Heme Metabolism

Heme is an iron-containing porphyrin (which is made of 4 pyrrole groups), synthesized mostly in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow and 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. Heme is a component of many crucial substances, including cytochromes, myoglobin, and hemoglobin. Biologic functions include the transportation of gases (e.g., O2), and electron transfer. Biosynthesis of heme is an 8-step process initiated by the synthesis of aminolevulinic acid. Iron availability affects heme production, as the last step involves insertion of ferrous ion. Iron is obtained from the diet and from the breakdown of heme-containing products. In the process of catabolism, heme is converted into bile pigments, out of which bilirubin is excreted. Mutations involving the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in heme synthesis lead to a group of disorders known as porphyrias Porphyrias Porphyrias are a group of metabolic disorders caused by a disturbance in the synthesis of heme. In most cases, porphyria is caused by a hereditary enzyme defect. The disease patterns differ depending on the affected enzyme, and the variants of porphyria can be clinically differentiated between acute and nonacute forms. Porphyrias, and a defect in the catabolism of heme causes hyperbilirubinemias.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Structure and Function of Heme

Structure

  • Heme is a flat, planar structure containing a porphyrin ring with a ferrous atom in the center (ferroprotoporphyrin).
  • Heme is present in:
    • Hemoglobin
    • Myoglobin
    • Cytochromes
    • Peroxidase
    • Catalase
    • Tryptophan pyrrolase
    • NO synthase
  • The 4 main types of heme are:
    • Heme A: part of complex IV of electron transport system 
    • Heme B: 
      • Most common type of hemoglobin
      • Present in hemoglobin, myoglobin, peroxidase, and cyclooxygenase 
    • Heme C: present in cytochrome c proteins and links via cysteines
    • Heme O: functions in bacterial oxidases

Function

  • Transport of O2 from the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs to the tissues
  • Transport of CO2 and protons from tissues to lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs for excretion
  • In cytochromes, oxidation and reduction of iron, which is essential in the electron transport chain Electron transport chain The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC)

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Biosynthesis of Heme

Heme is synthesized in the normoblasts, but not in the mature erythrocytes Erythrocytes 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. The biosynthesis of heme takes place in 8 steps.

Step 1

Step 1 is the synthesis of aminolevulinic acid.

  • Succinyl coenzyme A (CoA) and glycine condense (in the presence of pyridoxal phosphate) forming delta-aminolevulinic acid:
    • Enzyme: aminolevulinic acid synthase (rate-limiting step of the pathway)
    • Site: mitochondria 
    • Process controlled by presence of Fe²⁺-binding proteins
  • Because of the involvement of pyridoxal phosphate (an active form of vitamin B6) in delta-aminolevulinic acid synthesis, 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 is a manifestation of pyridoxine deficiency. 
  • Mutations in ALAS2 (gene for erythroid aminolevulinic acid synthase) cause X-linked sideroblastic anemia Sideroblastic anemia Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic Anemia (iron builds up because of reduced production of heme).
Step one of heme metabolism

Step 1 of heme metabolism

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Step 2

Step 2 is the formation of porphobilinogen (PBG).

  • Moving out to the cytosol, 2 molecules of aminolevulinic acid condense to form PBG (a pyrrole), removing 2 molecules of water in the process:
    • Enzyme: aminolevulinic acid dehydratase or PBG synthase 
    • Site: cytosol
    • Aminolevulinic acid dehydratase is sensitive to Mg2+ and pH and is easily inactivated by heavy metals.
  • This step is affected by lead poisoning. (Aminolevulinic acid dehydratase is inhibited by lead.)
  • Deficiency of the enzyme, a rare genetic disease, leads to aminolevulinic acid dehydratase porphyria.
Step 2 of heme metabolism

Step 2 of heme metabolism
Formation of porphobilinogen

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Step 3

Step 3 is the formation of hydroxymethylbilane (HMB).

  • 4 molecules of PBG condense to form HMB, a linear tetrapyrrole. 
    • Enzyme: PBG deaminase/HMB synthase
    • Site: cytosol
    • Molecules are joined through their amine rings.
  • Reduced activity of the enzyme results in intermittent porphyria (where there is accumulation of porphyrin precursors).
Step 3 of heme metabolism

Step 3 of heme metabolism:
Formation of hydroxymethylbilane

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Step 4

Step 4 is the formation of uroporphyrinogen (UPG).

  • HMB (a linear compound) is converted to UPG III:
    • Enzyme: UPG III synthase (UROS)
    • Site: cytosol
    • Cyclization of the linear HMB forms UPG III, the 1st cyclic intermediate of the pathway.
    • HMB can also spontaneously cyclize to UPG I (nonphysiologic), requiring UROS to convert to UPG III.
  • Enzyme deficiency is seen in the autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder congenital erythropoietic porphyria.
Step 4 of heme metabolism

Step 4 of heme metabolism:
Formation of uroporphyrinogen

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Step 5

Step 5 is the synthesis of coproporphyrinogen (CPG) III.

  • Involves the decarboxylation of UPG III to CPG III with the elimination of 4 CO2 molecules: 
    • Acetate groups are decarboxylated to methyl groups.
    • Enzyme: uroporphyrinogen decarboxylase (UROD)
    • Site: cytosol 
  • UROD mutations cause familial porphyria cutanea tarda and hepatoerythropoietic porphyria.
Step 5 of heme metabolism

Step 4 of heme metabolism:
Formation of coproporphyrinogen III

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Step 6

Step 6 is the synthesis of protoporphyrinogen (PPG).

  • Oxidation of CPG III to PPG IX:
    • Molecular oxygen is required for this reaction.
    • 2 propionic side chains are decarboxylated to vinyl groups. 
    • Enzyme: CPG oxidase (CPOX)
    • Site: mitochondria
  • Reduced amount of CPG III oxidase leads to hereditary coproporphyria.
Step 6 of heme metabolism

Step 6 of heme metabolism:
Synthesis of protoporphyrinogen

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Step 7

Step 7 is the generation of protoporphyrin (PP).

  • PPG IX is converted to PP IX by oxidation:
    • Methylene bridges are oxidized to methenyl bridges.
    • Enzyme: PPG oxidase (PPOX)
    • Site: mitochondria
  • Variegate porphyria is caused by mutations in PPOX.
Step 7 of heme metabolism

Step 7 of heme metabolism:
Generation of protoporphyrin from protoporphyrinogen IX

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Step 8

Step 8 is the generation of heme.

  • Attachment of ferrous ion to PP: 
    • The ferrous ion is inserted in the middle of the porphyrin ring.
    • Enzyme: ferrochelatase (FECH)/heme synthase 
    • Enzyme also facilitates chelation of PP with Zn, forming Zn PP.
    • Site: mitochondria
  • Mutations affecting FECH can lead to erythropoietic protoporphyria (EPP).
  • Lead also inhibits FECH.
The final step of heme metabolism

The 8th and final step of heme metabolism:
Formation of heme

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Summary of heme synthesis

Table: Steps of heme synthesis
Step Site of process Enzyme Disease associated with enzyme gene mutations
1. Synthesis of aminolevulinic acid Mitochondria Aminolevulinic acid synthase
  • X-linked sideroblastic anemia Sideroblastic anemia Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic Anemia (associated with aminolevulinic acid synthase 2 loss-of-function mutations)
  • X-linked protoporphyria (associated with aminolevulinic acid synthase 2 gain-of function mutations)
2. Formation of porphobilinogen (PBG) Cytosol Aminolevulinic acid dehydratase or PBG synthase Aminolevulinic acid dehydratase porphyria
3. Formation of hydroxymethylbilane (HMB) PBG deaminase/HMB synthase Acute intermittent porphyria
4. Formation of uroporphyrinogen (UPG) UPG III synthase Congenital erythropoietic porphyria
5. Synthesis of coproporphyrinogen (CPG) III UPG decarboxylase Porphyria cutanea tarda and hepatoerythropoietic porphyria
6. Synthesis of protoporphyrinogen (PPG) Mitochondria CPG oxidase Hereditary coproporphyria
7. Generation of protoporphyrin (PP) Protoporphyrinogen oxidase Variegate porphyria
8. Generation of heme Ferrochelatase/heme synthase Erythropoietic protoporphyria
ALA and PBG are porphyrin precursors
Heme synthesis

Heme synthesis:
The process of heme synthesis takes place in the mitochondria and cytoplasm.
In the mitochondria, succinyl coenzyme A (CoA) combines with glycine to form aminolevulinic acid.
This reaction is catalyzed by aminolevulinic acid synthase. The aminolevulinic acid exits to the cytoplasm, where 2 aminolevulinic acid molecules condense to produce porphobilinogen (PBG). The subsequent steps lead to the formation of coproporphyrinogen III, which is transported back to the mitochondria. Oxidase facilitates conversion of coproporphyrinogen III to protoporphyrinogen IX, which then is converted to protoporphyrin IX. Ferrous iron is inserted into protoporphyrin IX, forming heme (catalyzed by ferrochelatase).

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Regulation of Heme Synthesis

  • Synthesis of heme mostly occurs in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow (> 80%) and 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.
  • Rate of synthesis depends on the expression of ALAS gene (for aminolevulinic acid synthase): 
    • ALAS2 regulates aminolevulinic acid synthase in the erythrocyte.
    • ALAS1 has a housekeeping role in providing heme to nonerythroid cells.
  • Other factors:
    • Iron availability (↓ iron, ↓ ALAS2 translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation)
    • Heme synthesis has to be coordinated with globin synthesis to produce hemoglobin.
  • ↓ Heme synthesis:
    • Excess heme exerts a negative feedback on ALAS gene expression → ↓ synthesis of ALA synthase 
    • Hemin:
      • Produced when ferrous iron is oxidized to ferric iron in the presence of excess free heme
      • ↓ Aminolevulinic acid synthase synthesis and mitochondrial transport 
    • ↑ Cellular concentration of glucose:
      • Prevents induction of aminolevulinic acid synthase 
      • The basis for the administration of glucose in an acute attack of porphyria
  • ↑ Heme synthesis: 
    • Low intracellular heme (such as when hepatic heme oxygenase degrades heme) → stimulates synthesis of aminolevulinic acid synthase
    • Low oxygen prompts the kidney to release erythropoietin, stimulating erythrocyte production and hemoglobin synthesis.
  • Drugs and other agents:
    • Lead inhibits the steps catalyzed by ferrochelatase and aminolevulinic acid dehydratase. 
    • Isoniazid decreases the availability of pyridoxal phosphate.
    • Drugs that are metabolized via cytochrome P450 (which contains heme), such as barbiturates, induce heme synthesis.

Catabolism of Heme

Heme breaks down, resulting in bile pigments as the end products, with bilirubin excreted through the bile. The steps of heme catabolism are:

  • Degradation begins in the macrophages of 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, which remove senescent and damaged erythrocytes Erythrocytes 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 from the circulation.
  • Erythrocytes are engulfed by the reticuloendothelial system and release hemoglobin when lysed.
    • Heme is oxidized to biliverdin by heme oxygenase. 
    • Biliverdin is then reduced to bilirubin by biliverdin reductase.
  • Bilirubin is transported to 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 and is conjugated with glucuronic acid.
  • Conjugated bilirubin is transported to the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine through the bile duct and then to the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix.
  • Bilirubin is converted to urobilinogen via bacterial reduction:
    • A small fraction is reabsorbed and undergoes renal excretion. (Urobilin causes the yellow color of urine.)
    • In the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix, urobilinogen is converted to stercobilinogen, which is further oxidized to stercobilin. (Stercobilin causes the brown color of feces.)
  • Enterohepatic circulation is the reabsorption of urobilinogen from the intestine and return to 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 by the portal blood.
Normal extrahepatic circulation of bilirubin

Normal extrahepatic circulation of bilirubin

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Iron Metabolism

Iron absorption and transport

Iron absorption:

  • Sources of iron:
    • Food/diet
    • Breakdown of iron-containing products (e.g., hemoglobin)
    • Release from reticuloendothelial stores
  • Dietary iron is absorbed by the enterocytes of the duodenum and proximal jejunum.
    • Iron in the ferric state (Fe³⁺) is reduced to the ferrous state (Fe²⁺) by ferrireductase present on the surface of enterocytes. 
    • Ascorbic acid favors reduction of ferric iron to the ferrous state. 
    • Divalent metal transporter (DMT1) transports Fe²⁺ (not Fe³⁺) from the apical surface of enterocytes to the interior of the cell. 
    • Other transporters include endosomes and heme transporter.
    • For iron to reach the circulation, ferroportin helps export iron from the intestinal cell. 

Iron transport:

  • In order for ferroportin to transport the iron out of the cell, Fe³⁺ is needed to bind with transferrin (in circulation). 
  • Fe²⁺ is oxidized to Fe³⁺ with the aid of hephaestin (a copper-containing membrane protein that has ferroxidase activity) .
  • Fe³⁺ goes into circulation bound to transferrin (iron transport protein synthesized in 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).
  • Iron is then transported to the tissues.
  • Transferrin binds to transferrin receptors, which are expressed significantly in cells with high iron demands (e.g., erythroid marrow).
Intestinal ferric

Intestinal ferric (Fe3+) reductase reduces Fe3+ (ferric) to Fe2+ (ferrous). Fe2+ is transported from the lumen into the intestinal epithelial cell through divalent metal transporter 1 (DMT1), heme transporter (HT) and/or endosomes. Fe2+ can be converted back to Fe3+ and bound to transferrin within the intestinal cell or can be transported into the blood by ferroportin (FP) and hephaestin (HP). Oxidized iron (Fe3+), which binds to plasma transferrin, is carried through the circulation to the tissues.

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Iron storage

  • Transferrin carries iron for:
    • Hematopoiesis in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
    • Iron storage in 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 (primary storage site) and other organs
    • Cellular processes requiring iron 
  • Storage forms of iron:
    • Ferritin: 
      • Main iron storage protein
      • 4500 atoms of iron (when fully loaded)
  • Hemosiderin: ↑ iron → ferritin forms hemosiderin granules (hemosiderin pigment = aggregates of ferritin micelles)
Iron storage

Storage of iron:
Transferrin carries iron for hematopoiesis in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, iron storage in 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 (primary storage site) and other organs, and cellular processes requiring iron.

Image by Lecturio.

Iron regulation

  • Regulation at the molecular level via the iron response element (IRE) and IRE binding proteins (IRBPs) or iron regulatory proteins (IRPs):
    • Involved in posttranscriptional regulation of iron-related genes
    • Controls cellular iron uptake, storage and release
    • IRE: part of the untranslated region (UTR) of the mRNA of the target genes (e.g., ferritin, transferrin receptor, and other iron-metabolizing proteins)
      • Ferritin and ferroportin have the IREs in the 5′ UTR.
      • Transferrin receptor (TfR) has IREs in the 3′ UTR (where binding of IRBP protects from nuclease degradation).
    • IRBPs: either a translational enhancer or a translational inhibitor, binding to iron or IRE depending on the required regulation
  • In iron deficiency (low iron):
    • Ferritin:
      • Ferritin or iron for storage is not needed, as there is low iron for cell usage. 
      • IRBPs bind ferritin IREs at the 5′ UTR, and interrupt initiation of translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation.
      • Less ferritin frees up iron for the cells.
    • TfR:
      • Since transferrin is needed, IRBPs bind IREs of TfR and produce a different effect.
      • IRBP binding to IREs on the 3′ UTR stabilizes the mRNA (protecting from endonucleases).
      • This biding allows increased translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation of TfR, enhancing iron absorption.
  • In iron abundance (high iron):
    • Ferritin:
      • Ferritin is needed to bind excess iron.
      • Iron binds the IRBPs (preventing IREs to be bound), allowing translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation of ferritin.
    • TfR: 
      • Increased iron binds the IRBPs.
      • Dissociation of IRBPs from the IREs at the 3′ UTR exposes the transcripts to endonucleases, increasing mRNA degradation.
      • Thus, iron absorption will be inhibited.

Regulation of iron availability

Certain conditions require a decrease or increase in iron absorption and circulating iron, a pathway regulated by hepcidin:

  • Liver-derived peptide regulating the plasma iron concentration
  • Actions (through binding ferroportin):
    • Inhibits intestinal iron uptake
    • Inhibits release of iron from macrophages with old RBCs
  • Iron sensing mediated by different proteins: 
    • HFE (hereditary iron) protein
    • TfR2
    • Hemojuvelin
  • Affected by:
    • ↑ Iron: ↑ hepcidin to reduce iron
    • 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 to limit iron availability to microorganisms
    • ↑ Erythropoietin: ↓ hepcidin to increase iron for hematopoiesis

Clinical Relevance

  • Hereditary hemochromatosis Hereditary hemochromatosis 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: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder most often associated with HFE gene mutations. There is increased iron intestinal absorption and iron deposition in several organs, such as 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, heart, 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. Structure and Function of the Skin and 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. Clinical presentation includes the triad of 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, diabetes, 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. Structure and Function of the Skin bronzing. Diagnosis consists of iron studies showing transferrin and ferritin elevation. Genetic screening is recommended for family members. Management requires phlebotomy (or iron chelation therapy in some cases) to prevent disease progression. The presence of hepatic fibrosis is a poor prognostic factor.
  • Porphyrias: group of metabolic disorders caused by a disturbance in the synthesis of heme. In most cases, porphyria is caused by a hereditary enzyme defect. The disease patterns differ depending on the affected enzyme, and the variants of porphyria can be clinically differentiated between acute and nonacute forms. Individuals with porphyria present with photosensitive 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. Structure and Function of the Skin eruptions and sometimes systemic symptoms such as abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and neuropathy. Porphyrias are managed by avoiding triggers, such as sun exposure and consumption of alcohol. When flares occur, therapy is targeted toward symptom relief. 
  • Jaundice: abnormal yellowing of the 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. Structure and Function 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. Etiologies often involve 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 and can be prehepatic, intrahepatic, or posthepatic. Other symptoms of hyperbilirubinemia include pruritus, pale stools, and darkened urine. The diagnosis is made on the basis of 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 imaging. Management is focused on treatment of the underlying condition.

References

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