Hemochromatosis And Liver Manifestation

Ministry of Health of the Republic of Moldova

State Medical and Pharmaceutical University

“Nicolae Testemitanu“

Faculty of Medicine Nr.2

Department of Gastroenterology

DIPLOMA THESIS

“HEMOCHROMATOSIS AND

LIVER MANIFESTATION”

Name And Surname of The Student : MWASSI BASHER

6th Year , Group: 1043

Adviser:

Dr. Adela Turcanu, Associate Professor

Dr. Orit Sofer, Chief Unit of Hematology

Chisinau, 2016

Content

List of Abbreviation

HM – Hemochromatosis

ALT – alanine aminotransferase

AST – aspartate aminotransferase

HH- Hereditary Hemochromatosis

DM- Diabetes Mellitus

HEF – Human hemochromatosis protein

HCC – Hepatocellular carcinoma

Introduction

Hemochromatosis (HM) was first identified in the (1800 century) , and by “ it was understood to be an inherited disease resulting in iron overload and deposition. Today, Hemochromatosis "HM" is defined as a metabolic disorder affecting iron (Fe) absorption, that resulting in the accumulation of excess iron in the body’s organs. [1.1][1.2][1.3]

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that affects 1/300 people in the "". One in nine 1/9 people carry the gene—making "HM" the most common genetic disorder in the "". It is firstly seen in middle-aged men of Northern European origin, and postmenopausal women. Treatment is readily obtainable and the prognosis, with early diagnosis and proactive and adherence of treatment, is a normal life prospect . If untreated, HM may lead to cirrhosis. [1.4][1.5]

Aims: to evaluate the clinical features, the para-clinical results and laboratory peculiarities of liver and cardic and other organ function , those are presented in patients with HM in comparison with patients who presented HH

Objectives:

Assessment of clinical features in patients with HH and HM.

Evaluation of para-clinical results (Ultrasonography, liver biopsy) in patients with HM and HH

Estimation of CBC and laboratory liver syndromes (cytolytic, cholestatic, hepatodepressive, immuno-inflammatory) in patients with HM and HH.

Research in symptoms and first disease ,hepatosplenomegaly ,and skin color

Methods: 9 patients with HM and HH, with were randomly selected and followed up. liver biochemistry and physical examination were performed for them.

Results: patient complains, physical examination, biochemical analysis, all indicates that HM and HH , leads to increment of severity and worsening of liver and another organ diseases , and it’s symptoms and it’s complications .

Conclusions: HM and HH diseases, leads to worsening and deterioration of patient symptoms, biochemical analysis, which at the end high light the conclusion that the HM and HH diseases, worse the prognosis of the patient, of either getting

symptoms are the same as those seen with many other medical problems. The screening show the debate has the + effect of increase awareness and suspicion of hemochromatisis .Increased knowledge leads to earlier diagnosis and treatment of

symptomatic individuals, and increased testing of their asymptomatic at-risk relatives.

Bibliographic review and analysis

2.1 Definition

A hereditary disorder in which iron "Fe" salts are deposited in the tissues , leading to liver damage, DM, and bronze discoloration (BH) of the skin.

OR

A hereditary disorder of metabolism involving the deposition of iron (Fe+)-containing pigments in the tissues or organs that is characterized especially by the abdominal pain, joint weakness, and fatigue and that may lead to bronzing of the skin, arthritis, DM, cirrhosis, or heart disease if untreated.[2.2][2.3]

Primary "HM" Haemochromatosis Although it was famed for most of the 20th century “Author – Cam Patterson; Marschall S. Runge (2006)”, that most cases of haemochromatosis were inherited, they were incorrectly imagined to depend on a single gene. The overwhelming majority actually depend on mutations of the ( Human hemochromatosis protein ) gene discovered in 1996, but since then others have been discovered and sometimes are classify together as "non-classical HH" "non-HFE (Human hemochromatosis protein) related hereditary haemochromatosis", or "non-HFE haemochromatosis". [2.1][2.4]

Secondary HM

• Severe chronic haemolysis of any cause, including intravascular haemolysis and ineffective erythropoiesis (haemolysis within the bone marrow in the body)

• Multiple frequent blood transfusions (either whole blood or just RBC), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major, SCD, and Diamond–Blackfan anaemia) or by older patients with severe acquired anaemias such as in MDS.

• Excess parenteral iron supplements (addendum), such as what can acutely happen in iron poisoning

• Excess dietary iron

• Some disorders do not normally cause of "HM" on their own, but may do so in the presence of other predisposing factors. These include cirrhosis (fibrosis) (especially related to alcohol abuse), steatohepatitis (NASH) of any cause, porphyria cutanea tarda (pct) , prolonged haemodialysis, and post-portacaval shunting (or portal caval shunt.). [2.1][2.3]

2.2 Terminology & History

The term "haemochromatosis" (HM) is applied by many different fountain (sources) in many different ways.[3.1][3.2]

The term "haemochromatosis" has also been upon contexts where there had not been a known as genetic association for the iron (Fe+) accumulation. However, it should be noted that in some cases, the understanding of a condition that was deem due to behaviour can be refined to accommodate new recognized genetic associations, as in (African iron (Fe+) overload ).[3.4]

It is often used to imply an union with the Human hemochromatosis protein (HFE gene) . For many years, Human hemochromatosis protein was the only known gene associated with haemochromatosis (HM) ,and term "hereditary haemochromatosis(HH)" was used to portray HM type 1. However, it is now known that there are numerous different genetic associations with this stipulation. [3.3][3.2]

The illness was first described in 1865 by “ Armand Trousseau” in a record on diabetic patient's presenting with a bronze pigmentation of their skin. ‘Trousseau” did not associate diabetes (DM) with iron (Fe+) accumulation the recognition that infiltration of the pancreatic organ with iron-overload might disrupt endocrine function resulting in DM was discovered by Friedrich Daniel von Recklinghausen in 1890.[3.3][3.2][3.5]

2.3 What other names do people use for Hemochromatosis

Bronzed cirrhosis (BC)

Bronze Diabetes(BD)

Familial Hemochromatosis

genetic hemochromatosis

Haemochromatosis

HC

Hemochromatoses

HH

HLAH

Iron (Fe+) storage disorder

Pigmentary cirrhosis (PC)

Primary Hemochromatosis(PH)

Troisier-Hanot-Chauffard syndrome (THCS)

Von Recklenhausen-Applebaum disease (VRAD) [4.1]

“ Author – , ” [4.2]

2.4 Epidemiology

It’s most common in white people and occurs in (0.6%) of the population . Men with the disease are 24 times more likely to experience of the symptoms than influenced women.

Type 1 hemochromatosis (HM) is one of the most mutual genetic disorders in the U.S.That affecting about 1 million people. It most often affects people of Northern European descent. The other forms of hemochromatosis (HM) are consider rare form and have been studied in only a little number of families worldwide. [12.1][12.2][12.3]

2.5 Physiology OF Iron

Overview

in spite of the fact that iron (Fe+) is the second most abundant metal in the earth's crust, iron (Fe+) deficiency is the world's most common cause of anemia. When it comes to life, iron (Fe+) is more precious than gold. The body store the element so effectively that over (1000000) millions of years of evolution, humans have advanced no physiological means of iron (Fe+) excretion. Iron (Fe+) absorption is the insole mechanism by which iron (Fe+) stores are physiologically manipulated.[10.1]

The average adult stores about 1 – 3 grams of iron (Fe+) in his body. An exquisite equilibrium between dietary uptake and loss maintains this equilibrium. About 1 mg (1/d) of iron is wasted each day through remove of cells from the skin and mucosal surfaces, including the lining of the (GIT) gastrointestinal tract . Menstration raise the average daily iron (Fe+) losses to about 2 mg per day (2mg/d) in premenopausal female adults . There is no physiologic mechanism of iron (Fe+) excretion exists. Consequently, absorption alone regulates body iron (Fe+) stores . [10.2][10.1]

The growing of body mass during pediatric child and childhood grow spurts transiently enhance iron (Fe+) requirements .[10.1]

Physiology OF Iron

(Figure 2: by MWASSI BASHER)

Iron Absorption :-Iron (Fe+) absorption take place predominantly in the duodenum and upper jejunum The mechanism of iron (Fe+) transport from the bowels into the blood stream remains a mystique despite intensive investigation and a little tantalizing hits . A feedback mechanismul occur

(Figure 3: by MWASSI BASHER)

that enhances iron (Fe+) taking or absorption in people who are iron (Fe+) deficient. In contrast people with iron (Fe+) overload inabit iron (Fe+) absorption.[10.3]

The physical state of iron (Fe+) ente to the duodenum extremely impact its absorption but. At physiological pH, the ferrous iron level (Fe2+) is fastlly oxidized to the in-soluble ferric (Fe3+) form. Gastric acid is decresed the pH in the proximal duodenum, and stimulate the solubility and uptake of ferric iron (Fe+) . When gastric acid production is impaired or stopped (for instance by acid “hcl” pump inhibitors such as the drug, prilosec), iron (Fe+) absorption is decreased substantially.[10.4][10.3]

Heme (iron-containing compound of the porphyrin) is absorbed by machinery completely various to that of inorganic iron (Fe+). The practicability is more efficient and is independent of duodenal pH . Consequently meats are excellent nutrient exporter of iron (Fe+) . In fact, blockade of heme (iron-containing compound of the porphyrin) catabolism in the intestine by a the heme oxygenase inhibitor , can produce iron (Fe+). deficiency . The rareness of meats in the diets of a lot of the inhabitance in the world adds to the burden of iron (Fe+) deficiency. [10.5][10.4]

A number of dietary food factors influence iron (Fe+) absorption. Ascorbate and citrate inhance or stimulate iron (Fe+) uptake in part by acting as languid chelators to help to solubilize the metal or in the duodenum . Iron (Fe+) readily transferred from these products into the mucosal lining cells. in contrast, iron (Fe+) absorption is inhibited by and tannins plant and phytates. These products also chelators of the iron (Fe+) , but inhibit its uptake by the absorption machinery. “Phytates” are seen in cereals and some other wheat, while tannins are prevalent in the “non-herbal” teas.[10.6][10.7]

That Lead is a especially pernicious element to iron metabolism . that taken up by the iron (Fe+) absorption machinery, and secondary blockage the iron (Fe+) through competitive inhibition. Further, lead interferes with a number of important iron (Fe+)-dependent metabolic steps such as heme biosynthesis. This multi -afacted attack has particularly dire consequences in pediatric, were lead to not only produces anemia, but can impair cognitive growing and development. Lead exists naturally at high levels in ground water and wate in some regions, and can clandestinely attack children's (pediatric) health. For this issues, most pediatricians in the U.S. routine screanning and test lead at an early age through a simple blood (CBC) test.[10.8][10.9]

Immaturity of the GIT can exacerbate iron deficiency in newborns. The GIT doesn’t achieve the competency for iron (Fe+) absorption for several weeks after birth. The trouble is even more squeaky for premature infants (pediatric), who tend to be Anemic for the variety of purpose. A substantial section of iron stores in pediatric are transferred from the mother that late in pregnancy. Prematurity short circuits in this process. Parenteral iron (Fe+) replacement is possible, but not always used because of the often sensitive health of the premature infants. Transfusion becomes the default option in this circumstance. [10.11][10.10]

The mechanism by which iron (Fe+) enters to the mucosal cells lining the upper (GIT). GIT is unknown. Most cells at rest of the body are imagine to acquire iron (Fe+) from plasma transferrin (an iron-protein chelator), by specific transferrin receptors (TFR) and receptor-mediated endocytosis . The hypothesis that apo-transferrin (or an equivalent molecule) secreted by intestinal cells or present in bile chelator intestinal iron (Fe+) and facilitates and express its absorption is unsubstantiated.[10.8]

The transferrin gene is not expressed in intestinal cells. subsequent action indicated that transferrin found in the intestinal lumen is come from plasma .Plasma transferrin enter to the bile is fully saturated with iron (Fe+), obviating any intral-uminal chelating iron function . moreover hypoxia, which a lot of increases and stimulate iron (Fe+) absorption, has no impact on intestinal transferrin grade . Exogenous transferrin canno’t giving iron (Fe+) to intestinal mucosal cells , and the brush boarder membrance lack’s of transferrin receptors (TFR) ,(although they are present on the baso-lateral surface into the intestinal epithelial cells . finally or lastlly and perhaps most compellingly, humans and mice with hypo-transferrin-emia paradoxically absorb more dietary iron (Fe+) than normal. Although the erythron is iron (Fe+) deficient, these individuals develop hepatic iron overload (excess). “(Parmley et al., 1985) “[10.9]

Mechanism of Iron (Fe+) Absorption

In searching for molecules involved in intestinal iron (Fe+) transport, Conrad and co-workers took the approach of characterizing proteins that bind (Fe+) iron .[10.10]

Their hypothesis of iron (Fe+) transport is based on identification of iron binding proteins at several key sites. They suggest that mucins bind to iron (Fe+) in the acidic environment of the stomach, treatment maintain it in solution for a later uptake in the alkaline in the duodenum. According to their sample, mucin-bound iron (Fe+) subsequently crosses the mucosa of the cell membrane into association with integrins. Once inside the cell, a (cytoplasmic iron(Fe+) -binding protein), dubbed "mobilferrin", accepts the element, and shuttles it to the baso-lateral surface of the cell, where it is transmeted to plasma. In this model mobilferrin could serve as a rheostat sensitive to plasma iron(Fe+) concentrations. Fully occupied mobil-ferrin would dampen mucosal iron (Fe+) uptake, and while the process it would be stimulate by unsaturated mobil-ferrin . This model has not gained the universal acceptance.[10.13][10.12]

A very different planner of iron (fe+) uptake has been proposed by interrogators that studying iron (Fe+) transport in leaven. leaven face the issue of taking in iron (fe+) from the environment, the process similar to that of intestinal (GIT) mucosal cells. “Dancis et al”- used genetic selection to isolate “Sacchromyces cerevisiae” mutants with defec in iron (Fe+) transport . They constructed an term plasmid in which an enzyme necessary for histidine biosynthesis was under the monitoring of an iron (Fe+) -repressible promoter. The plasmid was introduced into a leaven histidine auxotroph “a strain of leaven that requires histidine to survive”. Mutation was selected in the absence of histidine , in the appear in a base of high levels of iron (Fe+). Among the mutant they secluded, were cells with defect the iron (Fe+) uptake. They discovered that membrane iron Fe+ transport depends absolutely of copper transport. In this model, ferric iron(Fe+) in yeast culture [10.14]medium is decreased to its ferrous shape by an externally oriented reductase “FRE1”. The element is shuttled fastly -into the cell by a ferrous transporter, which appears to be coupled to an externally oriented copper-dependent oxidase “FET3” embedded in the cell membrane . “FET3” is strikingly symmetric to the mammalian (copper-oxidase ceruloplasmin). The reoxi-dation of ferrous to ferric iron is apparently an obligate step in the transport mechanism, although the coupling mechanism of oxidation and membrane transport is unclear. . Although the genetic evidence for this planner is compelling, the central component, the ferrous transporter itself, residue elusive. These interrogators speculate that mammalian intestinal iron (Fe+) transport is analogous to the yeast iron (fe +) fe uptake process . This assertion is supported by studiy of the copper deficient , swine, which show co-existing iron (fe+) deficiency unresponsive to iron

Erythropoiesis and Iron (Fe+) Absorption

Approximately “80% “ of total body iron (TBI) is ultimately incorporated into red cell hemoglobin(HG) . An average adult produces (2 x 1011) red cells daily, for the red cell for renewal rate of “0.8” percent per day. Each red cell contains more than a (billion) atoms of iron (Fe+), and each ml of red cells contains 1 mg of iron (Fe+). To meet this daily need for 2 x 1020 atoms ( 20 milgram) of elemental iron (Fe+), the body was developed regulatory mechanisms whereby erythropoiesis profoundly influences iron (Fe+) absorption. Plasma iron (Fe+) turnover or stimulate (PIT) that represents the mass that turnover of transferrin-bound iron (TBI) in the circulation, expressed as (1mg/kg/day) . Accelerated erythropoiesis that increases amd stimulate plasma iron (Fe+) that begin, which is associated with enhanced iron (Fe+) uptake from the gastrointestinal tract (GIT) The mechanism by which PIT alters iron (Fe+) absorption is unknown.[10.16]

The circulating factor related to erythropoiesis that modulate the iron (Fe+) absorption has been hypothesized, but not identified correctly. Several factors have been excluded, including transferrin and erythropoietin . [10.15][10.13]

Clinical manifestations of the manifest communication between the marrow and the intestine includes iron (Fe+) increase or overload that develops in patients with severe B-thalassemia (thalassemia) in the absence of transfusion. The accelerated “but ineffective” erythropoiesis in this condition substantially driving the iron (Fe+) absorption. In some cases, the increased of the PIT and increased GIT iron (Fe+) absorption is beneficial. In pregnancy, placental removal of iron (Fe+) raises the PIT. This process enhances GIT iron (Fe+) absorption thereby increasing the availability of the element to meet the needs of the grow and develop of the fetus .

Competition studies suggest that several other heavy metals share the iron intestinal absorption pathway. These include lead, manganese, cobalt and zinc . Enhanced iron absorption induced by iron (fe+) deficiency also augments the uptake of these components. As iron (Fe+) deficiency often coexists with lead intoxication, this interaction can produce particularly serious medical complications in pediatric . Interestingly, that the copper absorption and metabolism appear to be handled mechanisms unlike to those of iron (Fe+)[10.11][10.15][10.16]

Body iron stores.

Mostly well -nourished people in industrialized countries have 4 -to- 5 grams of iron in their bodies. Of this, about (2.5 g) is contained in the hemoglobin (HG) needed to carry ( O2) oxygen through the blood, and most of the rest “approximately 2 grams in adult men, and somewhat less in women of the childbearing age” is contained in ferrittin complexes that are present in all cells, but especially common in bone marrow, spleen , and liver.[10.12]

The liver stores the ferritin are the primary physiologic (source) of reserve iron Fe+ in the body. The reserves of iron Fe+ in industrialized countries tend to be lower in children (pediatric) and women of child-bearing age than in men and in the elderly. [10.16]

Women who must utilize their storeses to compensate for iron (Fe+) lost through menstrual cycle, pregnancy and lactation have decreased non-hemoglobin (HG) body stores, which may consist of the (500 mg), or even less.[10.15][10.16][10.14]

IN the bodys total iron(Fe+) content, about (400 mg) that devote to the cellular proteins that use iron Fe+ for important cellular processes like storing oxygen (O2) (myoglobin) or performing energy-producing redox reactions (cytochromes). [10.13]10.14]

A relatively a less amount (3–4 mg) circulates through the plasma, bound to transferring receptor (TFR) . Because of its toxicity, free soluble iron (Fe+) (soluble ferrous ions Fe(II)) is kept in small concentration in the body.[10.13]

Iron (Fe+) deficiency first affects the storage iron (Fe+) in the body, and decrease of these stores is thought to be relatively non-symptomatic, although some vague and non-specific symptoms have been associated with it. Since iron (Fe+) is primarily required for hemoglobin (HG), iron deficiency anemia is the primary clinical manifestation of iron (Fe+) deficiency.[10.11][10.13][10.14]

Iron (Fe+) -deficient people will suffer or die from organ damage (MODS) well before cells run out of the iron (Fe+) needed for intracellular processes like electron transport.

Macrophages of the reticulo-endothelial system store iron (Fe+) as part of the process that breaking down and processing hemoglobin from engulfed red blood cells.[10.15][10.13]

Iron is also stored as a pigment called hemosiderin (HG) which is an ill defined deposit of protein and iron (Fe+) , created by macrophages where excess iron (Fe+) is present, either locally or systemically for example- people with iron(Fe+) overload due to frequent blood cell destruction and transfusions. If the systemic iron (Fe+) overload is corrected, over time the hemosiderin is slowly resorbed by macrophages.[10.16][10.15]

2.6 Reasons for iron deficiency

Functional or actual iron (Fe+) deficiency can result from a group of causes ,These causes can be grouped into several classification or categories: [9.1]

Increased demand for iron (Fe+), which the diet cannot accommodate.

Increased loss of iron (Fe+) (usually through loss of blood).

Nutritional deficiency- This can result due to a lack or abcent of dietary iron (Fe+) or consumption of foods that inhibit iron absorption, including , phytates ,calcium and tannins. Black tea steeped for long has high tannins.[9.1][9.2]

Inability to absorb the iron because of damage to the intestinal lining. Examples of causes of this kind of damage include surgery involving the duodenum, and diseases -like  celiac sprue , Crohn's or  which severely reduce the surface area available for absorption.

Inflammation leading to hepcidin-induced restriction on iron (Fe+) release from enterocytes[9.3]

Causes OF Hemochromatosis

Hereditary hemochromatosis is caused by a mutation in a genenom, that controls the amount of iron (Fe+) that the body will be absorbing from the food that we eating. The mutations that cause hereditary hemochromatosis (HH) are passed or Crossed from parent’s to children.[9.2][9.3]

Gene mutations that cause hemochromatosis

The gene that is mutated most often in people with hereditary hemochromatosis is called Human hemochromatosis protein (HFE). You inherit one Human hemochromatosis protein (HFE) gene from each of the parents. The HFE gene has 2 common mutations, H63D and C282Y. One of these mutations is found in about 85 % of people who have (HH) hereditary hemochromatosis. Genetic testing can reveal whether they have these mutations in your Human hemochromatosis protein HFE gene.[9.4][9.5]

If they inherit two abnormal genes, you may develop hemochromatosis (HM). About 70% of people who inherit 2 genes develop evidence of iron (Fe+) overload of hemochromatosis. You can also pass the mutation into the children.[9.1]

If they inherit one abnormal gene, they won't develop hemochromatosis (HM). they are considered a genenom mutation carrier and can pass the mutation to the children. They will not develop any disease unless they also inherit another abnormal genenom from another parent’s.[9.5][9.4][9.1]

2.7 Pathogenesis

Hereditary hemochromatosis is an adult-onset disorder that represents an error of iron (Fe+) metabolism characterized by inappropriately high iron(Fe+) absorption resulting in progressive iron(Fe+) overload. This disease is the most common cause of severe iron overload. The organs involved are the liver, pancreas heart, pituitary, joints, and skin. [6.1][6.2]

Excess iron (Fe+) is hazardous, because it produces free radical formation. The presence of free iron (Fe+) in biologic systems can lead to the rapid formation of damaging reactive oxygen (O2) metabolites, such as the hydroxyl radical and the superoxide radical. These can lead to produce “DNA cleavage”, that lead to protein synthesis or regulation, and impair of cell integrity and cell proliferation, finally leading to cell injury necrosis and fibrosis.[6.3][6.4]

Derangement of iron (Fe+) homeostasis is also linked with susceptibility to the infectious diseases. Studies performed on (HFE) “knockout mice” (the hemochromatosis model) showed an attenuated inflammatory response (IR) induced by lipopolysaccharide and Salmonella. Secretion of tumor necrosis factor-alpha “TNF-alpha” and interleukin (IL-6) -6 by macrophages was lowered OR decresed. However, feroporin , the macrophage iron (Fe+) exporter, was upregulated. This phenomenon was linked with the presence of a decreased level of iron (Fe+) in macrophages. Thus, the iron (Fe+) level in macrophages was reported to play a regulatory role in the inflammatory response (IR).[6.4]

Daily iron (Fe+) losses or decresed and absorption

Adults preserve a constant level of body iron Fe+ by efficient conservation, maintaining rigorous control over absorption to balance losses decresed. An adult man loses approximately (1 mg) of iron Fe+ daily, commonly in desquamated epithelium and secretions from the gut and skin. During the childbearing years, healthy women lose an average of an additional milligram (mg) of iron (Fe+) daily from menstrual bleeding (40 mL blood loss) and approximately 500/day mg with each pregnancy. In addition, normal daily fecal loss of approximately 0.7 Ml/day of blood (0.3 mg of iron Fe+) occurs. Only a small quantity of iron Fe+ is excreted in urine (< 0.1 mg/d).[6.5]

In healthy adults, losses are balanced by absorption of sufficient dietary iron (Fe+) (1-2 mg) to maintain a relatively constant amount of body iron( Fe+) throughout life. Also excretion is quantitatively as important and absorption in the maintenance of iron (Fe+) balance, absorption usually cosedered the more active regulatory role. In hereditary hemochromatosis (HM), dysregulation of intestinal iron (Fe+) absorption occurs, wherein iron (Fe+) continues to be efficiently absorbed even in the face of substantial elevation of body iron (Fe+) stores.[6.6][6.7]

HFE gene missense mutations

The gene responsible for the disease is called “HFE”, and it is located within the human leukocyte antigen , class I region on chromosome 6 (ch.6) between the genes coding for HLA-A and HLA-B. This gene is mutated in most individuals with hereditary hemochromatosis (HH), and the 2 missense mutations (C282Y and H63D) of the HFE gene are responsible for most cases of hereditary hemochromatosis (HH) in patients of European descent.[6.7][6.8]

HFE protein, the product of the HFE gene, is homologous to major histocompatibility complex (MHC) class I proteins. But also, HFE doesn’t present peptides to T cells, and transferrin receptor (TFR) is a ligand for the “Hemocrhomatosis FE protein”. HFE interacts with THR and causes a clear decrease in the affinity with which the receptor ® binds transferring , thus, there's a direct association of the HFE protein and the TfR-mediated regulation of iron (Fe+) homeostasis, and this interaction may also modulate cellular iron (Fe+) uptake and decrease ferritin levels. So a mutant or nonfunctional variant of the HFE genenom is found, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced or stimulate accumulation of iron (FE+) in peripheral tissues.[6.9][6.11]

Although the mutation underlying most of the cases of hereditary hemochromatosis (HH) is now known, considerable uncertainty exists or found by the mechanism by which the normal genenom product, the Human hemochromatosis protein HFE protein, regulates iron (Fe+) homeostasis. Findings suggestive of increased iron (Fe+) transport at the basolateral membrane of enterocytes in hemochromatosis (HM) have emerged from numerous studies of HFE -related hemochromatosis (HM) in humans and in “mice”.[6.10]

“Knockout mice” models of the HFE gene confer the hereditary hemochromatosis HH phenotype.and studies on Human hemochromatosis protein “HFE” expressed in culture of the cells have not clarified by the mechanism which “HFE” mutant produce increased dietary iron (Fe+) absorption. There have been seen the data that implicate other genes, including those encoding a 2nd “TfR” and the circulating hepcidin, which may participate in pathway with HFE in the regulation of iron(Fe+) absorption.[6.11]

Hemochromatosis (HM) types 2 and 3

The gene for hemochromatosis (HM) type 1 (HFE1), the result of the “C282Y” and “H63D” mutations, is located at band 6p22 chromosme and encodes a protein containing 342 to 343 amino acids. However, 2 other types of hemochromatosis (HM) have been identified: juvenile hemochromatosis (JH) ,or type 2 (gene HFE2), which has been mapped to band “1q21”, and an adult form defined like hemochromatosis (HM) type 3 (HFE3), which results from mutations of the transferrin receptor second gene “TfR2” located on band “7q22”. The clinical appearance of different types of hemochromatosis (HM) could be similar. This speculation also relates to “JH” with late onset. Therefore, patients with hemochromatosis (HM) without HFE mutations should be evaluated for other possible types of hemochromatosis(HM).[6.10]

Hepcidin deficiency

All types of hemochromatosis (HM) have been found to originate from the same metabolic error, disruption of tendency for circulatory iron (Fe+) constancy. Severe iron(Fe+) overload of iron was found in patients with mutations of genes encoding “hemo-juvelin”. These changes correlated with a decrease level of hepcidin . Hepcidin is a human antimicrobial peptide (HAP) synthesized in the liver that plays a key role in the downregulation of iron (Fe+) release by enterocytes and macrophages (inhibits iron (Fe+) absorption in the gut and iron (Fe+) mobilization from the hepatic stores). The degradation of cellular iron (Fe+) exporter “ferroportin” caused by hepcidin is the mechanism of cellular iron (Fe+) efflux inhibition. The absence of this peptide is associated with severe, early-onset, iron (Fe+)-loading phenotype. It is also inappropriately low in adult-onset HFE -related disease.[6.9]

Hepcidin synthesis or patway remains under the regulatory influence of

(hemo-juvelin), which is a member of the repulsive guidance molecule “RGM” and is the coreceptor of the bone morphogenetic protein that , De-arranged (BMP) signaling in hemojuvelin mutants associated with hemochromatosis (HM) disturbs hepcidin synthesis in hepatocytes. Thus, decreased (BMP) signaling by hemojuvelin (HJ) disfunction lowers hepcidin secretion. The hepcidin deficiency due to mutations of hepcidin gene or genes of hepcidin regulators is supposed to be the main factor leading to different types of hemochromatosis (HM).[6.11]

“SLC11A3” gene missense mutation and autosomal dominant (AD) hemochromatosis (HM)

A big or large family was described with autosomal dominant (AD) hemochromatosis (HM) not linked to HFE ( Human hemochromatosis protein) and distinguished by early iron (Fe+) accumulation in reticulo-endothelial cells. This form of the disease was mapped to band “2q32”. The gene encoding ferroprotein “SLC11A3”, which is a transmembrane iron (Fe+) export protein, is within a candidate interval defined by highly significant logarithm of odds (lod) scores. [6.12][6.13]

The iron (Fe+)-loading phenotype in autosomal dominant

Hemochromatosis (HM) was shown to be associated with a nonconservative missense mutation in the ferroprotein gene. This missense mutation, converting “alanine” (ALA) to aspartic acid at residue -77 (A77D mutation), was not identified in samples from one handred unaffected control subjects. “Montosi” and associates proposed that partial loss of ferroprotein function leads to an imbalance in iron (Fe+) distribution and a consequent increase in tissue iron( Fe+) accumulation.[6.14]

2.8 Risk factors

Factors that increase the risk of hereditary hemochromatosis (HH) that include:

Having TWO copies of a mutated (Human hemochromatosis protein gene) HFE. This is the greatest risk factor for hereditary hemochromatosis (HH).[8.1]

Family history. If you have a first 1st-degree relative — a sibling or parent — with HM, they more likely to have or develop the disease. If you have a family history of alcoholism, heart attacks, diabetes, liver disease, arthritis or impotence, your risk of hemochromatosis is greater.[8.1][8.2]

Ethnicity. People of Northern European (NE) descent are more prone to hereditary hemochromatosis (HH) than are people of other ethnic backgrounds. HM is less common in “African Americans” Pepole, Asian-Americans and the Hispanics.

Being a man. Men are more likely to develop a signs and/or symptoms of HM at an earlier age. Because women lose iron through menstruation and pregnancy, they tend to store less of the mineral than men do. After menopause or a hysterectomy, the risk for women increases.[8.3]

Risk factors for secondary hemochromatosis (HM) include:

alcoholism

a family history of diabetes, heart disease, and live disease

taking dietary supplements with iron and vitamin C, which can increase the amount of iron that is absorbed by the body[8.4]

2.9 Types of Hemochromatosis

There are 2 forms of HM: primary and secondary.

Primary HM

Primary HM is an inherited genetic disorder that causes to absorb too much iron(Fe+) from food.

It is caused by a mutation in the Human hemochromatosis protein gene. The Human hemochromatosis protein gene has 2 common mutations which cause HM: H63D and C282Y. A person must inherit a copy of the defective genenom from each parent in order to develop this condition. The person who inheritied only 1 copy of a mutated gene is considered a(“carrier”) of the condition, but may never apparent symptoms.[17.1]

According to the National Heart, Lung, and Blood institution, people with the inherited form of this disease typically develop it between the ages of 40 to 60 y/o .

There are 2 special subtypes of primary HM: neonatal and juvenile.[17.2]

Juvenile HM causes symptoms similar to those of primary HM, but affects people at a much younger age. This form typically affects individuals between the ages of 15 to 30. Additionally, this form is caused by a mutation in the hemo-juvelin gene, not the Human hemochromatosis protein gene.

Neonatal HM causes severe buildup of iron (Fe+) in an infant’s liver, occasionally resulting in death.

Secondary HM

Secondary HM is when a buildup of iron (Fe+) is brought on by other medical conditions, such as:

chronic liver diseases, often a result of HCV infection or alcoholism

anemia (when the body does not make enough RBC)

frequent blood transfusions

kidney dialysis

Primary HM

Most type’s of HH have AR inheritance , while type four has AD inheritance.

[17.1][17.2][17.3]

HM type 1: "classical" HM :-

Is a hereditary illness characterized by excessive intestinal absorption of dietary iron (Fe+) resulting in a pathological increase in total body iron(Fe+) stores. Humans like most animals, have no mean to excrete high or excess iron (Fe+).Excess iron(Fe+) accumulates in organs and tissues disrupting their normal function. The most sensitive organs include the adrenal glands, heart, skin, liver, gonads, pancreas, joints, and the- patient’s preserve with polyarthropathy ,cirrhosis, , adrenal insufficiency, heart failure or DM.The hereditary type of the illness is most typically in those of -Northern European ancestry, in individual those of Celtic descent. The disease is inherited in an AR pattern, which imply the both copies of the gene in each cell have mutation. Most often the parents of an individual with an AR condition each carry 1 copy of the mutated gene, but do not show signs and symptoms of the situation.[17.4]

HM type 2A : juvenile HM :-

Is, as its name indicates, a form of HM which emerges during youth.

There are 2 forms:

HFE2A- is associated with hemojuvelin

HFE2B- is associated with hepcidin antimicrobial peptide

Some provenance only specifically include hemo-juvelin as a cause of juvenile HM.

HM type 2B: juvenile HMs :-

is, as its name indicates, a form of HM which emerges during youth.

There are 2 forms:

HFE2A- is associated with hemojuvelin

HFE2B- is associated with hepcidin antimicrobial peptide

Some provenance only specifically include hemojuvelin as a cause of juvenile HM.[17.5][17.4]

HM type 3 :-

is a form of Iron (Fe+) overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an AR inheritance pattern.

HM- type 4 -African iron overload :-

African iron(Fe+) overload, also known as “Bantu siderosis” ,or “Dietary iron overload”, is an iron(Fe+) high disorder primarly observed among people of African , in Central Africa and Southern Africa. Dietary iron(Fe+) overload is the consumption of large amount of home-brewed beer with high amount of iron(Fe+) content in it. Preparing beer in iron(Fe+) pots or drums results in high iron(Fe+) content. The iron(Fe+) content in home–brewed beer is around (46–82 mg/l) compared to (0.5 mg/l) in commercial beer. Dietary high or overload was prevalent in both the urban Black and rural African population, with the introduction of commercial beer in urban areas, the condition has virtually lowerd. However, the condition is still common in rural areas. Until recently, studies have shown that genetics might play a role in this disorder. Combination of excess Fe+ and functional changes in ferro-portin appear to be the probable cause. This disorder can be treated with iron-chelation or phlebotomy therapy therapy.[17.6][17.7]

Mechanism :-

Originally, this was blamed on galvanised barrels drive to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only around people drink this isolate of beer get an iron (Fe+) high overload syndrome, and that a comparable syndrome happen in people of African who have had no contact with this type of wine.

This led interrogators to the discovery of a gene- polymorphism in the gene for ferro-portin, which predisposes some people of African descent to iron(Fe+)overload.[17.6][17.8]

SLC-40A1 gene association to African iron overload :-

SLC40A1 gene encodes for ferroportin. It is the main iron(Fe+)export protein. A mutation in “SLC40A1” was seen in minority of Native African and African American with primary iron(Fe+) overload ,but the ferro-portin Q248H mutant was not found more regularly in Native southern Africans with dietary iron(Fe+) overload.

Polymorphisms in “SLC40A1” have newly been investigated in Americans of African descent .Ferro-portin “SLC40A1 -Q248H” mutation in exon “6” occurs as a polymorphism in individuals of subSaharan African ,but it was’nt identified in western Caucasians.”Q248H” mutant seen to be unique to African populations. also, studies have shown that “SLC40A1- Q248H’ aggregate allele frequency is increased or higher in Native Africans than the aggregate allele frequency in African Americans.[17.9]

African Dietary iron(Fe+) overload as a cause of hepatocellular carcinoma :-

Ferro-portin Q248H mutation in African families with dietary iron(Fe+) overload showed small mean cell volume and higher ferritin concentration. that suggested that the mutation might interfere with iron(Fe+)supply.

Excess hepatic iron(Fe+) in dietary iron(Fe+) overload is typically associated with serum ferritin saturation of greater than (700pg/l)and transferrin saturation of greater than “55 percentage”.

high hepatic iron(Fe+) generates chronic oxidative stress by disrupting the redox equilibrium of the cell, which harm DNA, lipids, hepatocytes and  protein . Increased lipid peroxidation is thought to be a vital contributor to HCC in iron over-load. Oxidative stress leads to lipid -peroxidation of unsaturated fatty acids in organ and cell membrane.

Neonatal HM :-

is a unusual and severe hepatic illness  of unknown cause, though research propose that it may be allo-immune condition. Its feature are similar to HH, where iron(Fe+) deposition causes injury to the liver and other tissues and organs.

The causes of neonatal HM are still unknown, but modern research has led to the hypothesis that it is an allo-immune disease. guide supporting this hypothesis includes the high recurrence rate within sibships >80 percent. This evidence along with other research indicates that neonatal HM could be categorized as a congenital allo-immune hepatitis.[17.5][17.6]

Acaeruloplasminaemia:-very rare :-

 is a rare AR disorder in which iron (Fe+) gradually accumulates in the basal ganglia, and retina and other organs . Iron(Fe+) piling up in the brain lead to the results in neurological problems that mainly appear in adulthood and worsen over the time.

Aceruloplasminemia has been seen in worldwide, but its overall prevalence still unknown. Studies in Japan have estimated that approximately “1 in 2 million adults in this population are affected”.[17.8][17.9]

Aceruloplasminemia belongs to the set of genetic disorders called neuro-degeneration with brain iron(Fe+)  accumulation (NBIA).

is caused by a mutation (a 5-base pair insertion in exon seven) in the CP gene, which provides instruction for making a protein called ceruloplasmin protin, a protein involved in iron(Fe+) transport and processing. Ceruloplasmin helps move iron(Fe+) from the tissues and organs of the body and prepares it for incorporation into a molecule called transferrin, which transports it to RBC to help carry O2. The CP gene mutation results in the production of ceruloplasmin protein that is unstable or non-functional by alter the open reading frame such that the amino acid ligands in the

essential carboxyl terminal region are finished .When ceruloplasmin is unavailable, transport of iron(Fe+)out of the body's tissues is damge. The resulting iron(Fe+) accumulation damages cells in those tissues, leading to the neurological impairment and other health problems.[17.6][17.9]

Congenital atransferrinaemia “very rare)” :-

also named familial hypotransferrinemia, is an AR  metabolic disorder in which there is an absence or decreased of transferrin, the plasma protein that transports iron(Fe+) through the blood.

Atransferrin-emia is recognize by anemia and hemosiderosis in the liver and heart. The iron(Fe+) damage to the heart can lead to heart damge or failure. The anemia is typically microcytic and hypochromic “the RBC are abnormally small and pale”. Atransferrin-emia is rare, with only 8 cases documented worldwide.[17.8][17.7]

-GRACILE syndrome- “very rare”:-

is an AS genetic disorder, one of the (Finnish heritage) illness . It is caused by mutant in “BCS1L “gene that occurs in 1 out of 1500000 (1/1500000) live births.

GRACILE is an acronym for growth retardation, cholestasis,  amino acid-uria, iron overload, lactic acidosis, and premature death. Other reputation for this syndrome include Finnish lethal neonatal metabolic syndrome (FLNMS)- lactic acidosis, Finnish, with hepatic hemosiderosis:-and Fellman syndrome.[17.9]

2.10 Signs and symptoms

Organs mostly affected by HM are the liver, heart, and endocrine glands.

Haemochromatosis may present with the following clinical syndromes:

Cirrhosis of the liver

DM because pancreatic islet cell failure

Cardiomyopathy

Arthritis (calcium pyrophosphate deposition in joints)

Testicular failure

Slate grey discoloration of the skin

Joint pain and bone pain.[16.][16.2]

Human hemochromatosis protein hereditary haemochromatosis

HM is protean in its manifestations, i.e., usually presenting with signs and symptoms suggestive of other diagnoses that affect particular organ systems. Many of the signs and symptoms beneath are uncommon and most of the patients with the HH form of HM do not show any undisguised signs of disease nor do they experience premature morbidity.

The classic triad:- is bronze skin, cirrhosis and DM is not the common any more because of previously diagnosis. [16.1][16.3]

The more common clinical manifestations include:

Fatigue

Malaise

Joint and bone pain

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, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema and spider naevi. Cirrhosis can in addition present with jaundice (yellowing of the skin) and ascites.[16.2]

Insulin resistance (usually patients have already been diagnosed with DM type 2) due to pancreatic damage from iron(Fe+) deposition

Erectile dysfunction and hypogonadism, resulting in decreased libido

Congestive heart failure, pericarditis arrhythmias. 

Arthritis of the hands (especially the 2nd and 3rd MCP joints), but also the knee and shoulder joints

Damage to the adrenal gland, resulting to adrenal insufficiency[16.3]

minimal common findings including:

Deafness

Dyskinesias, including Parkinsonian symptoms

Dysfunction of certain endocrine organs:

Parathyroid gland (leading to hypocalcaemia)

Pituitary gland.[16.4][16.5][16.1]

African iron overload

Symptoms can vary from one person to another. It depends on the extent of accumulation and on the body location of the accumulation. African iron (Fe+) overload can be considered in patient with some of these situation.

mild to moderate liver dysfunction

portal hypertension

Fibrosis

hepatomegaly

ascites

diabetes due to iron accumulation in pancreas

cardiac abnormalities

osteoporosis

liver cirrhosis

hepatocellular carcinoma (HCC)[16.1][16.5]

2.11 Complications from Hemochromatosis

Complications of haemochromatosis (HM) are more common likely to occur if the condition is not diagnosed early :-

Liver disease

The liver can be very ticklish to the effects of iron (Fe+) and many people with haemochromatosis (HM) will have some small degree of liver damage.

But the liver is a relatively harsh and resilient organ so they may experience no noteworthy symptoms even if they liver has become damaged. If test does not show that this is the case they may be told to stop drink alcohol as a precaution.[11.1][11.2]

If significant scarring of the liver “cirrhosis” occurs they may experience symptoms such as:

tiredness and weakness

feeling sick

weight loss

loss of appetite

tenderness and pain surround the liver

very itchy skin

yellowing of the eyes and skin (jaundiced)

More critical symptoms of advanced “cirrhosis” include vomiting blood and passing out bloody stools (poorly) – both of them which are caused by internal bleeding.

medication and Surgery can be used to alleviate the symptoms of “cirrhosis” but the only direct to achieve a complete cure is to have a “liver transplant”.

However, not everyone of the population is appropriate for a liver transplant and the request for transplanted livers is away higher than the supply, so because of that there is often a long waiting time for a transplant to become available.[11.2][11.3]

Cirrhosis also increases the risk of developing liver cancer (HCC). Treatment choice for liver cancer (HCC) include radiotherapy, chemotherapy and removing a section of the liver.

In a small number of cases it may be possible to treat liver cancer (HCC) with a liver transplant.[11.4]

Arthritis

In more severe and advanced cases of haemochromatosis (HM), constant damage, stiffness and inflammation (swelling) can occur in one or more of they joints. This is known as arthritis.

In some cases it can be relieve symptoms of arthritis with medication such as the non-steroidal anti-inflammatory drugs , kind of painkillers and corticosteroids .

In more severe cases where important damage has occurred it may be necessary to subrogate the damaged joint with an artificial one, such as a  knee replacement or hip replacement.[11.1][11.2]

Heart failure

If excess iron (Fe+) is allowed to make up in and surround the heart it can harm the muscles of the heart “cardiomyopathy”.

This can drive to heart failure, which is the heart has become so deteriorate it struggle to pump enough blood to meet the demands of the body.

Symptoms of heart failure include:

breathlessness (dyspnoea) when they more active than usual or sometimes when they resting

extreme weaknes and tiredness

swelling in the ankles legs and feet (edema)

Heart failure can be remedy using a combination of:

lifestyle changes, such as becoming more physically active to strengthen they heart

medications such as “beta-blockers”, which slow they heart rate reducing the strain on they heart.[11.4][11.3][11.2]

Pancreas problems 

Damage to the pancreas can lead to DM.

Reproductive problems

 Excess iron (Fe+) can lead to impotence (erectile dysfunction), and loss of sex drive in men and absence of the menstrual cycle in women (amenorrhea).

Skin color changes

Deposits of iron in skin cells can make your skin appear bronze or gray in color.

By points :-

Cirrhosis (scarring of the liver)

Enlarged liver

Arthritis

Osteoporosis

Irregular heartbeat

Hypothyroidism

Congestive heart failure

Enlarged spleen

Diabetes (from damage to the pancreas)

Liver cancer

Liver failure

Enlarged heart

Impotence

Early menopause

Damage to adrenal glands[11.5][11.4][11.3]

End-organ damage

Iron is stored in the liver, the pancreas and the heart. Long term effects of HM on these organs can be very serious, even fatal if untreated. For ex:- similar to alcoholism, haemochromatosis (HM) can cause cirrhosis of the liver. The liver is a firstly storage area for iron (Fe) and will naturally accumulate excess iron (Fe) to his on. Mean-while time the liver is likely to be destroyed by iron overload. Cirrhosis itself may lead to additional and more serious /danger complications :- including bleeding from dilated veins in the esophagus “esophageal varices” and the stomach “gastric varices” and critical fluid retention in the abdomen “ascites)”. Toxins may accumulate in the blood and eventually impact mental functioning. This can lead to the confusion or even to coma “hepatic encephalopathy”.

Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer (HCC). (Nearly 1/3 of people with HM and cirrhosis eventually develop HCC.)

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

Congestive heart failure:- If increase iron (Fe+) level in the heart interferes with the its ability to circulate enough blood, a numeral of problems can happen including death. The condition may be reversible when HM is treated and excess iron (Fe) stores decreased.

Heart arrhythmias/ disturbance: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life-threatening. This condition can often be invert with the therpy for HM.

Pigment changes: grey or Bronze coloration of the skin is caused primarily by increased melanin deposition, with iron (Fe+) deposition playing a small role.

2.12 Diagnosis of Haemochromatosis

There are various of methods available for diagnosing and monitoring iron (Fe+) loading including:

Liver biopsy

Serum ferritin

MRI

HFE

Serum ferritin :- testing is a cheap, readily obtainable, and minimal invasive method for estimate body iron (Fe+) stores. However, the main problem with utilize it as an indicator of iron (Fe+) overload is that it can be increased in a domain of other medical conditions unlike to iron (Fe+) levels including fever, inflammation, infection, liver disease, cancer, and renal disease. Also total iron (Fe+) binding capacity may be small, but can also be normal.[13.1][13.2]

The standard of practice in diagnosis of haemochromatosis (HM) was lately reviewed by “Pietrangelo”. Positive Human hemochromatosis protein (HFE) investigate confirms the clinical diagnosis of haemochromatosis (HM) in asymptomatic individual with blood tests showing high iron (Fe+) stores, or for prophetic testing of individuals with a family history of haemochromatosis. The alleles evaluated by Human hemochromatosis protein (HFE gene) analysis are evident in ~80% of patients with haemochromatosis (HM) a negative report for Human hemochromatosis protein (HFE) gene does not rule out haemochromatosis (HM). In a patient with negative Human hemochromatosis protein (HFE) gene testing, elevated iron (Fe+) status for no other evident reason, and the family history of liver disease, further evaluation of liver iron (Fe+) concentration is indicated. In this case diagnosis of haemochromatosis (HM) is instituted on biochemical analysis and histologic examin of a liver biopsy. estimate of the hepatic iron (Fe+) index (HII) is considered the "gold standard" diagnosis of haemochromatosis (HM).[13.3][13.2]

Magnetic resonance imaging (MRI)

Is emerging as a noninvasive alternative to accurately estimate iron (Fe+) deposition levels in the liver as well as joints, heart, and pituitary gland.[13.2]

Screening:-

Family members of those with primary haemochromatosis (HM) should or msut be screened to determine if they are a carrier or if they could develop the illness. This can allow preventive measures to be taken.

Screening / testing the general population is not recommended.[13.3][13.4]

HFE hereditary haemochromatosis (HH)

The diagnosis of haemochromatosis (HM) is usually made following the incidentally finding on routine blood screening of increased serum liver enzymes or increase of the transferrin saturation. Arthropathy with stiff joints, fatigue or diabetes, may be the presenting complaint

Blood tests:-

Serum transferrin and transferrin saturation (TRFS) are commonly used as screening for haemochromatosis (HM). Transferrin binds iron (Fe+) and is responsible for iron (Fe+) transport in the blood. Measuring transferrin supply a crude measure of iron (Fe+) stores in the body. Fasting transferrin saturation values in excess of 45% percent (or 35% in premenopausal women) are recognized as a threshold for further evaluation of haemochromatosis (HM). Transferrin saturation greater than 62% percent is suggestive of homozygosity for mutations in the Human hemochromatosis protein (HFE) gene. [13.5][13.6]

[13.6][13.7]

Serum Ferritin:-  

Ferritin a protein synthesized by the liver is the primary form of iron (Fe+) storage within cells and tissues. Measuring ferritin provides another crude estimate of whole body iron (Fe+) stores though many conditions, particularly inflammation (and also chronic alcohol consumption, non-alcoholic fatty liver disease (NASH) and others), can elevate serum ferritin: which can account for up to 90% percent of cases where increased levels are seen. Normal values for males are 12–300 (ng/ml) , and for female-(12–150 ng/ml). Serum ferritin in excess of (1000 nanograms per millilitre of blood) is almost always attributable to haemochromatosis (HM).

another blood tests routinely performed:- renal function, blood count, , liver  ,enzymes, electrolytes, (OGTT).[13.8][13.6]

Liver biopsy

 Involve taking a sample of tissue from the liver, use a thin needle. The amount of iron (Fe+) in the sample is then quantified and compared to normal, and evidence of liver injury, particularly cirrhosis, measured microscopically. Formerly this was the only way to emphasize a diagnosis of haemochromatosis (HM) but measures of transferrin and ferritin with a history are deem adequate in determining the existence of the illness. Risks of biopsy involve bleeding and infection ,bruising. Now when a history and measures of transferrin or ferritin point to haemochromatosis (HM), it is debatable whether a liver biopsy is yet needful to quantify the amount of accumulated iron (Fe+).[13.9]

MRI

MRI is founded on testing is a noninvasive and accurate alternative to measure liver iron (Fe+)

amount or concentrations .

Other imaging

Clinically the illness may be wordless, but distinctive radiological features may point to the diagnosis. The increased iron (Fe+) stores in the organs implicated, especially in the pancreas and liver, result in special findings on unenhanced CT and a lowerd signal intensity in MRI scans. Haemochromatosis(HM) arthropathy includes chondrocalcinosis degenerative and osteoarthritis. The divide of the arthropathy is distinctive, but not unique, frequently affect the 2nd and 3rd metacarpophalangeal joints (MCP) of the hand. The arthropathy can there-fore be an early clue as to the diagnosis of haemochromatosis (HM). [13.10][13.9]

Functional testing

established on the history, the doctor might consider certain tests to monitor organ dysfunction, such as an echocardiogram (EKG) for heart failure, blood glucose monitoring for patients with haemochromatosis (HM) diabetes (DM).[13.10][13.9][13.8]

Screening

Base of diagnostic measures for haemochromatosis (HM), ferritin tests and  transferrin saturation , are not a part of routine medical testing. checking for (HM) is recommended if the patient has a family history or parent or sibling and child with the illness.

Manual screening of the general population for (HH) is generally not done. Mass genetic testing and checking has been evaluated by the  United States. Preventive Services Task Force (USPSTF), and the among other set. The USPSTFrecommended against genetic screening of the general population for HH because the likelihood of discovering an undiagnosed patient with clinically relevant iron (Fe+) overload is less than 1 in 1,000 (1/1,000). also there is vigorous evidence that therpy of iron (Fe+) overload can save lives in patients with transfusional iron (Fe+) increase or overload, there is no clinical study has seen that for asymptomatic carriers of HH treatment with phlebotomy- provides any clinical interest. Recently – it has been propose that patients be screened for iron (Fe+) overload using serum ferritin as a marker- If serum ferritin exceeds 1000 (ng/Ml), iron (Fe+) high or overload is very likely the cause of HH.[13.11]

African iron (Fe+) overload

overload or Elevation in ferritin concentration without elevation in transferrin saturation (TFrs) does not rule out an iron (Fe+) overload disorder. This combination can be observed in loss-of-function- of ferroprortin mutation and in acerulo-plasminemia. Elevated or high level of ferritin concentration can be observed in acute or chronic inflammatory process without pathologic iron(Fe+) increase or overload.[13.12][13.11]

Ferritin level above/more -200- (ng/mL) (449 pmol/L) in women or 300 (ng/mL) (674 pmol/L) in men who have no signs of inflammatory illness need additional testing. Transferrin saturation (TFRs) above normal domain in male and female also need additional testing.

Chemical evidence of tissue vitamin-C deficiency or low and mild to moderate liver dysfunction are likely to be seen in individuals with African iron (Fe+) overload. Elevation in Gamma-glutamyl- transpeptidase(GGT) can be used as a marker for abnormalities in liver mission.[13.12][13.9]

The seriousness of iron (Fe+) high or overload can be determined and monitored using a combination of tests. Measurement of serum ferritin indicates for total body iron (Fe+) overload. Liver biopsy measures the iron (Fe+) concentration of liver. It provides the microscopic examination of the liver. Measurement of serum-hepcidin  levels may be useful in diagnostic for iron (Fe+) high or overload .MRI can demonstrate the degree of magnetic disruption due to iron (Fe+) accumulation. MRI can measure iron (Fe+) accumulation within the liver, heart, and pituitary .Accumulation of iron (Fe+) in a single organ does not provide proper representation of the (TBI) total body iron (Fe+) overload.

It is important to use both the imaging technicality and serum ferritin level as indicators to start the therapy of iron (Fe+) overload. Serum level and the imaging technicality can be used as markers for the treatment progress.[13.9][13.12][13.10]

[13.2][13.11]

2.13 Different Diagnosis

When evaluate a patient with suspected HM, alcoholic liver disease (NASH), ineffective erythropoiesis with bone marrow hyperplasia, iron (Fe+) overload associated with multiple transfusions ,chronic anemia, and porphyria cutanea tarda must also be consider. In addition, patients may have susceptibility to specfic bacterial infections, such as , pseudotuberculosis sepsis, Yersinia enterocolitica liver abscess Vibrio vulnificus sepsis, and Listeria monocytogenes meningitis. as well, take note of the high risk of hepatoma in cirrhotic livers of patients with HM.[14.1][14.2]

Distinguishing HM arthropathy from rheumatoid arthritis (RA) is important for several purpose. For ex, patients with HH do not require corticosteroid treatment. In addition, if a diagnosis of RA is made falsely, treatment with phlebotomy is not started early, and familial genetic counseling is not considerd. [14.3]

Alcoholic liver disease

Patients with alcoholic disease include those who are intense drinkers, perhaps of iron (Fe+)-containing fortified wine, who have cirrhosis. Liver biopsy in these patients may show a modest increase in iron (Fe+) while, contrary to patients with HM, the hepatic iron (Fe+) levels are relatively normal and iron (Fe+) stores are less than (4 g).[14.5][14.4]

Ineffective erythropoiesis with marrow hyperplasia

Patients with hyperplastic erythroid bone marrow absorb an high amount of iron (Fe+) to the point where they may have clinical iron(Fe+) overload. Ex:- include the hereditary sideroblastic anemias, serious alpha and beta thalassemia, and the MDS forms, such as refractory anemia with ringed sideroblasts (RARS).[14.5]

Iron (Fe+) overload associated with chronic anemia

Patients who have iron (Fe+) high or overload due to chronic anemia have increased effective erythropoiesis and increased iron (Fe+) absorption. Ex:- include hereditary spherocytosis and acquired sideroblastic anemia.

Multiple transfusions

Hypertransfusion is performed in patients with sickle cell anemia and beta thalassemia major, refractory aplastic anemia, and MDS. like patients may receive as many as 100 units of red RBC, which contain as much as (20-25) g of iron (Fe+), identical to or extra than the amount retained in many symptomatic patients with HH.[14.6][14.7]

Porphyria cutanea tarda (PCT)

Porphyria cutanea tarda is firstly a skin and liver disease that occurs in familial and sporadic forms. The cause of hepatic siderosis in sporadic porphyria cutanea tarda has not been determined, but it may be related to a mutation in the Human hemochromatosis protein(HFE) gene in most patients.

6) Dysmetabolic hyperferritinaemia

Common syndrome that presents in patients with metabolic syndrome (hypertension, obesity hyperlipidaemia, type 2 DM, and hyperuricaemia) and high ferritin levels

Can present with an raised serum ferritin, low transferrin saturation (TFRs), mild hepatic iron (Fe+) ohigh or verload on biopsy or MRI (lower than expected when compared with serum ferritin), and mixed iron(Fe+) deposition in both hepatocytes and macrophages on liver biopsy.[14.8]

7) hereditary acerulo-plasmin-aemia

Very rare familial. Can be associated with DM and often is associated with a neurological cerebellar ataxia syndrome, extrapyramidal syndrome, retinal degeneration, and dementia).)

These patients have increased elevation of the serum ferritin (without evidence of inflammation), but have decrease transferrin saturation and can have severe hepatic iron(Fe+) overload. The diagnosis request documentation of undetectable levels of serum ceruloplasmin.[14.8][14.7]

2.14-FOOD That Contain Iron

1: Mollusks (Clams, Mussels, Oysters)

2: Liver (Chicken, Pork,Lamb, Beef)

3: Squash and Pumpkin Seeds

FOOD That Contain Iron

4: Nuts (Cashew, Pine, Hazelnut, Peanut)

5: Beef and Lamb (Lean Tenderloin)

FOOD That Contain Iron

6: Beans and Pulses (White Beans and Lentils)

: Whole Grains, Fortified Cereals, and Bran

FOOD That Contain Iron

8: Dark Leafy Greens (Spinach, Swiss Chard)

9: Dark Chocolate and Cocoa Powder

FOOD That Contain Iron

10: Tofu

2.15 Iron chelator and hepatotoxicity

Hepatotoxicity

In large clinical trials of deferasirox, elevations in serum aminotransferase levels above 5 times the upper limit of normal (ULN) occurred in 6% of patients and led to drug discontinuation in 1% to 2%.  In addition, there have been several single case reports of clinically apparent liver injury arising during deferasirox therapy which was often severe and occasionally fatal.  The onset of acute liver injury ranged from a few days to 8 weeks after starting deferasirox, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels.  Immunoallergic and autoimmune features were absent.  Recovery was usually rapid once deferasirox was stopped, but some cases were associated with progressive liver injury and hepatic failure.  Deferasirox has a boxed warning regarding hepatotoxicity and regular monitoring of serum bilirubin and aminotransferase levels is recommended. [19.1][19.2][19.3]

Mechanism of Injury

The mechanism of injury accounting for serum enzyme elevations during deferasirox therapy is not known.  Deferasirox is metabolized in the liver largely by glucuronidation and biliary excretion.[19.4][19.5]

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation.  Deferasirox has been implicated in cases of acute liver failure, but not in instances of chronic hepatitis or vanishing bile duct syndrome.  There does not appear to be cross reactivity in risk for hepatic injury between deferasirox and other chelators including deferoxamine or deferiprone.[19.6][19.7][19.8]

2.16 Neuro-degeneration with brain iron accumulation type I (NBIA 1)

General outline

NBIA 1 is a rare familial and sporadic progressive autosomal recessive neurodegenerative disease. Condition in wich extrapyramidal movement disorders are associated with a combination of neuroaxonaly dystrophy and iron accumulation in basal ganglie.

symptoms and course

Slowly progressive gait disorders, stiffness, cramps in legs, muscular hypotonia, rarely progressing into rigidity, clubfoor, stuttering, speech and visual disorders rare. Delay of psychomotor development often antedates neurologic symptoms.[20.1][20.2]

Causes and risk factors

Due to mutations of PANK 2 (pathothenate kinase), mapped on chromosome 20p13 or other mutations. PANK is a rate-determining enzyme in coenzyme A biosynthesis.

Another, similar disorder was mapped to chromosome 19q13.3 that contains the gene for fertitin light peptide (FTS). This “new” disease was called “neuroferritinopathy”. In patients reported as HARP syndrome, changes in exon 5 of PANK 2 gene were seen. Risk factors are consanguinity in families, and missense mutations in PANK 2 gene.[20.3][20.2]

Diagnostic procedures

Laboratory tests and blood chemistry are unremarkable. CerebroSpinal Fluid (CFS) may show increased non-protein bound iron. Electromyograph (EMG) may show rigidospasticity. CCT shows highs signal lesions in globus pallidus; MrI T-2 weighted images show marked decreased intensity in globus pallidus and nigra due to increased iron and feritin content, and small hyperintensive area in internal segment (gliosis and tissue vacuolation).[20.3]

Care and treatment

Causal treatment is unknown. Symptomatic strategies include L-Dopa and dopamine agonists showing limitied efficacy. Trials with iron-chelators gave negative results.[20.3][20.4]

2.17 Hemochromatosis Treatment & Management

Surgical Intervention

Surgical םبprocedures are used to treat two important complications:- severe arthropathy and end-stage liver disease.[18.1]

When end stage liver illness progresses despite iron (Fe+) reduction treatment, orthotopic liver transplantation is the only therapeutic choice.  different indication for liver transplantation is the development of HCC.

Delicate patientب selection is advised for liver transplantation to treat patients with HCC. specially, these patients should have بa single tumor of five cm (5cm) or less in diameter. If multiple tumors are present,ب the acceptable number is three tumors or small, smaller than three cm. The fourth-year survival rateب can be approximately 90% (percent) if these criteria are respected.

Surgical arthroplasty is بconsider if joint destruction becomes severeب despite medical treatment.[18.2]ب

Approach Considerations

in spite of advances in the بmolecular understanding of HM and the impact of “C282Y” on diagnosis, therapy residue simple, cheap, and safe.

The goal of treatment in patients with ironب (Fe+) overload disorders is to remove the iron(Fe+) before it can produce irreversible parenchymal injury. Because a normal life span can be expected if iron (Fe+)ب reduction is initiated before the development of cirrhosis, بclinical suspiciousness and early diagnosis are essential.[18.3]

The therapy of cirrhosis, DM,ب hyperpigmentation of the skin,ب and cardiac damage may be evident in only a minority بof patients. each patient admitted to the hospital with an isolated case of arthralgia or asthenia with لor hypertransamin-asemia should be examined by means of transferrin-saturation testing (TFrs).ل

Heart manifestations of HH بcould have sudden onset and could be poorly reacting to treatment. The hemochromatic بcause of the cardiomyopathy should be specified to ensure appropriate therapy .ي

Admission to ICU may beب warranted for patients who evolve heart ,hepatic, and infectious complications. يIndications for inpatient care, preferably in an intensive care unit, include the following:ب

Hepatic encephalopathyب

Gastr-oesophageal- bleedingب

Arrhythmias ditarbance

Sepsisي

Congestive cardiac failureض

Transfer considerationsث

In condition ofي endstage hepatic illness that is refractory to all methods of medical therpy, transferring the patient يto a facility experienced in hepatic transplantation is preferable.ي

When the diagnosis of HCC is being deem or if the diagnosis is confirmed, transfer the patient to a cancer department ( institution) .[18.4][18.3]

Phlebotomy ض

Once diagnosed,ي HM is treated by phlebotomy to rid the body of excess of iron (Fe+) and to maintain normal ironي (Fe+) stores. Phlebotomy remains the sole that recommended therapy for HH and should beي undertaken in a case Specific manner.ي

The AASLD يguidelines state HH patients who have evidence of iron(Fe+) overload are -strongly encouraged- to receiveي phlebotomy regularly يuntil iron (Fe+) stores are depleted. The regular phlebotomies should continue for life, and the frequency of maintenance therapy should be based onي serum ferritin levels.[18.5]ي

In the induction phase,ي weekly phlebotomy is require, with blood removalي of (7 mL/kg) per phlebotomy (not to exceed (550 mL)ي per phlebotomy). The efficacy of treatment is controlled by ferritin level يevaluation in plasma once يmonthly until the values remain above or higher than upper limits of normal ((300 mcg/L in men)- (200 mcg/L in women)). The hemoglobin (HG) level must be checked يbefore each execution – the reference value is 12to13g/dL (120-130g/L). thereafter, evaluation of ferritin concentration should be done bimonthly until its level is reduced below 50 mcg/L.

In the embalmment phase, the phlebotomyي should be performed every 2 to 4 months. The interval in the midst procedures is يdetermined by the level of ferritin, which should be lower than -50 mcg/mL-.

One study manifest that phlebotomy treatment يي can reduce hepatic fibrosis, and the effects of treatment are dependent on the stage يof the illness.  amid individuals with biopsy results positive for hepatic fibrosis, phlebotomy was associated with an improvement of 13to50%, with the superي improvement among individuals with the least degree of hepatic fibrosis. Individuals render as their own controls, and perfection was based on the qualitativeي histologic features.ي When the liver cirrhosis is present and in its early stages, treatment of phlebotomy يappears to control or slow the progression of hepatic disease. also, the outcome of phlebotomy treatment can be predicted by the natural (simple) biochemical tests.[18.6][18.5]ي

Summaryب

Phlebotomy is generally a safe and efficient method of iron (Fe+) removal. promote patients to have weekly therapeutic phlebotomy of 500/ mLweek of whole blood (equivalent toب approximately 200-250 mg of iron (Fe+) ). Some patients can endure twice-weekly phlebotomy, but this regimen is uninteresting and often unprofitable. Therapeutic phlebotomy should be performed until iron(Fe+) -limited erythropoiesis develops, specified by damge of بthe hemoglobin(HG) level and-or hematocrit (HT) to recover before the next phlebotomy.ب It should be continued until transferrin saturation is(TFRS) less than 50% (percent) and serum ferritin levels are less than 50 ng /mL – preferably 20 ng/mL.[18.7][18.6]ب

Most patientsب require maintenance phlebotomy in which one unit of blood is removed every 2 to 3 months. Therapeutic phlebotomy might ameliorate or even treat some of the manifestations and complications بof the illness, such as elevated liver enzymes, fatigue, hepatomegaly, abdominal pain, hyperpigmentationب and arthralgias . another complications usually show small or no change after phlebotomy.ي

Avoid excessive phlebotomyي and the risk of dehydration and hypovolemia.

Chelation Therapy ب

In patients with HM and cardic disease, anemia, or poor venous access, therpy with iron (Fe+) chelation agents is recommended. The treatment of perspectives comprise compounds inhibitingؤ intestinal absorption of iron (Fe+) , chelators of iron(Fe+) , ؤferroportin or hepcidin,ؤ supplementation. In illness caused by hepcidin deficiency, protein supplementation with hepcidin is advised.[18.6][18.8]

Deferasiroxء

Deferasiroxء “Exjade’ is the oral iron (Fe+) chelator that should be taken 1/ daily as an adjunct to phlebotomies or instead of phlebotomy in patients in whose these procedures are poorly tolerated. Deferasirox is very efficacious in hepatic iron(Fe+)ء removal. During therpy with Exjade, ؤkidney function should be controlled.[18.6]ؤ

In a study that evaluatedؤ the effects of Exjade in Hjv / mice (knockout animals lackingر hemojuvelin [HJV] , an experiential model of HH),ر a dose of -100 mg/kg- markedly decreased the iron(Fe+) level in the hepatic and cardic. However, in the pancreas, Exjade was less effective, and the splenic iron (Fe+) count was not influenced. Exjade was administered once daily(1/day) 5 times a week.ر

Dendrimers

The family of dendrimers,ل iron(Fe+)-selective chelators, have been synthesized .Dendrimers terminated with hydroxyl-piridinone have high affinity to iron(Fe+) and reduce its absorption in the rat GIT.ب Therefore, the application of the dendrimers in the treatment of iron(Fe+) overload diseases is deemed.[18.9]ل

In experiments performed on لrats compared the protective effect of two iron (Fe+) chelators, deferoxamine and deferiprone, بon iron overload in the cardic, deferiprone was found to reduce histopathologic changes in the بcardic of rats chronically loaded with iron (Fe+). The two compounds were administered بindividually or in combination with vitamin C (vitamin رC was used as رthe antioxidative compound aimed at preventing cardic oxidative injury). Additional administration of vitamin C improved histo-pathologic changes and biochemical markers in the cardic.[18.8]ر

Juvenile HM

The primary رpatient affected by juvenile HM was successfully treated with chelation cure. Becauseر of severe congestive cardiac failure, phlebotomy was contradicted. Simultaneous administration of “ deferiprone” andر “deferoxamine” reduced /decreased the myocardial dysfunction and improved the clinical state of that patient.[18.9]ر

Anemia

Patients affected with anemiaر cannot be cured with phlebotomyب. Thus, application of iro (Fe+) رchelation agents (eg, deferasirox ,deferoxamine, deferiprone) is recommended.

Deferoxamine is administered I.V or subcutaneously at dosesب ranging from 25 to the 40 mg/kg. I.V infusion is usually 8 to10 hours in durationب and is repeated 5 nights per week. Similar effects can be obtained يwith subcutaneous bolus injections administered Two (2) daily. The main side effects are inflammatory reactions at the sites of injection, visual bone growth disturbances ,ب auditory disturbances and allergic reactions, inclusive anaphylaxis.[18.10]ي

Deferiprone isب given orally in 3 (three) divided doses of 75 (mg/kg/d). arthralgia Agranulocytosis, neutropenia, ب, GIT reactions, and elevation of liver enzyme levels are the major adverse effects. heart iron(Fe+) بoverload is better reduced by deferiprone than deferoxamine.ب

Deferasirox is an oral chelation agent,بب administered at 10to 30 mg/kg. Deferasirox adverse effects can include- skin exanthem ,ب elevation of the creatinine level, , diarrhea, and auditory disturbances and visual.[18.11]

Dietary Considerations and Prevention ب

Dietary factors may impact the phenotypic expression of HM. Some modulate absorption of iron(Fe+) and may affectب the variability of phenotypic penetrance. However dietary changes intended to minimize or eliminate the iron (Fe+) ingestion are usually unnecessary and are often not feasible.ب

Patients should not eat foods that contain بlarge concentrations of bioavailable Fe+, such as organ meats and red meats. In addition, they should not use iron (Fe+) supplements, including multivitamins بwith ironب(Fe+). In addition, vitamin C(ascorbic acid) supplements should be avoided. Substances in foods and drinks, including phytates, tannates (in tea), oxalates, calcium, phosphates, can bind iron(Fe+) and inhibit its absorption.[18.12]ب

Ethanol abuse mayب accelerate disease progression.ب Alcohol sometimes increases iron (Fe+) absorption, and certain Ethanol drinks, especially red wine, contain relatively high concentrations of iron (Fe+) . Activityب of hydroxyl free radicals is elevated by iron(Fe+) -containing diets combined with Ethanol intake, and this is implicated in hepato-carcino-genesis. Ingestion of 30g or more of Alcohol daily potentiates liver injury due to iron(Fe+) overload and increasesي the relative risk for firstly ب liver cancer in persons with cirrhosis. Patients with evidence of liver damge should consume small or no Alcohol. Other patients should consume Alcohol in moderation.[18.13]ب

Studies shown or يappear on healthy يsubjects living in the Spanish-Mediterranean coast present that some genotypes (H63D heterozygote ,C282Y heterozygote, and homozygote, as well as H63D/S63C compound heterozygote) together with Ethanol and iron (Fe+) intake increased indicators of iron (Fe+) يstatus; however, Ca+ intake lowered them. These effects were not observed in S63C heterozygotes. ي

Vitamin C (ascorbic acid) stimulate or increases intestinal absorption of inorganic iron (Fe+). No reason exists to discourage patients from eating fresh vegetables and fruits containing ascorbic acid, but advising them to limit ingestion of ascorbic acid in supplements to 500 mg/day is prudent.ر utilize mineral supplements for specific deficiencies only.[18.14][18.24]ر

Sea-food from potentially- contaminated waters must be cooked thoroughly. Raw or improperly cooked shellfish is occasionally contaminated with Vibrio vulnificus and can cause sepsis in patients with HM.ر

Consultations ر

Promptly indicate patients to a gastroenterologist and a hepatic transplant center in ؤcase of end-stage liver illness, particularly if it is refractory to therapy. ؤMost often, a gastroenterologist isؤ required to confirm the diagnosis by hepatic biopsy and to assist in the treatment of end-stage hepatic illness. A surgeon specializing in liver transplantation may be needed in cases of highly advanced hepatic disease.[18.15][18.23]ر

In addition, due to theؤ multi-organ nature of the illness and the damage or injury to many intrinsic systems, care and therpy of patients with HM require the collaboration of other physicians in different surgicalر or medical specialties, such as the following:-

A cardiologist assists in the management of severe congestive cardic failure and other cardiac complications, such as the arrhythmiasر

An endocrinologist isؤ helpful in treating patients with DM or other endocrineؤ complications, such asؤ gonadal dysfunction and thyroid and

A geneticist is valuable for familyؤ screening in all 1st-degree relatives of newly diagnosed individuals

An infectious illness specialist canؤ treat patients with sepsis and can also choose the appropriate antibiotic treatment forؤ rare infectious complications

A rheumatologist or an orthopedistؤ is required for the management of joint complications.[18.16][18.22]

Long Term Monitoringؤ

The patient must have a primary care provider who can coordinate treatment with the other specialists involved. Physicians should be aware of the possibility of HH and they should perform diagnostic tests when HH is suspected. Then , رpatient education as to the significance of premature diagnosis and lifelong treatment is essential for symptom-free life.ر

Regular monitoring of hemoglobin (Hg) ,ر hematocrit (Ht) , and serum ferritin levels is necessary in patients undergoing phlebotomy. Genetic testing for HH should also be performed in family رmembers of patients with HH.[18.17][18.21]

Continuous observation of patients with HH regarding the potential complications of the illness is recommended. رconstant follow-up visits should be scheduled with the gastroenterologist. Others, such as endocrinologist, cardiologist or a hematologist, may be needed for serial diagnostic and treatment intervention. Quarterly visits with health-care providers may be necessary depending on the severity of the symptoms and complications.[18.24]ر

HCC is one of the most dangerous complications of HM. Most hepatologists recommend periodic testing and screening withر serum AFP every six ؤ months in patients with cirrhosis. The most cost-effective imaging test used to supplement serum alpha fetoprotein screening is ultra- sonography, theر sensitivity is approximately 80 percent when serum alpha fetoprotein and ultra-sonograms are combined for the screening of ؤHCC.[18.18][18.21][18.24]ر

Medication Summary

Chelation treatment withر deferoxamine -induced iron (Fe+) depletion is administered in people with “C282Y” homozygosity unable to undergo phlebotomy. How-ever, compliance and acceptability ofر deferoxamine treatment in patients with non-HM iron (Fe+) overload is poor.ر

The oral chelators, deferasirox and deferiprone also remove iron (Fe+) from hepatocytes, the primary site of excess iron (Fe+)ؤ deposition in Human hemochromatosis protein -associated HM, but there are no record of the use of these drugs in people with the “C282Y” homozygosity.[18.19][18.20]ؤ

2.18 Prevention

Screening for hemochromatosis is cost- effective high, espically for certain groups of people.  Relatives of  patients with hemochromatosis HM—including , siblings, children and parents should be screaning and tested by the most appropriate method. The best screening method may be iron and ferritin studies or genetic screanning or testing. If the affected persons diagnosed  has been confirmed by  genetic testing and screanning ,  relatives of the patint  may have genetic testing or screaning to determine whether or not they have the genetic predespostion changes present in the affected  individual person. [7.1]

 Many medical groups opposegenetic testing of children. Relatives who are affected but do not  have symptoms can reduce iron (Fe+) intake and / or begin phlebotomy prior to the onset of symptoms, possibly preventing ever becoming symptomatic.

In the winter of “2000”– population screening for hereditary hemochromatosis HH is being widely  debated. 

Many doctors and scientists they want for the population screening because hemochromatosis is easily and cheaply treated , and quite common. Arguments against

the  treatment includethe range of symptoms seen (and not seen) with certain genenom 

mutations, and the risk of discrimination in health and life insurance. Whether or not population  screening and tested becomes favorable by a majority of population, the publicity is the beneficial. Hemochromatisis “HM” is a  common, easily and effectively treated condition. However, diagnosis may be difficult because the presenting  symptoms are  the same as those seen with many other medical problems. The screening show the debate has the  + effect of increase  awareness and  suspicion of hemochromatisis.Increased knowledge leads to earlier diagnosis and treatmen

of symptomatic individuals, and increased testing of their asymptomatic at-risk relatives.[7.2][7.1]

2.19 Prognosis of hemochromatosis

The stage of organ damage, particularly in the liver, is critical for a prognosis. Patients with intense liver tissue scarring (cirrhosis) and DM appear to have a shortened life expectancy. Otherwise life expectancy is normal. Conditions such as tiredness, first signs of liver disease, skin pigmentation, upper stomach pain and potency problems are alleviated by blood-letting. Joint pain usually does not respond to treatment. Patients with cirrhosis of the liver and high ferritin values over 1000µg/l when diagnosed , should have constant liver ultrasound examinations. [15.1][15.2]

2.20 Key Points

● Most people who develop iron (Fe+) overload have HFE-related hereditary hemochromatosis (HHC), an autosomal recessive (AR) genetic condition caused by mutations in the HFE gene.[5.3][5.4]

●Elevated transferrin saturation (TS), a serum iron (Fe+) measure, occurs in more than 2% of the population. A small proportion of these people in the word will expertise progressive iron accumulation and iron overload in body tissues.[5.1][5.2]

● Iron (Fe+) overload can cause serious complications such as cirrhosis, DM, cardiomyopathy, and liver cancer (HCC).[5.3]

● Complications of iron (Fe+) overload can be prevented with phelobotomy (iron removal) (periodic removal of 1-2 units of blood), yet many individuals with clinically critical or significant iron overload are not diagnosed until organ damage has occurred.[5.5][5.1]

● Biological relatives of a person with HFE-related hepatocellular carcinoma (HHC) are at increased risk of having hepatocellular carcinoma (HHC) themselves. Risk is highest for siblings of an influenced person.[5.5][5.4][5.1]

● Early symptoms of iron(Fe+) overload are typically nonspecific (NS), and include common symptoms such as –- fatigue and joint pain.[5.4][5.2]

-Material and research methods

3.1 Protocol

I have evaluated the levels of serum Ferritin, TRANSFERRIN and iron value, and all symptoms of primary and secondary HM and HH.

In addition, all clinical complains and feature, and para-clinical investigations of general blood, and biochemical analysis was evaluated too.

All patients that has been evaluated and investigated were obtained from the department of gastroenterology in “REPUBLICAN HOSPITAL CHISINAU” and in the hepatology and hematology and gastroenterology from the “HILLEL YAFFE MEDICAL CENTER” in Israel.

3.2 Patients

Nine patients, 2 with secondary HM and 7 patient with primary HH, 7 males and 2female , that 2 males have H63D and one male with C282Y and one female with C282Y, were observed, evaluated and investigated consecutively in the period of their hospitalization (Fig.3.2),The control group (III) consisted of 9 practically persons, 78% (7) males and 22% (2) women(Fig.3.1),

Figure 3.1. Gender distribution – HEMOCHROMATOSIS

Figure 3.2 Primary or Secondary Hemochromatosi:-

Because the 7 patient that have TRFs above 45 so we must cheek the genetic test and after that we must do a biopsy:-

Bone marrow iron stain negative in the pigment

Liver HE with hemosiderosis high power

Prussian blue stain for iron

In addition questionnaire about presumptive diagnosis of patient that collected and order to demonstrates certain risk of disorders that lead to HM , The majorty of patient have MYELODYSPLASTIC SYNDROM “MDS” (60%) and other like DM and Thalassemia (40%) (Fig.3.3).

(MDS:- are a group of diseases that affect the bone marrow and blood. In MDS, the blood-forming cells in the marrow slow down, or even stop, making the 3 types of blood cells. Most patients with MDS will develop anemia (low numbers of red blood cells) and may need blood transfusions.)

Figure 3.3 – Presumptive Diagnosis of Patient

After that we collect to demonstrates the first symptom that the patient begin in order to know if we can establish in future some symptom that appear early in the HM ,and we can seen that chronic tiredness and heart problem is equals (40%) most commonly found.(Figure 3.4).

Figure 3.4 – First Symptom in patient with HM/HH.

Then I begin with the physical exam by checking the skin color that I find 3 patients with brownish bronze, and 2 with slate gray to yellowish and 2 with pale white and the 2 with yellow brownish.(Figure 3.5) and after that the palpation and the percussion we see that 4 patients have splenomegaly and 4 patients have hepatomegaly and 1 without HepatoSplenomegaly. (Figure 3.6)

( Figure 3.5) The most common skin color

(Figure 3.6) Patient present with hepato –splenomegaly

Finally the analaysis of Iron level ,and the transferrin saturation and the ferritin value and last the transferrin value was cheeked and :-

Firstly the IRON level normally 59-158 microgr/dl:-

2) Secondarily the TRANSFERRIN VALUE level normally level 200-360 mg/dl:-

3) Tertiary the FERRITIN VALUE normally level 30-400 ng/ml:-

NOTE :- IF more than 200 in Female , and more than 300 in Men

Can suspect HH.

4) Quarterly the TRANSFERRIN SATURATION normally level 20-50%:-

NOTE :- If TRANSFERRIN SATURATION more than 45% we can

Can suspect for HH.

3.3 Methods

Iron Level ,and the transferrin saturation and the ferritin value and last the transferrin value The biochemical evaluation was performed for all patients according to the standard international criteria.

The physical examination and general clinical evaluation was performed for all patients according to general physical examination of patients with HM.

In order to establish the diagnosis of HM was made a complex clinical, laboratory and instrumental research. Clinical characterization of patients was based on following symptoms and clinical syndromes:

Icteric and cholestatic syndrome:- manifested by jaundice of different intensity, skin itching.

Heart syndrome :- palpation and tachycardia (arrhythmia)

Articular syndrome :- manifested by pain in the small or large joints.

Endocrine syndrome:- characterized amenorrhea or infertility.

Hepatomegaly, splenomegaly:- assessed both by clinical and imagistic methods.

Laboratory methods

Evaluation of liver alteration was performed by laboratory research that reflect basic pathological liver syndromes:

Cytolytic syndrome was estimated by determining the values of transaminases: alanine aminotransferase (ALT ) and aspartate aminotransferase (AST ).

The evaluation of cholestatic syndrome has appreciated the level of bilirubin and its conjugated fraction, y –GT, alkaline phosphates .

To assess hepatodepressive syndrome was tested serum proteinum, serum albumin, prothrombin index.

3.4 Statistical Analysis

Clinical research results were statistically processed logically and according to a special program. The results were evaluated by the statistical method of analysis, with the use of indicators.. Statistical analysis was mainly descriptive in nature, calculated and performed using Microsoft Excel 2010.

3.5 General Discussion

In the world we see HM increased in prevalence, because the problem in the diagnosis that not discovered early because the disease is the asymptomatic and misdiagnosed i show that :-

-Iron chelator can lead to cholestatic hepatitis and how we can deal with that.

-Every how much we must check liver biochemistry when we begin to treat with iron chelator.

-How much gene have hemochromatosis , and how we can detect that for diagnosis of primary hemochromatosis.

-liver cirrhosis may developed in the patient.

-when patient will be progressive (late diagnosis)

-How iron affect the nervous system and lead to Neurodegeneration with brain iron accumulation type I.

-discovered this disease early as possible with cheek – ferritin ,TRF,TRFs in primary care because it's not expensive.

-SO evaluation in this disease can come with anemia so you must suspect HM so begin to cheek IRON level after that cheek TRF and then biopsy after that genetic test because it's not expensive test to make possible early diagnosis and early treatment.

3.6 Take Home Messages

1) Hemochromatosis is not an “old man’s disease” Biochemical iron overload occurs in young adults

2) There are now at least 4 other genes than HFE1 in which mutations cause hemochromatosis

3) The most severe form of hemochromatosis – Juvenile Hemochromatosis -occurs in children and young adults – though rare

4) Classical hemochromatosis:

Molecular hemochromatosis (C282Y homozygosity) 1:200

but clinical disease much less frequent

5) IF suspected: measure transferrin saturation and ferritin.

Elevated saturation – genetic testing

High ferritin – consider phlebotomy

6) Juvenile Hemochromatosis:

Rare but much more lethal if diagnosis missed

7) Suspect:

Unexplained cardiomyopathy

Hypogonadism: delayed puberty

Look for very high transferrin saturation and hyperferritinemia

IV-Conclusion

The typical profile of HM has changed and more patient now in younger age and the color has changed also and I find that :-

1) Acording to our result the hereditary hemochromatosis is necessary to be screened in all the categories patients.

2) Is necessary especially patients with hyperferritinemia higher than 1000 ng/dl and saturation coefficient higher than 45.

3) Is necessary independently of patient’s age the color of his skin the presence of absence of diabetes or any other extrahepatic manifestations.

4) The symptoms of liver disease developed in early stage of disease of hemochromatosis

5) TRFs test more sensitive for screening of HM and i recommend in primary care in all the ages

6) Genetical test recommended when the TRFs test above 45 Can suspect for HH

7) Deferasirox, elevations in serum aminotransferase levels above 5 times the upper limit of normal (ULN) occurred in 6% of patients and led to drug discontinuation because can lead to hepatotoxicity so regular monitoring of serum bilirubin and aminotransferase levels is recommended.

8) Neurodegeneration with brain iron accumulation type I (NBIA 1), Symptomatic strategies include L-Dopa and dopamine agonists showing limited efficacy. Trials with iron-chelators gave negative results.

9) Rapid progression in patient who is in late diagnosed so much you diagnosed early you treat early and prevent complication and have better prognosis

V-References

1-Introduction-

Kim and Kang, 2002- Reinhart Speeckaert†,*, Mireille Van Gele†, Marijn M. Speeckaert, Jo Lambert andNanja van Geel. Article first published online: 20 MAR 2014 DOI: 10.1111/pcmr.12235 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. The research was supported by a research grant to N. van Geel from the Scientific Research Foundation-Flanders (FWO Senior Clinical Investigator).

John's Hopkins Medicine 

 (US World and News) 

http://chrominc.net/Iron.html

© Copyright 2001-2013 | All Rights Reserved. 600 North Wolfe Street, Baltimore, Maryland 21287 (http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/liver/hemochromatosis.pdf

2-Definition-

2.1 http://www.bbc.co.uk/health/physical_health/conditions/haemochromatosis1.shtml 
http://en.wikipedia.org/wiki/Iron_overload 
http://www.netdoctor.co.uk/diseases/facts/haemochromatosis.htm

2.2 Cam Patterson-Marschall S. Runge (2006). Principles of molecular medicine. Totowa, NJ Humana Press. pp. 567 ISBN 1-58829-202-9

2.3 Mendes, Ana Isabel- Ferro, Ana; Martins, Rute- Picanço, Isabel;Gomes, Susana; Cerqueira, Rute- Correia, Manuel- Nunes, António Robalo et al. (2008). "Non-classical

2.4 labtestsonline.org > TIBC & UIBC, Transferrin Last reviewed on October 28, 2009.

3-Terminology & History –

3.1 Franchinii M (March 2006). "Hereditary iron overload: update on the pathophysiology, diagnosis, and treatment". Am. J. Hematol. 81 (3): 202–9. doi:10.1002/ajh.20493.PMID 16493621. 3.2 Trousseau A (1865). "Glycosurie, diabète sucré". Clinique médicale de l'Hôtel-Dieu de Paris 2 : 3.3 von Recklinghausen FD (1890). "Hämochromatose". Tageblatt der Naturforschenden Versammlung 1889 : 3.4Biography of Daniel von Recklinghausen 3.5 http://disease-journalist.blogspot.md/search/label/Hemochromatosis%20reference

4-other names do people use for hemochromatosis-

4.1 https://www.nhlbi.nih.gov/health/health-topics/topics/hemo/names

4.2 1Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas, USA. [anonimizat]

5- Key Points-

5.1- Adams P, Brissot P, Powell LW (2000) EASL international consensus conference on

haemochromatosis. J Hepatol 33:485-504 [Medline]

5.2 Alper JS, Geller LN, Barash CI et al (1994) Genetic discrimination and screening for

hemochromatosis. J Publ Health Pol 15:345-58 [Medline]

5.3 Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelonning K, Fjosne U, Halvorsen TB,

Smethurst HB, Sagen E, Bjerve KS (2001) Screening for hemochromatosis: high

5.3 prevalence and low morbidity in an unselected population of 65,238 persons. Scand J

Gastroenterol 36:1108-15 [Medline]

5.4 Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002) Penetrance of 845G A (C282Y)

HFE hereditary haemochromatosis mutation in the USA. Lancet 359:211-8 [Medlin]

5.5 Gleeson F, Ryan E, Barrett S, Crowe J (2004) Clinical expression of haemochromatosis in

Irish C282Y homozygotes identified through family screening. Eur J Gastroenterol Hepatol

6-Pathophysiology –

6.1O'Reilly FM, Darby C, Fogarty J, Tormey W, Kay EW, Leader M, et al. Screening of patients with iron overload to identify hemochromatosis and porphyria cutanea tarda. Arch Dermatol . Sep 1997;133(9):1098-101.

6.2Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ. Attenuated inflammatory responses in the hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol . Aug 15 2008;181(4):2723-31. 

Conrad ME, Umbreit JN, Moore EG. Iron absorption and transport. Am J Med Sci . Oct 1999;318(4):213-29. 

6.4Parkkila S, Niemelä O, Britton RS, Fleming RE, Waheed A, Bacon BR, et al. Molecular aspects of iron absorption and HFE expression. Gastroenterology . Dec 2001;121(6):1489-96. 

6.5Rolfs A, Bonkovsky HL, Kohlroser JG, et al. Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol . Apr 2002;282(4):G598-607. 

6.6Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet . Jan 2004;36(1):77-82. 

6.7Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, et al. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis . Jul-Aug 2001;27(4):744-9. [View Abstract]

6.8 http://celticcurse.org/july-is-hemochromatosis-awareness-month/

http://emedicine.medscape.com/article/177216-overview#a0156

http://blogcritics.org/may-is-international-hemochromatosis-awareness-month/

6.9 Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002. 64:663-80. 

6.10 .McCullen MA, Crawford DH, Hickman PE. Screening for hemochromatosis. Clin Chim Acta. 2002 Jan. 315(1-2):169-86. 

6.11 Department of Pediatrics, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, Missouri 63104, USA. [anonimizat]

6.12 Sanjay Rastogi, MDS, Al-Yamamah Hospital, Ministry of Health, Riyadh, Saudi Arabia

6.13 Fleming RE, Britton RS, Waheed A, et al. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis . Nov 2004;8(4):755-73, vii. 

6.14 Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest . Aug 2001;108(4):619-23. 

7-Prevention

7.1 Barton, James C., and Corwin Q. Edwards, editors. Hemochromatosis: Genetics, Pathophysiology, Diagnosis andTreatment . Cambridge: Cambridge University Press, 2000

7.2 Baden, Howard P. “Ichthyosiform Dermatoses.” In Emery and Rimoin’s Principles and Practice of Medical Genetics.

Edited by David L. Rimoin, J. Micheal Connor, and Reed E. Pyeritz. 3rd ed. St. Louis, MO: Churchill Livingstone, 1997, pp. 1205-1214.

8-Risk factors

8.1Ferri FF. Hemochromatosis. In: Ferri's Clinical Advisor 2016. Philadelphia, Pa.: Mosby Elsevier; 2016. https://www.clinicalkey.com. Accessed Sept. 5, 2015.

8.2 Crownover BK, et al. Hereditary hemochromatosis. American Family Physician. 2013;87:183.

8.3 Hemochromatosis. National Institute of Diabetes and Digestive and Kidney Diseases. http://www.niddk.nih.gov/health-information/health-topics/liver-disease/hemochromatosis/Pages/facts.aspx. Accessed Sept. 5, 2015.

8.4 1998-2015 Mayo Foundation for Medical Education and Research (MFMER). All rights reserved. www.mayoclinic.org/about-this-site/terms-use-licensed-content

9-Reasons for iron deficiency

9.1 1998-2015 Mayo Foundation for Medical Education and Research (MFMER). All rights reserved. www.mayoclinic.org/about-this-site/terms-use-licensed-content

9.2 Ferri FF. Hemochromatosis. In: Ferri's Clinical Advisor 2016. Philadelphia, Pa.: Mosby Elsevier; 2016. https://www.clinicalkey.com. Accessed Sept. 5, 2015.

9.3 Hemochromatosis. National Institute of Diabetes and Digestive and Kidney Diseases. http://www.niddk.nih.gov/health-information/health-topics/liver-disease/hemochromatosis/Pages/facts.aspx. Accessed Sept. 5, 2015.

9.4 Picco MF (expert opinion). Mayo Clinic, Jacksonville, Fla. Sept. 24, 2015.

9.5 Andrews NC. (2000). Intestinal iron absorption- current concepts circa 2000. Dig Liver Dis Jan-Feb;32(1):56-61.

10-Physiology OF Iron

10.1 Bothwell, T. H., and Charlton, R. W. (1982). A general approach of the problems of iron deficiency and iron overload in the population at large. Seminars in Hematology 19, 54

10.2 Banerjee, D., Flanagan, P. R. Cluett, J. and Valberg, L. S. (1986). Transferrin receptors in the human gastrointestinal tract. Relationship to body iron stores. Gastroenterology 91, 861.

10.3 Cook, J. D. Skikne, B. S., and al. e. (1986). Estimates of iron sufficiency in the US population. Blood 68, 726.

10.4 Muir, A. and Hopfer, U. (1985). Regional specificity of iron uptake by smal intestinal brush-boarder membranes from normal and iron deficient mice. Gastrointestinal and Liver Pathology 11, 6376-6379.

10.5 Kappas, A. Drummond, G. S. and Galbraith, R. A. (1993). Prolonged clinical use of a heme oxygenase inhibitor: hematological evidence for an inducible but reversible iron-deficiency state. Pediatrics 91, 537-539

10.6 Craven, C. M., Alexander, J. Eldridge, M., Kushner, J. P., Bernstein, S. and Kaplan, J. (1987). Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proceedings of the National Academy of Sciences (USA) 84, 3457.

10.7 Klausner R.D. van Renswoude J., Ashwell G., Kempf, C, Schechter, AN, Dean, A, Bridges, KR. (1983) Receptor-mediated endocytosis of transferrin in K562 cells. J. Biol. Chem. 258: 4715 – 4724.

10.8Lahey, M. E. Gubler, C. J., Chase, M. S.,Cartwright, G. E., and Wintrobe, M. M. (1952). Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine. Blood 7, 1075.

10.9 Levin, M. J., Tuil, D.and al. e. (1984). Expression of transferrin gene during development of non-hepatic tissues: High level of transferrin mRNA in fetal muscle and adult brain. Biochem. Biophys. Res. Commun. 122, 212

10.10 Conrad, M. E. and Umbreit, J. N. (1993). A concise review: Iron absorption – the mucin-mobilferrin-integrin pathway. A competitive pathway for metal absorption. American Journal of Hematology 42, 67.

10.11 Goyer, 1993, pp. 177-187

10.12 Cook et al., 1986)

10.13 De Silva, D. M., Askwith, C. C. Eide, D., and Kaplan, J. (1995). The FET3 gene product required for high affinity iron transport in yeast is a cell surface ferroxidase. Journal of Biological Chemistry 270, 1098-101

10.14. Stearman, R.Yuan, D. S., Yamaguchi-Iwai, Y. Klausner, R. D., and Dancis, A. (1996). A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science 271, 1552-1557.

10.15 Lahey, M. E. Gubler, C. J. Chase, M. S. Cartwright, G. E.and Wintrobe, M. M. (1952). Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine. Blood 7, 1075.

10.16 Harford, J. B. Rouault, T. A. Huebers, H. A., and Klausner, R. D. (1994). Molecular mechanisms of iron metabolism. In The Molecular Basis of Blood Diseases, G. Stamatoyannopoulos, A. W. Nienhuis, P. W. Majerus and H. Varmus, eds. (Philadelphia: W.B. Saunders Co.), pp. 351-378.

11-Complications from Hemochromatosis-

11.1 http://www.nhs.uk/Conditions/Haemochromatosis/Pages/Complications.aspx

11.2 http://www.pharmacycareplus.co.uk/pages/health_advice_184063-action=condition&condition=haemochromatosis&article=complications.cfm

11.3 © Neighbourhood Direct Ltd 2016

11.4 "Hemochromatosis: Complications". Mayo Foundation for Medical Education and Research (MFMER) 

11.5 Pedrup A, Poulsen H (1964). "Hemochromatosis and Vitiligo". Archives of Dermatology90 (1): 34–37. doi : 10.1001/archderm.1964.01600010040010. PMID   14149720.

Epidemiology

12.1 http://geneticdiseasesforlife.blogspot.md/2011_04_01_archive.html

12.2http://www.hinsdale86.org/staff/kgabric/Disease12/Hemochromatosis/Introduction%20Page.htm

12.3 https://quizlet.com/14146869/medgen-genetic-disordersdisease-flash-cards/

Diagnosis of Haemochromatosis-

13.1Non-Clinician Misinterpretation of DTC Genetic testing (thegenesherpa.blogspot.com)

13.2 http://www.goldbamboo.com/topic-t1404-a1-6Haemochromatosis.html

13.3 a b Pietrangelo, Antonello (2010). "Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment". Gastroenterology 139 (2): 393–408. DOI : 10.1053/j.gastro.2010.06.013. PMID 20542038.

13.4 ^ labtestsonline.org > TIBC & UIBC, Transferrin Last reviewed on October 28, 2009

13.5  http://dynaweb.ebscohost.com/Detail.aspx?id=116469&sid=14aa79e5-a881-407c-94e7-339b81c4cd18@sessionmgr3 accessed October 15, 2008.

13.6 a b c "Hemochromatosis: Tests and diagnosis". Mayo Foundation for Medical Education and Research (MFMER). Retrieved 2009-04-20

13.7 Screening and Diagnosis Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007

13.8 http://www.doctorslounge.com/hematology/diseases/hemochromatosis.htm

: 299–304 PMID 14636642. doi : 10.1016/S1079-9796(03)00164-5 .13.9

13.10 Gordeuk V, Caleffi A, Corradini E, Ferrara F, Jones R, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo I, Gomo Z, Moyo V, Rouault T, MacPhail P, Pietrangelo A (2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene". Blood Cells Mol Dis31 (3): 299–304. PMID 14636642. doi:10.1016/S1079-9796(03)00164-5.

13.11 "Summaries for patients. Screening for hereditary hemochromatosis: recommendations from the American College of Physicians". Ann. Intern. Med. 143 (7): I46. 2005.PMID 16204158. doi:10.7326/0003-4819-143-7-200510040-00004.

13.12 http://www.remedyspot.com/content/topic/1045623-phytic-acid-or-ip6-for-iron-overload-hemochromatosis/.

14-Different Diagnosis-

14.1 Adams, P.C., Barton, J.C. Haemochromatosis. Lancet. 2007;370:1855–1860.

14.2 Rolfs, A.Bonkovsky, H.L. Kohlroser, J.G., McNeal, K., Sharma, A., Berger, U.V. et al, Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol.2002;282:G598–G607.

14.3 Galbraith, R. Heme oxygenase: who needs it?. Proc Soc Exp Biol Med. 1999;222:299–305

14.5 Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population.

14.6 Barton, J.C. Wiener, H.W., Acton, R.T., Go, R.C. HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. Blood Cells Mol Dis. 2005;34:38–47.

14.7 Article: Iron Absorption and Transport – an Update

14.8 Duchini, A. Hemochromatosis Differential Diagnosis. Diagnostic Considerations. http://emedicine.medscape.com/article/177216-differential (accessed 29 March 2012). – See more at: http://www.duplichecker.com/compare-results#sthash.W65PgcJr.dpuf

15-Prognosis of hemochromatosis

15.1 http://www.haemochromatose.ch/en/prognosis.php

15.2 http://www.medhelp.org/posts/Liver-Disorders/NAFLD-and-NASH/show/1847337?page=1

16-Signs and symptoms-

16.1 Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services

16.2  Pietrangelo A (June 2004). "Hereditary hemochromatosis—a new look at an old disease". N. Engl. J. Med. 350(23): 2383–97. doi:10.1056/NEJMra031573. PMID 15175440.

16.3 Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services

16.4 "Hemochromatosis: Symptoms". Mayo Foundation for Medical Education and Research MFMER).)

16.5  Jones H, Hedley-Whyte E (1983). "Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs".Neurology 33 (11): 1479–83. doi:10.1212/WNL.33.11.1479. PMID 6685241.

17-Types of Hemochromatosis

17.1 http://dxline.info/diseases/hemochromatosis

17.2 Hemochromatosis (iron storage disease): Risk factors and causes. (2015, June 19). Retrieved from http://www.cdc.gov/ncbddd/hemochromatosis/causes.html

17.3 Mayo Clinic Staff. (2015, December 22). Hemochromatosis. Retrieved from http://www.mayoclinic.org/diseases-conditions/hemochromatosis/home/ovc-20167289

17.4 Franchini M (March 2006). "Hereditary iron overload: update on pathophysiology, diagnosis, and treatment". Am. J. Hematol. 81 (3): 202–9. doi : 10.1002/ajh.20493.PMID   16493621.

17.5 Allen KJ, Gurrin LC, Constantine CC, et al. (January 2008). "Iron-overload-related disease in HFE hereditary hemochromatosis". N. Engl. J. Med. 358 (3): 221–30. doi :10.1056/NEJMoa073286. PMID   18199861.

17.6 Jacobs EM, Verbeek AL, Kreeftenberg HG, et al. (December 2007). "Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis". Neth J Med 65 (11): 419–24. PMID   18079564.

17.7Gordeuk VR, Caleffi A, Corradini E, et al. (2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene". Blood Cells Mol. Dis. 31 (3): 299–304. doi : 10.1016/S1079-9796(03)00164-5. PMID   14636642.

17.8Beutler, E; Barton, JC; Felitti, VJ; Gelbart, T; West, C; Lee, PL; Waalen, J; Vulpe, C (Nov–Dec 2003). "Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.". Blood cells, molecules & diseases 31 (3): 305–9. doi : 10.1016/s1079-9796(03)00165-7. PMID   14636643.

17.9 McNamara, L; Gordeuk, VR; MacPhail, AP (Dec 2005). "Ferroportin (Q248H) mutations in African families with dietary iron overload.". Journal of Gastroenterology and Hepatology 20 (12): 1855–8. doi : 10.1111/j.1440-1746.2005.03930.x. PMID   16336444.

18-Treatment-

18.1Swinkels DW, Jorna AT, Raymakers RA. Synopsis of the Dutch multidisciplinary guideline for the diagnosis and treatment of hereditary haemochromatosis. Neth J Med. 2007 Dec. 65(11):452-5. 

18.2 [Guideline] Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.Hepatology. 2011 Jul. 54(1):328-43. 

18.3 Worwood M. Pathogenesis and management of haemochromatosis. Br J Haematol. 1999 Apr. 105 Suppl 1:16-8. 

Khanna A, Jain A, Eghtesad B, et al. Liver transplantation for metabolic liver diseases. Surg Clin North Am. 1999 Feb. 79(1):153-62, ix. 

Seravalle G, Piperno A, Mariani R, et al. Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study. Eur Heart J. 2015 Dec 28. 

Gattermann N. The treatment of secondary hemochromatosis. Dtsch Arztebl Int. 2009 Jul. 106(30):499-504, I. 

Janssen MC, Swinkels DW. Hereditary haemochromatosis. Best Pract Res Clin Gastroenterol. 2009. 23(2):171-83. 

Galbraith R. Heme oxygenase: who needs it?. Proc Soc Exp Biol Med. 1999 Dec. 222(3):299-305.

Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008 Aug 15. 181(4):2723-31. 

Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004 Jan. 36(1):-77-82. 

Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, et al. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis. 2001 Jul-Aug. 27(4):-744-9. 

Fleming RE, Britton RS, Waheed A, et al. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. 2004 Nov. 8(4):-755-73, vii. 

Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001 Aug. 108(4):619-23. 

Himmelmann A, Fehr J. Cloning of the hereditary hemochromatosis gene: implications for pathogenesis, diagnosis, and screening. J Lab Clin Med. 1999 Mar. 133(3):229-36. 

Bittencourt PL, Marin ML, Couto CA, et al. Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis. Clinics (Sao Paulo). 2009. 64(9):837-41. 

Ramrakhiani S, Bacon BR. Hemochromatosis: advances in molecular genetics and clinical diagnosis. J Clin Gastroenterol. 1998 Jul. 27(1):41-6. 

Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology. 2002 Mar. 122(3):646-51. 

Powell LW. Diagnosis of hemochromatosis. Semin Gastrointest Dis. 2002 Apr. 13(2):80-8. 

Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001 May 2. 285(17):2216-22. 

Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997 Apr. 34(4):275-8. .

Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for population screening?. Genet Test. 2001 Summer. 5(2):127-30. 

Wood MJ, Skoien R, Powell LW. The global burden of iron overload. Hepatol Int. 2009 Jul 29. 

http://celticcurse.org/july-is-hemochromatosis-awareness-month/

http://emedicine.medscape.com/article/177216-overview#a0156

http://blogcritics.org/may-is-international-hemochromatosis-awareness-month/

-Iron chelator and hepatotoxicity

19.1 Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of deferasirox).

19.2 Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.  (Textbook on hepatotoxicity; iron chelating agents are not discussed).

19.3 Byrns MC, Penning TM. Treatment of metal exposure. Environmental toxicology: carcinogens and heavy metals. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1872-6.  (Textbook of pharmacology and therapeutics).

19.4 Deferasirox (Exjade): a new iron chelator. Med Lett Drugs Ther 2006; 48 (1233): 35-6.PubMed Citation  (Concise review of the efficacy, safety and costs of deferasirox mentions that it has been associated with serum aminotransferase elevations and several cases of hepatitis).

19.5 Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, Aydinok Y, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006; 107: 3455-62. PubMed Citation  (Among 586 patients with beta thalassemia treated with either oral deferasirox or subcutaneous deferoxamine for one year, decreases in liver iron concentrations were similar with the highest doses; side effects of deferasirox included elevations in creatinine in 38% and ALT [ ≥2 times ULN] in two patients).

19.6 Galanello R, Piga A, Forni GL, Bertrand Y, Foschini ML, Bordone E, Leoni G, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica 2006; 91: 1343-51. PubMed Citation  (Among 40 children [ages 2-17 years] with beta thalassemia treated with deferasirox for 48 weeks, liver iron concentrations gradually increased and 5 developed ALT or AST elevations ≥5 times ULN, which resolved on stopping and did not recur on restarting deferasirox).

19.7 Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, et al.; Deferasirox in Sickle Cell Investigators. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007; 136: 501-8. PubMed Citation  (Among 195 adults with sickle cell disease and iron overload treated with either deferasirox or deferoxamine for 1 year, both groups had similar decreases in liver iron concentration, while ALT elevations ≥5 times ULN occurred in none on deferoxamine vs 5 [4%] on deferasirox, resolving despite continuing therapy in 4, but recurring with reexposure in 1 patient).

19.8 Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev 2008; 22 Suppl 2: S35-41. PubMed Citation  (Review of the efficacy and safety of deferasirox, mentions that reversible elevations in serum aminotransferase levels occur in some patients).

20-Neuro-degeneration with brain iron accumulation type I (NBIA 1)

20.1 K.A.Jellinger, J. Duda: Hallervorden-Spatz disese. In; Neurodegenertion. DW Dickson et al. (eds) ISN edition, Los Angeles 2003 (in press).OMIM #234200 (update 09/18/2002)

20.2 Gordon N. Euro J Peadatri. Neurol 6:243, 2002

20.3 Racette BA et al. Mov Disord 16:1148-52 (2001)

20.4 Ching KH et al. Neurology 58:1673-74 (2002)

VI. Annexes

Statement

I hereby declare that the license thesis titled “ HEMOCHROMATOSIS AND

LIVER MANIFESTATION ” is written by me and has never been submitted to another university or institution of higher education in the country or abroad. Also, that all sources used, including those on the Internet, are given in the paper with the rules for avoiding plagiarism:

* all the fragments of text reproduced exactly, even in his own translation from another language are written between quotation marks and have a detailed reference source;

* reformulation of the texts in own words written by other authors have detailed reference;

* summarizing the ideas of other authors have detailed reference to the original text.

Date :–––––––

MWASSI BASHER
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