Lecture 7: Iron Chemistry Flashcards
Where is ferritin stored?
instestinal epithelia
How is Fe3+ transported
Bound to transferrin
Iron homostasis:
cellular uptake:
Storage:
Depletion:
average daily diet contains about 10 to 15mg of iron mainly in the form of the haemo of red meats.
Uptake of iron in the small instestine: FE2+- free bound to to haem
occurs mainly in the duodenum where the ferric iron is reduced to ferrous by intestinal agents.
absorbed ferrous iron is oxidised to the ferric form iron combines with the protein apoferritin
Transient storage as ferritin inside the instestinal epithelia
- Transport in blood: FE3+- bound to transferrin in very high affinity
- Cellular uptake: endocytosis of trasnferrin, release of iron in acidic endosome
- Storage: intracellular ferritin particles
- Depletion: scaled off cells, blood loss, breast milk
Draw the cellular uptake diagram
Lecture slide
What cells and proteins are involved in iron homeostasis
Enterocytes of the proximal small intestine absorb iron
Circulating iron transferrin is taken up by erythrocyte precursors in the bone marrow,
where the iron is incorporated into the heme component of haemoglobin
Hepcidin, the iron-regulatory protein produced by hepatocytes, controls the flow of iron into the plasma
Iron stores are sensed by hepatic sinusoidal endothelial cells, which produce BMP6, a key endogenous regulator of hepcidin expression.
Assessing iron status
Serum iron: measures the level of iron in the liquid part of your blood.
Ferritin: Stored iron in the body
Transferrin or total iron binding capacity:
Transferrin is the main transport protein of iron.
TIBC is a good indirect measurement of transferrin.
Your body makes transferrin in relationship to your need for iron; when iron stores are low, transferrin levels increase, while transferrin is low when there is too much iron.
Transferrin saturation: represents the percentage of transferrin that is saturated with iron.
Souble trasnferrin receptor: Transferrin receptors are present on cell surfaces and are responsible for the internalisation of transferrin resulting in intracellular release or iron.
The amount of soluble transferrin receptor closely reflects iron stores
Disorders of iron metabolism: Iron overload due to what other complications?
Iron overload:
Is the accumulation of excess iron in body tissues.
Iron overload usually occurs as a result of a genetic predisposition to absorb iron in excess of normal.
Iron overload can also occur as a complication of
Other hematologic disorders
Chronic transfusion therapy
Chronic hepatitis.
Excessive iron ingestion.
What are two ways which cause disorder of iron metabolism
Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss (i.e., pregnancy, menstruation or other bleeding.)
When iron absorption exceeds the storage capacity of ferritin molecules, unbound iron may promote free-radical formation in cells, resulting in membrane lipid peroxidation and cellular injury
What is haemochromatosis and causes
Hemochromatosis is a disease that occurs as a result of significant iron overload.
Genetic (HFE gene mutation) or non genetic causes
Effects of haemochromatosis
Accumulates where?
Symptoms?
Excess iron accumulates in organs (particularly the liver, pancreas,
heart), joints, and the pituitary gland.
After several decades of increased iron absorption non-specific symptoms (i.e., fatigue, weakness, joint stiffness) develop, followed by advanced conditions (i.e., arthritis, cirrhosis, liver cancer).
HFE gene mutations codes for what? AND how does this relate to iron overload?
codes for a transmembrane glycoprotein that modulates iron uptake. This protein is highly expressed in intestinal cells at the site of dietary iron absorption.
HFE protein is bound to transferrin receptor and when bound prevents iron from being absorbed and modulates iron absorption. If there is a mutation and the HFE protein is not coded for and thus not present, this allows the transferrin receptor to absorb as much iron that comes to it.
Recent studies suggest that loss of a functional HFE protein leads to increased iron uptake in the intestinal epithelial cell, which results in increased dietary iron absorption.
HFE protein stops iron absorption, makes hepcidin (stop iron export) SO aim is to increase ferritin stores
What is herditary haemochromatosis
Hereditary hemochromatosis is the genetic disease that results
from significant iron overload.
The majority of hereditary hemochromatosis (also known as Type 1 Hemochromatosis) is associated with homozygous mutations in the HFE gene.
Clinical aspects of haemochromatosis (what is tests are elevated)
elevated transferrin saturation,
elevated serum ferritin,
elevated transaminase (indicative of liver disease), or
elevated blood glucose (indicative of diabetes)
Tests confirming haemochromatosis
A. Indirectly by quantitative phlebotomy.
The amount of mobilizable iron removed from the body by weekly or biweekly phlebotomy measures the degree of iron overload and confirming a hemochromatosis diagnosis
B. HFE genotyping.
Genotyping for HFE mutations can provide additional confirmatory evidence that a patient has hereditary hemochromatosis.
Causes of Iron Defiency Anaemia
Diets low in iron
Body changes
An increased iron requirement and increased red blood cell production is required when the body is going through changes such as growth spurts or pregnancy.
Gastrointestinal tract abnormalities
Malabsorption of iron is common after some forms of gastrointestinal surgeries. Most of the iron taken in by foods is absorbed in the upper small intestine. Any abnormalities in the gastrointestinal (GI) tract could alter iron absorption and result in iron-deficiency anemia.
Symptoms of IDA
Fatigue, alteration in mentation, sore tongue, pica, dysphagia
Signs of IDA
Pale skin, spoon nails, smooth tongue, plummer vinson syndrome
How is anaemia related to chronic liver disease (haemorrhage)
A major cause of anaemia associated with chronic liver disease is haemorrhage, especially into the gastrointestinal tract.
In severe hepatocellular disease, decreased synthesis of liver- produced plasma proteins leads to reduced serum levels of several blood clotting factors causing a haemorrhage.
Splenomegaly may lead to secondary haemolysis, an increase in plasma volume, macrocytosis and megaloblastic anaemia.
PORTAL HYPERTENSION (CIRRHOSIS) AND ANEAMIA (haemorrhage)
In some patients with cirrhosis, chronic haemorrhage into the gastrointestinal tract occurs.
Oesophageal and gastric varices and/or portal hypertensive gastropathy may be associated with slow chronic loss of blood into the gut and development of chronic iron deficiency anaemia.
Hypersplenism secondary to portal hypertension is another mechanism of anemia in patients with chronic liver disease. Hypersplenism is when your spleen becomes overactive in doing its job. Its job is to filter out old and damaged cells from your bloodstream. When your spleen becomes overenthusiastic about filtering your blood, it removes too many blood cells too soon, leaving you with a deficit of blood cells (cytopenia)
Defien Thalassemia and what causes it
is an inherited autosomal recessive blood disorder which results in excessive destruction of red blood cells and further leads
to anaemia.
It is caused by variant or missing genes that affect how the body make haemoglobin. People with thalassemia make less haemoglobin and fewer circulating red blood cells than normal result in mild or severe anaemia.
What is alpha thalassemia
Alpha thalassemia is the result of changes in the genes for the alpha globin component in haemoglobin.
Results when there is disturbance in production of α-globin from any or all four of the α-globin genes.
What chromosome codes for alpha, beta, delta and gamma genes for haemoglobin
Alpha - chromosome 16
γ, δ, and β- globin genes are encoded on chromosome 11
What is beta thalassemia?
an autosomal recessive pattern, which means both copies of the HBB(Haemoglobin beta) gene in each cell have mutations.
Iron panel for IDA, Anaemia of chronic disease, IDA with inflammation, Acute phase response and iron overload
IDA Serum Iron: Decreased Serum transferrin/TIBC: Increased Transferrin saturation: Decreased Serum ferritin: Decreased Soluable transferrin receptor: Increased
Anaemia of chronic disease: Serum Iron: Decreased Serum transferrin/TIBC: Decreased Transferrin saturation: Decreased Serum ferritin: Normal Soluable transferrin receptor: Normal
IDA with inflammation
Serum Iron: Decreased
Serum transferrin/TIBC:Decreased (low normal)
Transferrin saturation: Decreased (or normal)
Serum ferritin: Normal
Soluable transferrin receptor: Increased
Acute phase response: Serum Iron: Decreased Serum transferrin/TIBC: Decreased Transferrin saturation:Decreased Serum ferritin: Increased Soluable transferrin receptor: Normal
Iron overload: Serum Iron: Increased Serum transferrin/TIBC: Decreased or normal Transferrin saturation: Increased Serum ferritin: Increased Soluable transferrin receptor: Decreased
How does HFE gene, Hepcidin, Ferroportin, TRF1 all interact in normal and HH conditions
Normal:
The HFE gene makes HFE protein. The HFE protein is bound to transferrin receptor 1, hepcidin production is turned on and therefore ferroportin can not release iron into plasma. As Hepcidin blocks iron export through ferroportin.
When the HFE protein is not bound to transferrin receptor 1, hepcidin production is turned off and therefore iron can leave the cell via ferroportin to plasma.
HH:
The mutated HFE gene causes decreased hepcidin production and therefore ferroportin is not under control and therefore unregaulated iron absorption and release into plasma. Thus, elevated plasma iron levels which are high because of the ferritin being released so more can be absorbed.
Hepcidin: serves to decrease export of iron from cell. So In HH it must be low as in HH there is mass exporting of iron to plasma.
