhea, testicular atrophy, and sparse body hair result from hypogonadism and impairment of the hypothalamic-pituitary axis by iron deposition. Hypogonadism is due to gonadotropin deficiency, and the impairment is most likely at the level of the pituitary, since gonadotropic-releasing hormone administration is not usually helpful. Since hemosiderin deposition in the pituitary is primarily localized to the gonadotropic cells, secretion of other anterior and posterior pituitary hormones is not drastically impaired.
Hypogonadism may be related to the few cases of osteoporosis found among hemochromatosis patients. Diminished sexual function is a very important symptom as it is often present in early forms of the disease and is almost always present in younger patients.
Arthropathy is reported in 40-85% of symptomatic patients and is often an early presenting complaint. The second and third metacarpophalangeal joints are usually the first to be affected. Involvement of proximal interphalangeal joints, radiographic joint space narrowing and cartilage destruction is often evident in hemochromatosis. Arthropathy was rated the clinical finding with the greatest impact on the quality of life by 50 consecuative hemochromatosis patients, so consultation with a rheumatologist may be highly valuable with respect to patient care. Removal of excess iron has little effect on hypogonadism or arthropathy.
Young patients, like those with in juvenile hemochromatosis, frequently present with cardiac manifestations, including congestive cardiomyopathy with bilateral ventricular dilation, ventricular ectopic beats, and flattening inversion of T waves. Arrhythmias suggest a poor prognosis. Cardiac manifestations are almost always the cause of death in young patients. If iron is not removed, death usually occurs within a year.
Congestive heart failure can develop rapidly, but prognosis improves drastically if iron is removed before concentrations reach critical levels. If the diagnosis is not made and treatment is not implemented until high concentrations are reached, then irriversible disease and shortened survival lead to poorer prognoses.
Treatment of hemochromatosis for those who have developed iron overload consists of lifelong venesection, monitoring of iron levels, and therapy addressing any organ damage.
Patients must be referred to hematology for venesection treatments. Weekly or twice-weekly phlebotomy of 400-500mL should be carried out until iron deficiency is reached. It is also used to assess the iron load. Since one 500-mL unit of blood contains 200-250mg of iron, the quantity removed should be calculated after each treatment.
During venesection therapy, absorption of iron in the gut rises to high levels, and it may remain above normal even after iron deficiency is established and maintained, so patients should be advised to reduce iron consumption and supplementation. Weekly phlebotomy may in some cases continue for a few years before the serum ferritin level drops below 50µg/L. Once this occurs, phlebotomy is carried out as needed to keep ferritin levels between 50 and 100µg/L.
When anemia or hypoproteinemia is severe, chelating agents, like deferoxamine, may be useful. Deferasirox (Exjade) is a newer oral chelating agent that is effective in thalassemia and secondary iron overload. Its role in primary iron overload has yet to be established. Deferoxamine may also be effective, but the medication can be inconvenient, due to method of administration, and expensive.
Addressing Organ Damage
Referral to respective specialists is recommended. Loss of libido and change in secondary sex characteristics are usually managed with hormone replacement or gonadotropin therapy. The degree of cardiac involvement may be assessed by radiography, electrocardiography and other cardiac tests before initiating the venesection treatments. Alcohol consumption should be avoided completely since it increases risk of cirrhosis.
Optimal Therapeutic Approach for this Disease
Lifelong venesection and monitoring of iron levels is usually necessary and is the treatment of choice due to the ability to assess iron overload of the noninvasive procedure. Treatment for organ damage follows classical management of the particular organ system by referral to appropriate specialist. Skin pigmentation will decrease as iron is removed.
Newer oral iron chelators, such as deferiprone and deferasirox, are promising for those who struggle to tolerate phlebotomy, but there are no studies to guide practice at the moment. Deferoxamine is also effective, particularly in iron overload secondary to anemias. However, the medication must be administered through nightly subcutaneous infusions, which is inconvenient. In addition, deferoxamine treatment is expensive.
Reductions in both absorption of dietary non-heme iron and venesection requirements have been observed in hereditary hemochromatosis patients prescribed proton pump inhibitors (PPIs). Though there is little data on use and efficacy in hemochromatosis, it is useful to consider as an adjunct to phlebotomy in the future.
First-degree relatives of patients with hemochromatosis, C282Y homozygotes, and compound heterozygotes should be tested with the HFE gene test, fasting transferrin saturation, and ferritin. Genetic testing of family members should be conducted even if iron studies are normal, because some C282Y homozygotes develop iron overload later in life. Late complications such as bronze diabetes and cirrhosis may be prevented if the mutation is identified before iron stores reach toxic levels.
Regular blood donation can protect against iron overload and is recommended. Avoidance of iron and vitamin C supplements is also helpful for both asymptomatic individuals and those undergoing phlebotomy treatments. Diets restricting the amount of absorbable iron should be implemented. The patient usually needs to schedule lifelong check-ups every few months or as instructed for monitoring.
Unusual Clinical Scenarios to Consider in Patient Management
Risk of fibrosis should be monitored in hemochromatosis patients who also have psoriasis and are receiving methotrexate therapy. In chronic HCV infection HFE mutations are not more common, but some patients have increased hepatic iron. Before initiation of antiviral therapy in these patients, it is reasonable to perform phlebotomy therapy to remove excess iron stores, as this reduces liver enzyme levels. There may be an association between homozygosity at C282Y and venous leg ulcerations.
What is the Evidence?
Beutler, E, Bothwell, T, Charlton, R, Motulsky, A, Scriver, C, Sly, W, Childs, B, Beaudet, A. The metabolitic and molecular bases of inherited disease. vol. 2. pp. 6338(This is one of the leading texts on inherited diseases. The chapters provide a thorough description of genetic diseases and inborn errors of metabolism. The 8th edition explains mutations and the diseases they cause as well as pathogenesis in great detail. Although the last publication was 2000, the chapters are written by renowned experts in the field. Part 14, Chapter 127 on Hemochromatosis is written by authors who have contributed significantly to the field of genetics, including Ernest Beutler and Arno G. Motulsky.
Dr. Ernest Beutler was a hematologist and biomedical scientist who contributed data leading to explanations for etiologies of anemias, Gaucher Disease, disorders of iron metabolism and Tay-Sachs Disease. He was also among the first to identify X-inactivation as the genetic basis of tissue mosaicism in female mammals and was presented the Award for Lifetime Achievement from American Society of Hematology. Dr. Arno G. Motulsky is Professor Emeritus Active of Medicine and Genetics, Attending Physician, University of Washington Hospital, Division of Medical Genetics, Department of Medicine, University of Washington, Seattle Washington. He was awarded the Lifetime Achievement Award by the American College of Medical Genetics Foundation (ACMGF) and is the founder of the field of pharmacogenetics. The chapter on Hemochromatosis provided extensive explanation of the genetic defects, pathogenesis and treatment options for the disease among other genetic ailments.)
Bloom, PD, Gordeuk, VR, MacPhail, AP. “HLA-linked hemochromatosis and other forms of iron overload”. Derm Clin. vol. 13. 1995. pp. 5(Drs. Peter D. Bloom and A. Patrick MacPhail are faculty in the Department of Medicine at the University of the Witwatersrand Medical School in Johannesburg, South Africa. Dr. Victor R. Gordeuk is Director of the Center for Sickle Cell Disease, Director of the Division of Hematology and Oncology, and Professor of Medicine in the College of Medicine at George Washington University Medical Center in Washington, DC. Each issue of Dermatologic Clinics focuses on a single topic relevant to diagnosis and treatment of dermatologic conditions and aims to provide information for practicing physicians and residents. The article HLA-linked hemochromatosis and other forms of Iron Overload was under the journal topic “Genodermatoses with Malignant Potential.” The article discusses the potential increase in susceptibility of patients suffering from HLA-linked hemochromatosis and African iron overload to hepatocellular carcinoma.)
Englander, L, Friedman, A. “Iron overload and cutaneous disease: an emphasis on clinicopathological correlations”. J Drugs Dermatol. vol. Jun’9. 2010. pp. 719-22. (The Journal of Drugs in Dermatology is a peer-reviewed publication that provides information regarding methods, techniques and drug therapy. It is the official publication of the International Society of Dermatologic Surgery (ISDS) and the Orlando Dermatology Aesthetic and Clinical (ODAC) Conference. It reaches 14,500 dermatology healthcare professionals. “Iron overload and cutaneous disease: and emphasis on clinicopathological correlations” is a review addressing diseases in which iron can be implicated including hereditary hemochromatosis, porphyria cutanea tarda, chronic venous disease, diabetic wounds, sunburn and skin cancer. It also provides a brief summary of normal iron metabolism.)
Habif, T. “Clinical dermatology: a color guide to diagnosis and therapy”. 2009. pp. 1040(Thomas P. Habif created one of the most popular and best-loved dermatologic texts through Clinical Dermatology: A Color Guide to Diagnosis and Therapy. Within its pages, Dr. Habif passes on knowledge addressing diagnosis, appearance and symptoms, treatments and complications of dermatologic disease. The text is clearly organized into the major categories for dermatologic disease and is concisely explained with text, tables and plenty of pictures. The book is not only suitable for dermatologists and dermatology residents but is also used by general practitioners in their practices.)
Kluger, N, Raison-Peyron, N, Rigole, H, Bessis, D, Blanc, F, Guillot, B. “Generalized Pruritus revealing hereditary haemochromatosis”. Acta Dermato-Venereologicaogica. vol. 87. 2006. pp. 1(Generalized itching is rarely the presenting symptom of hemochromatosis. However, Drs. Kluger, Raison-Peyron, Rigole, Bessis, Blanc, and Guillot present a case in which pruritus was the presenting complaint in a patient who was diagnosed subsequently with hereditary hemochromatosis. This reference provides food for thought for dermatologists with prurigo or generalized pruritus patients. The case is presented in an international, peer-reviewed journal presenting articles in dermatology and venereology.)
Mathew, J, Leong, MY, Morley, N, Burt, A.D. “A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis”. BMC Dermatol. vol. 5. 2006. pp. 6(BioMed Central offers hundreds of journals on topics within science, technology and medicine. All peer-reviewed articles published are free and consistently available online. The article “A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis” addresses the trouble a physician may encounter when administering methotrexate therapy to a patient with both psoriasis and hereditary hemochromatosis. It is thus a more specific reference and is not intended as a general explanation for hemochromatosis. The authors, Drs. Joseph Mathew and May Y. Leong, are both with the Department of Histopathology at Royal Cornwall Hospital in Truro, United Kingdom and thus use their background in pathology to speak about risk factors for liver fibrosis in this subset of patients.)
Newstead, J, Delatycki, M, Aitken, M.A. “Haemochromatosis and family testing. What should a GP do”. Austral Fam Pnysician. vol. 31. 2002. pp. 5(Australian Family Physician is the official journal of the Royal Australian College of General Practitioners that aims to guide Australian general practitioners, researchers and educators through diagnosis and treatment by presenting relevant information in concise descriptions and illustrations. Drs. Jennifer Newstead, Martin Delatycki, and Mary Anne Aitken provide a practical and quick description of hemochromatosis, diagnosis and treatment and illustrate application of the information provided through two case studies.)
Pietrangelo, A. “Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment”. Gastroenterology. vol. 139. 2010. pp. 16(The article by Dr. Antonello Pietrangelo gives a review of hemochromatosis from a gastroenterologic perspective. Gastroenterology is the official journal of the American Gastroenterological Association (AGA) Institute. The information within its pages covers both basic and clinical sciency in addition to reviews on important topics. This particular article is on hemochromatosis and explains the pathogenesis, diagnosis and treatment of the disorder. Dr. Pietrangelo is in the Second Division of Internal Medicine and Centre for Hemochromatosis at the University of Modena in Modena, Italy. Gastroenterology is ranked 1st of 65 journals in the Gastroenterology and Hepatology category on the 2010 Journal Citation Reports.)
Powell, LW, Kasper, DL, Braunwald, E, Fauci, AS, Hauser, SL, Longo, DL, Jameson, JL. “Principles of internal medicine”. ((Harrison’s Textbook of Internal Medicine is the #1 selling medical textbook worldwide and is an authoritative reference for practicing physicians, residents and students during their clerkships. The book explains disease processes according to presenting symptoms, treatment options and tiers, and pathophysiology sections. The final updates for the 17th edition are dated October 2, 2007. So, this is a relatively current resource. The authors are all leaders in internal medicine: some work with the National Institute of Health, and others work and teach at prestigious medical centers and universities such as Harvard Medical School, University of California and Northwestern University, Feinberg School of Medicine in Chicago, IL.)
Rochett, J, Le Gac, G, Lassoued, K, Ferec, C, Robson, KJH. “Factors influencing disease phenotype and penetrance in haemochromatosis”. Hum Genet. vol. 128. pp. 16(Human genetics discusses all topics within the vast field of human genetics including gene structure and organization, disease association studies, molecular diagnostics and genetics of cancer among numerous other topics. The article, “Factors influencing disease phenotype and penetrance in HFE hemochromatosis,” reviews hepcidin’s involvement in iron homeostasis, the penetrance and expressivity in HFE hemochromatosis, influence of various modifiers in hemochromatosis and the influence of mouse models on our understanding of the disease. Drs. J. Rochett and Kaiss Lassoued write from Université de Picardie Jules Verne, UFR Médecine in Amiens, France. Drs. G. Le Gac and C. Férec work with Centre Hospitalier Universitaire de Brest, Université de Bretagne in Brest, France. Dr. K.J. H. Robson is currently with the Weatherall Institute of Molecular Medicine and the University of Oxford, John Radcliffe Hospital in Oxford, United Kingdom.)
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