Iron, Porphyrins, and Hemoglobin

Apotransferrin

A beta 1 globulin used to transport of Fe3+ (ferric)

Transferrin

The complex of apotransferrin + ferric iron. This complex transports iron in the blood

Ferritin

The protein that stores iron in the body

Hemosiderosis

Iron overload WITHOUT tissue injury

Hemochromatosis

recessive genetic disorder leading to high iron absorption resulting in bronzing of the skin, cirrhosis, and diabetes. TISSUE DAMAGE

What is another name for Hemochromatosis?

Bronze diabetes

Secondary hemochromatosis

Iron overload caused by external iron overload (transfusions, supplements, hemolysis)

What does serum total iron measure?

The amount of iron bound to transferrin in the blood (Fe3+)

What does TIBC reflect, and how does it change in iron deficiency?

TIBC reflects the total capacity of transferrin to bind iron; it increases in iron deficiency

Which form of the iron binds to transferrin in the blood, and which form is stored in ferritin?

Fe3+ (ferric) binds transferrin; Fe2+ (ferrous) is stored in ferritin and used in cells

What does serum ferritin indicate?

Ferritin reflects body iron stores

What is the role of transferrin and how does its level change in iron deficiency?

Transferrin transports iron in the blood it increases in iron deficiency

How is transferrin saturation (%) calculated, and what does a low value indicate?

% saturation = (serum iron/TIBC) x 100. Low saturation indicates iron deficiency

You see lab results: low serum iron, high TIBC, low ferritin. What is the likely condition?

Iron deficiency anemia

What is the structure of hemoglobin?

A tetramer made of 4 polypeptide chains (2 alpha and 2 beta in adults) and 4 heme groups, each heme containing 1 Fe atom that binds 1 O2 molecule

What hemoglobin variant do people have at birth?

HbF

What chains does HbF have?

2 alpha and 2 gamma

Within how many days after birth does HbF production stop and is replaced by adult hemoglobin (HbA)?

120 days

The rare hemoglobin variant (HbA2) is composed of what chains?

2 alpha and 2 delta

Sickle Cell disease (Hgb S) comes from a defect in the amino acid chain where what amino acid is substituted for glutamine at 6th position?

Valine

Hemoglobin C disease comes from a defect in the amino acid chain where what amino acid is substituted for glutamine at 6th position?

Lysine

What happens in Hemoglobin SC?

1 beta chain codes for Hgb S and the other codes for Hgb C.

What are Thalassemias?

Defects in the rate and quantity of production. Alpha thalassemia is where alpha chain synthesis is reduced or absent. Beta thalassemia is reduced (B+) or absent (B0)

Hydrops Fetalis

Complete absence of alpha chains. Incompatible with life

What is the structure of myoglobin and its main function?

A monomer with 1 heme group, found in muscle, and stores O2. Has high O2 affinity

What is the structure of hemoglobin?

Is a tetramer with 4 heme groups, found in blood, and transports O2

What state does Iron have to be in to transport oxygen?

In the reduced state (Fe2+)

What is methemoglobin?

Hemoglobin with oxidized iron (Fe2+ —→ Fe3+). This cannot bind oxygen

Sulfhemoglobin

Hemoglobin bound to sulfur

Carboxyhemoglobin

Hemoglobin bound to carbon monoxide

Hematin

Oxidized heme, usually released from methemoglobin

What are porphyrins, and how do they relate to heme?

Cyclic organic molecules made of 4 pyrrole rings. When iron is inserted into a porphyrin, it forms heme, the oxygen binding prosthetic group of hemoglobin, myoglobin, and other heme proteins

So what are porphyrins?

Rings inside heme

Porphyrias

Inherited diseases in which a partial deficiency of one of the enzyme of porphyrin synthesis leads to decreased formation of heme resulting in formation of xs quantities of porphyrin precursors or porphyrins

Porphyria symptoms of neurological issues is due to the accumulation of what?

Porphyrin precursors

Porphyria symptoms of photosensitivity is due to the accumulation of what?

Porphyrins

What porphyrin precursor is most responsible for neurological symptoms of porphyria?

d-aminolevulinic acid (ALA)

Why does photosensitivity happen in porphyrias?

Due to the elevated levels of light absorbing pathway intermediates and their degradation products

What enzyme converts heme into biliverdin?

Heme oxygenase

What pigment is formed after biliverdin?

Bilirubin

Is bilirubin initially conjugated or unconjugated?

Unconjugated/indirect

How is unconjugated bilirubin transported in blood

Bound to albumin

Where does bilirubin conjugation occur?

Liver

What is added to bilirubin during conjugation?

Glucuronic acid

Is direct/conjugated bilirubin water or lipid soluble?

Water soluble

How does conjugated bilirubin leave the body?

Excreted in bile through the intestine

What is bilirubin converted into in the intestine?

Urobilinogen

What is urobilinogen converted into in stool?

Stercobilin

What is urobilinogen converted into in urine?

Urobilin

Where does extravascular hemolysis occur?

Spleen and liver

Where does intravascular hemolysis occur?

within blood vessels

What happens to hemoglobin in extravascular hemolysis?

Broken down in macrophages to heme to bilirubin

What happens to hemoglobin in intravascular hemolysis?

Released free into plasma

What proteins binds free hemoglobin in intravascular hemolysis?

Haptoglobin

What urine finding is seen in intravascular hemolysis?

Hemoglobinuria

A high indirect (unconjugated) bilirubin indicates a problem where?

Before the liver (impaired hemolysis) OR liver (impaired conjugation)

A high direct (conjugated) bilirubin indicates a problem where?

After the liver (bile duct obstruction)

Which bilirubin can cause the brain barrier in neonates?

Unconjugated. Can cross and cause brain damage

What is jaundice?

A condition characterized by yellow discoloration of the skin, sclera, and mucous membranes

Hemolytic jaundice

Facilitation of the XS degradation of the red blood cell (Unconjugated)

Hepatocellular jaundice

Unable to form conjugated bilirubin

Obstructive jaundice

Unable to excrete through bile ducts

Why is jaundice so common in neonates?

Due to the increase breakdown of the fetal RBCs as a result of shortened lifespan of fetal RBCs and higher RBC mass in neonates. The liver excretory capacity is low because its nots fully developed. Increased levels of unconjugated bilirubin

Why is Urine bilirubin absent in Hemolytic jaundice?

Because the liver has not conjugated the bilirubin so it remain water insoluble so it cannot appear in urine

Why is urine urobilinogen increased in Hemolytic jaundice?

Increased because more bilirubin has not been conjugated and excreted in urine. So the gut “catches” all the bilirubin converts it to urobilinogen and excretes in urine

Why is urine bilirubin mild in Hepatic jaundice?

Because there is some conjugation possible and it leaks into urine

Why is urine urobilinogen normal/mild in Hepatic jaundice?

Because the bilirubin that has not been conjugated in the liver slips through to the gut and is converted to urobilinogen

Why is urine bilirubin present in Obstructive jaundice?

The conjugated bilirubin leaks into the blood and filtered in urine

Why is urine urobilinogen absent in obstructive jaundice?

Due to obstruction, the bilirubin is not released into gut and so none is formed

What is the Van den Bergh reaction?

Rxn between bilirubin and Ehrlich diazo reagent giving a reddish purple compound

What bilirubin directly reacts with the Erlich reagent?

Conjugated/Direct

What bilirubin does not react directly with the Erlich reaction except after addition of methyl alcohol?

Unconjugated/Indirect

The modified and now widely used reaction is the …

Jendrassik-Grof reaction

How does the Jendrassik Grof reaction distinguish direct bilirubin?

Direct reacts immediately with diazo reagent —→

How does Jendrassik Grof reaction distinguish total bilirubin?

Accelerators added converts indirect bilirubin to react —→ measures total

Why doe we need an accelerator in the Jendrassik-Grof rxn?

Because unconjugated bilirubin in water-insoluble, the accelerator solubilizes it so it can react with diazo reagent