Hereditary Hemochromatosis (Clinical)

Overview

Definition^[1,8]

Hereditary hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis ( HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis) is an inherited disorder characterized by iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis that results in tissue injury and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans.

Etiology^[1,7–9,11]

There are 4 types of hereditary hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis; classification depends on the mutated gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.

• HFE gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics: 
  • Specific for HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis ( type 1 Type 1 Spinal Muscular Atrophy, most common)
  • Within the human leukocyte antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (HLA) region on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 6
  • Common missense mutations in the HFE gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • C282Y (cysteine-to-tyrosine substitution at amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids position 282)
    • H63D (histidine-to-aspartic acid substitution at amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids position 63)
  • Common HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis genotypes:
    • Homozygosity for C282Y (C282Y/C282Y)
    • Compound heterozygosity (C282Y/H63D) 
  • Low and variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables clinical penetrance Penetrance The percent frequency with which a dominant or homozygous recessive gene or gene combination manifests itself in the phenotype of the carriers. Familial Juvenile Polyposis:
    • Not all people who are homozygous for the HFE mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations develop hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis.
    • 50% of women and 25% of men have normal serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis levels and never require phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis.
• Non-HFE gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
  • Mutations in other genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure involved in iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements metabolism:
    • HAMP ( hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis antimicrobial peptide) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics or HJV ( juvenile hemochromatosis Juvenile Hemochromatosis Hereditary Hemochromatosis) genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure → type 2 HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis
    • TFR2 ( transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 2) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → type 3 Type 3 Spinal Muscular Atrophy HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis
    • SLC40A1 (solute carrier Carrier Vaccination family 40 member 1) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → type 4 Type 4 Spinal Muscular Atrophy HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis ( ferroportin Ferroportin Helps export iron from the intestinal cell. Heme Metabolism disease)
  • Other rare genetic disorders
• Effects of gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations:
  • ↑ Iron absorption Iron absorption Digestion and Absorption in the intestine: up to 2–4 mg of dietary iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements/day (normal: 1–2 mg/day)
  • ↑ Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deposition in different organs (e.g., liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy)

Iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis^[1,6,11]

It is important to note that causes of iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis may overlap or occur at the same time.

Secondary iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis disorders (acquired):

• Common causes:
  • Increased iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements intake (transfusions) 
  • Ineffective erythropoiesis Erythropoiesis The production of red blood cells (erythrocytes). In humans, erythrocytes are produced by the yolk sac in the first trimester; by the liver in the second trimester; by the bone marrow in the third trimester and after birth. In normal individuals, the erythrocyte count in the peripheral blood remains relatively constant implying a balance between the rate of erythrocyte production and rate of destruction. Erythrocytes: Histology ( thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia)
  • Loss of hepatocyte mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast resulting in reduced hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis (chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease) 
• Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deposits affecting different organs exhibit similar clinical and pathologic features as HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis.

Epidemiology

A common genetic disorder among those of Northern European ancestry^[1,2,6,7]

• 1 in 200–500 people
• Highest in people of Celtic or Nordic origin
• C282Y variant:
  • Most common finding in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis
  • 85% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis are homozygous for the C282Y mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
• Less common in people of African descent
• Men affected 2–3 times more often than women
• Age at onset:
  • Men: after 40 years
  • Women: after 50 years
  • Juvenile hemochromatosis Juvenile Hemochromatosis Hereditary Hemochromatosis: onset at age 10–30 years
• Mortality Mortality All deaths reported in a given population. Measures of Health Status: 1.7 cases associated with hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis per 10,000 deaths

Pathophysiology

The mechanism of iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis in all 4 types of hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis is increased iron absorption Iron absorption Digestion and Absorption by the GI tract; it is regulated by hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis and results in tissue iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deposition.^[11–14]

Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death

1. Dietary iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements undergoes intestinal uptake in the duodenum Duodenum The shortest and widest portion of the small intestine adjacent to the pylorus of the stomach. It is named for having the length equal to about the width of 12 fingers. Small Intestine: Anatomy.
2. Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements moves from the duodenum Duodenum The shortest and widest portion of the small intestine adjacent to the pylorus of the stomach. It is named for having the length equal to about the width of 12 fingers. Small Intestine: Anatomy via the iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements exporter, ferroportin Ferroportin Helps export iron from the intestinal cell. Heme Metabolism ( Fpn Fpn Hereditary Hemochromatosis), and enters the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment via transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism (Tf).
3. Transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism supplies iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements to the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis for hemoglobin synthesis Synthesis Polymerase Chain Reaction (PCR).
4. As the red blood cells Red blood cells Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology ( RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology) age, they are phagocytosed by macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation (in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy), releasing iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements again into the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment through Fpn Fpn Hereditary Hemochromatosis. 
5. Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements that is not used for biochemical processes is stored in ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis.

Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements regulation via  hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis^[5]

Certain conditions require a decrease or increase in iron absorption Iron absorption Digestion and Absorption and circulating iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, a pathway regulated by hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis:

• Liver-derived peptide regulating the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements concentration
• Actions (through binding Fpn Fpn Hereditary Hemochromatosis):
  • Inhibits intestinal iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements uptake
  • Inhibits the release of iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements from macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation with old RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology
• Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements sensing is mediated by different proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:
  • HFE
  • Transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism (Tf) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 2 (Tfr2)
  • Hemojuvelin Hemojuvelin Hereditary Hemochromatosis
• Affected by:
  • ↑ Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements: ↑ hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis to reduce iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements
  • ↑ Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: ↑ hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis to limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements availability to microorganisms
  • ↑ Erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology: ↓ hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis to increase iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements for hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis

Mutations in the hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis pathway^[5,11]

• HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis:
  • Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations involving the HFE protein and non-HFE proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (Tfr2, hemojuvelin Hemojuvelin Hereditary Hemochromatosis, Fpn Fpn Hereditary Hemochromatosis, and hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis) → decreased hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis release and increased iron absorption Iron absorption Digestion and Absorption
  • Increased iron absorption Iron absorption Digestion and Absorption → saturation of Tf and progressive increase of ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis → iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis → iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deposition
• ↑ iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements results in excess oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death → inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death → organ damage

Clinical Presentation

Men usually present in their 40s or later; women have slower iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements accumulation (presumably due to menstrual blood loss) and present after menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause. With patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship being diagnosed earlier since the beginning of the 21st century, end-organ damage secondary to iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis is not often seen in clinical practice.^[9,12]

General findings^[6,8,11]

• Manifestations depend on the degree of iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements accumulation.
• Often asymptomatic; diagnosed incidentally on blood tests or on family screening Screening Preoperative Care
• There is no “typical presentation;” patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship often report fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction in men.
• Clinical features have evolved substantially from the “usual presentation” a few decades ago—classic triad (found late in the disease):
  1. Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  2. Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (“ bronze diabetes Bronze Diabetes Hereditary Hemochromatosis” due to the associated discoloration)
  3. Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions bronzing/increased pigmentation

Specific findings and complications^[6,11]

• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy:
  • Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
  • Hepatomegaly (in 95% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship), abdominal pain Abdominal Pain Acute Abdomen
  • Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease/ cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis: palmar erythema Palmar Erythema Cirrhosis, spider Spider Arthropods of the class arachnida, order araneae. Except for mites and ticks, spiders constitute the largest order of arachnids, with approximately 37, 000 species having been described. The majority of spiders are harmless, although some species can be regarded as moderately harmful since their bites can lead to quite severe local symptoms. Spider Bites angiomas, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Hepatic failure Hepatic failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis: encephalopathy Encephalopathy Hyper-IgM Syndrome, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)
• Pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy:
  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus: elevated glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation, polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, recurrent infections Recurrent infections Common Variable Immunodeficiency (CVID)
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
  • Bronze/slate gray skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions coloration ( melanoderma Melanoderma Bronze/slate-grey skin coloration. Hereditary Hemochromatosis)
  • Prominent on face, neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, forearms Forearms Part of the upper extremity in humans and primates extending from the elbow to the wrist. Bowen Disease and Erythroplasia of Queyrat, and genital regions
  • Koilonychia Koilonychia Iron Deficiency Anemia (spoon-shaped nails)
• Heart:
  • Dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy, heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
  • Arrhythmias
• Joints:
  • Arthralgia Arthralgia Pain in the joint. Rheumatic Fever: small joints of the hands, especially the 1st, 2nd, and 3rd metacarpophalangeal joints Metacarpophalangeal joints The articulation between a metacarpal bone and a phalanx. Examination of the Upper Limbs
  • Others: knees, wrists
  • No joint warmth, redness Redness Inflammation, or deformity Deformity Examination of the Upper Limbs
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
• Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland:
  • Hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (most common pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types dysfunction): infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, loss of libido Loss of libido Male Sexual Dysfunction, amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System
  • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison Disease
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
• Decreased host defenses:
  • Impaired phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation and reduced lymphocyte proliferation, with readily available iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements to microorganisms
  • ↑ Risk of infection from Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes/Listeriosis monocytogenes, Yersinia enterocolitica Yersinia enterocolitica A species of the genus yersinia, isolated from both man and animal. It is a frequent cause of bacterial gastroenteritis in children. Yersinia spp./Yersiniosis, and Vibrio vulnificus Vibrio vulnificus A species of halophilic bacteria in the genus vibrio, which lives in warm seawater. It can cause infections in those who eat raw contaminated seafood or have open wounds exposed to seawater. Vibrio

Diagnosis

HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis should be considered as a diagnosis in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests and abnormal iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements study results. Note that ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis is an acute-phase reactant and can be falsely elevated in other diseases.

Laboratory tests^[7,9,12,13]

• Tf saturation Tf saturation Ratio of serum iron to total iron-binding capacity. Hereditary Hemochromatosis ( TSAT TSAT Ratio of serum iron to total iron-binding capacity. Hereditary Hemochromatosis): ratio of serum iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements to total iron-binding capacity (TIBC):
  • If > 45% → screen for hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis
  • If > 60% (men) and > 50% (women) → highly specific for diagnosis
• Serum iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements: > 150 µg/dL
• TIBC: 200–300 µg/dL
• Serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis: 
  • An acute phase Acute phase Short Bowel Syndrome reactant
  • Less sensitive, because serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis can be ↑ in other liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and inflammatory diseases (including HIV HIV Anti-HIV Drugs)
  • Indicative of disease when:
    • > 200 µg/L in premenopausal women
    • > 300 µg/L in men and in postmenopausal women
    • If > 1,000 µg/L → increased risk of organ damage
• Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests: ↑ alanine Alanine A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. Synthesis of Nonessential Amino Acids transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids ( ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests), ↑ aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests)
• Additional tests:
  • Hormone tests in cases consistent with pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types disorders
    • Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH)
    • Luteinizing hormone ( LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) and follicle-stimulating hormone ( FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System or erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
  • Hemoglobin A_1c and metabolic panel in those with diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C testing if with hepatomegaly or elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests

Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies^[11]

• C282Y and H63D mutations in the HFE gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
• Homozygous for C282Y or heterozygous for C282Y/H63D: indicative of HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis
• Screen all 1st-degree relatives of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship diagnosed with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis.
• Do not order HFE genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies for individuals without a family history Family History Adult Health Maintenance of HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis or lab results showing iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis.^[9]

Imaging

• Magnetic resonance imaging (MRI) of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy:^[11,16]
  • Evaluates liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy damage or tumor Tumor Inflammation development
  • Noninvasive way to estimate iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements stores 
  • Assesses liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements concentration (LIC), which is related to total body iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements store
  • LIC is expressed in milligrams of iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements per gram of tissue (mg/g) or micromolars of iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements per gram (μmol/g) of dry tissue.
    • Normal: < 1.8 mg/g (32 μmol/g)
    • Borderline: between 1.8 and 3.2 mg/g (57 μmol/g) 
    • Mild iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis: 3.2–7.0 mg/g (57–125 μmol/g) 
    • Moderate iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis: between 7.0 and 15.0 mg/g (125–269 μmol/g), which carries an increased risk of iron-induced complications
    • Severe iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis: > 15.0 mg/g (269 μmol/g), which is associated with increased risk of early death
• Cardiac MRI Cardiac MRI Imaging of the Heart and Great Vessels: performed for those with cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Heart Failure
• Echocardiogram Echocardiogram Transposition of the Great Vessels: shows dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy, diastolic dysfunction Diastolic dysfunction Restrictive Cardiomyopathy
• MRI of anterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types: considered in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with endocrine dysfunction
• Radiography:
  • Cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly and pulmonary vascularity may be seen on chest-X-ray.
  • Obtain X-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays of affected joints to evaluate for other arthropathies.

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma^[11,13]

• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
  • Performed when initial approach yields uncertain results and/or staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis of hepatic fibrosis Hepatic fibrosis Autosomal Recessive Polycystic Kidney Disease (ARPKD) is needed
  • Indications:
    • Abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
    • Ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis > 1,000 µg/L
    • Other liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease is suspected.
  • Helps determine the extent of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy damage and iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements concentration
  • Hepatic fibrosis Hepatic fibrosis Autosomal Recessive Polycystic Kidney Disease (ARPKD): most important prognostic factor
  • Risks:
    • Bleeding
    • Perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions: can sample any site except for legs (may be nonspecific owing to stasis)

Management and Prognosis

Management approach^[11,13–15]

• Objectives:
  • Remove excess iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements from the body → reduce ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis level to < 1,000 µg/L (may take several years of therapy)
  • Reduce progression of disease and complications, including risk for HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases.
• Hepatologist referral:
  • For liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, if indicated
  • For initiation of therapy
• Therapy in C282Y homozygotes:
  • In those with serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis > 1,000 µg/L or elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests:
    • Perform liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (for fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis and to rule out other liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease).
    • Therapeutic phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis
  • In those with elevated serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis but < 1,000 µg/L and normal elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests, proceed with therapeutic phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis.
    • While end-organ damage risk is low with ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis < 1,000 µg/L, there are no consistent indicators of who will develop complications.
    • Initiating treatment ( phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis) is favored given that it is inexpensive, safe, and reduces mortality Mortality All deaths reported in a given population. Measures of Health Status from cardiovascular events.
  • In those with no iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements accumulation (normal transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism saturation and ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis) and normal elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests:^[11] 
    • Low risk of developing relevant iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements accumulation
    • Observation and annual follow-up can be done.
• Therapy in compound heterozygotes (C282Y/H63D):
  • Treatment initiation is individualized.
  • Risk of iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis is relatively low based on mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations but can occur in those with comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus (fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease).
  • Consider liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma to determine LIC, degree of hepatic fibrosis Hepatic fibrosis Autosomal Recessive Polycystic Kidney Disease (ARPKD), and treatment benefit in these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
  • Those with elevated LIC and ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis > 1,000 µg/L should have treatment initiated.

Therapeutic options^[11,13,15]

Phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis:

• Treatment of choice 
• Performed weekly or twice weekly, removing 500 mL, and continued until the serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis level is approximately 50–100 µg/L
  • Check hemoglobin and hematocrit Hematocrit The volume of packed red blood cells in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, anemia shows a low value; polycythemia, a high value. Neonatal Polycythemia before each session (fall of hemoglobin and hematocrit Hematocrit The volume of packed red blood cells in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, anemia shows a low value; polycythemia, a high value. Neonatal Polycythemia should not exceed 20% from previous level).
  • Volume of blood removed can be increased (up to 1 L) or decreased depending on patient tolerance Tolerance Pharmacokinetics and Pharmacodynamics.
• After ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis drops to the goal level, it is maintained with phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis (the frequency depends on serum iron studies Iron Studies Iron Deficiency Anemia and blood count). 
• Can improve or slow the natural disease progression

Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements chelating agents:

• Treatment option for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who are intolerant of or unresponsive to phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis and/or have heart disease, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, or difficult intravenous access
• Options:
  • Deferoxamine Deferoxamine Natural product isolated from streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the mesylate form. Hereditary Hemochromatosis: intravenous/subcutaneous
    • Has a relatively short half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics in the body, and tissue iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements stores release iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements continuously
    • IV infusion: 20–40 mg/kg/day infused over 8–24 hours (can be painful and time-consuming)
    • Subcutaneous: 20–40 mg/kg/day (in a small battery-driven pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols over 8–12 hours each night) for at least 3 days weekly
    • Potential adverse effects: ototoxicity Ototoxicity Damage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation. Glycopeptides, visual loss (requiring periodic ophthalmologic and hearing exam)
    • Monitoring: elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests, serum chemistries/BUN/creatinine, and urine protein every 3 months
  • Deferiprone Deferiprone A pyridone derivative and iron chelator that is used in the treatment of iron overload in patients with thalassemia. Hereditary Hemochromatosis: oral chelator (↓ cardiac iron overload Iron overload An excessive accumulation of iron in the body due to a greater than normal absorption of iron from the gastrointestinal tract or from parenteral injection. This may arise from idiopathic hemochromatosis, excessive iron intake, chronic alcoholism, certain types of refractory anemia, or transfusional hemosiderosis. Hereditary Hemochromatosis)
    • Dosing: 75 mg/kg in 2 divided doses (using 1,000 mg twice-a-day tablet formulation only) or in 3 divided doses (using oral solution, 500 mg tablet, or 1,000 mg 3-times-a-day tablet formulation)
    • Maximum: 99 mg/kg/day
    • Potential adverse effects: neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia and agranulocytosis Agranulocytosis A decrease in the number of granulocytes; (basophils; eosinophils; and neutrophils). Lincosamides
  • Deferasirox Deferasirox A triazole and benzoate derivative that acts as a selective iron chelator. It is used in the management of chronic iron overload due to blood transfusion or non-transfusion dependent thalassemia. Hereditary Hemochromatosis: oral iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements chelator
    • Dosing: 20 mg/kg/once daily
    • Potential adverse effects: ↑ elevated liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests, gastrointestinal upset, rash Rash Rocky Mountain Spotted Fever, and renal toxicity Toxicity Dosage Calculation

Erythrocytapheresis:^[17]

• Alternative to phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis
• Removes RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology with the remaining components (e.g., plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, clotting factors, and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology) returned to the patient
• An option for those with hypoproteinemia or thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
• Up to 1,000 mL of RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology can be removed per procedure.
• More costly than phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis

Additional management^[11,15]

• Dietary restrictions:
  • No iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements supplements
  • Limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies supplements (↑ iron absorption Iron absorption Digestion and Absorption).
  • No alcohol to limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy injury
  • No raw seafood ( Vibrio vulnificus Vibrio vulnificus A species of halophilic bacteria in the genus vibrio, which lives in warm seawater. It can cause infections in those who eat raw contaminated seafood or have open wounds exposed to seawater. Vibrio contamination → sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock) 
• Hepatitis A Hepatitis A Hepatitis A is caused by the hepatitis A virus (HAV), a nonenveloped virus of the Picornaviridae family with single-stranded RNA. HAV causes an acute, highly contagious hepatitis with unspecific prodromal symptoms such as fever and malaise followed by jaundice and elevated liver transaminases. Hepatitis A Virus and B vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination is recommended for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis.^[12] 
• Complication-specific treatments:
  • Conventional therapy for diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, and cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Heart Failure/arrhythmia 
  • Hormone replacement or gonadotropin therapy for pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types effects
  • HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases screening Screening Preoperative Care for those at high risk
    • Insufficient data on occurrence of HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis but without cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (low risk) 
    • The American College of Gastroenterology (ACG) guidelines recommend against routine surveillance Surveillance Developmental Milestones and Normal Growth in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HH HH Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with hfe gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Hereditary Hemochromatosis and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans of stage 3 or less.^[11] 
• Surgical management for advanced complications:
  • Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases: for liver failure Liver failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis
  • Arthroplasty Arthroplasty Surgical reconstruction of a joint to relieve pain or restore motion. Osteoarthritis: for severe joint infiltration

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[10,11,15]

• With treatment:
  • 5-year survival rate: 89%
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship without hepatic fibrosis Hepatic fibrosis Autosomal Recessive Polycystic Kidney Disease (ARPKD): expected to have a normal life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids
• Effects of treatment/ phlebotomy Phlebotomy The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda. Hereditary Hemochromatosis on complications:
  • Cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Heart Failure may be reversed.
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions pigmentation improve.
  • 40% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus reach better glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance control.
  • Minimal effect on arthropathy Arthropathy Osteoarthritis and hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (unlikely to improve)
• Once liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis sets in, it is irreversible; HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases is a late sequela.
• Main causes of death:
  • Cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Heart Failure
  • Hepatic failure Hepatic failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases

Differential Diagnosis

• Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease: Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with a history of chronic alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder who have developed chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis may manifest with increased iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements and serum ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis levels. Treatment is alcohol cessation.
• Multiple transfusions: In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who require a lot of blood transfusions Blood transfusions The introduction of whole blood or blood component directly into the bloodstream. Transfusion Products (e.g., sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease, thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia, myelodysplastic syndrome), there may be an increased iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements level, comparable to patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis. Levels return to normal after transfusions are stopped. 
• Chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: a condition of chronically low RBC counts and ineffective erythropoiesis Erythropoiesis The production of red blood cells (erythrocytes). In humans, erythrocytes are produced by the yolk sac in the first trimester; by the liver in the second trimester; by the bone marrow in the third trimester and after birth. In normal individuals, the erythrocyte count in the peripheral blood remains relatively constant implying a balance between the rate of erythrocyte production and rate of destruction. Erythrocytes: Histology. Due to the body adjusting to chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, there is increased iron absorption Iron absorption Digestion and Absorption. Treatment is iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements replacement in addition to treating the underlying cause.