Heme Synthesis and Degradation

Question 1

What is the function of the gene ALAS1 and on which chromosome is it located?

Answer 1

It is a ubiquitous/housekeeping gene located on chromosome 3

Question 2

What is the rate-limiting step in heme synthesis? What are the reactants and product? Where is it produced?

Answer 2

Synthesis of δ-aminolevulinic acid (δ-ALA) from succinyl-CoA and glycine. It is produced in the bone marrow

Question 3

Which part of the cell do the steps for heme synthesis take place?

Answer 3

The first and last three steps takes place in the mitochondria. The intermediates take place in the cytosol

Question 4

The accumulation of hydroxymethylbilane and intermediates after leads to what?

Answer 4

The accumulation of hydroxymethylbilane leads to photosensitivity

Question 5

What enzyme catalyzes the synthesis of δ-aminolevulinic acid (δ-ALA)?

Answer 5

δ-ALA synthase

Question 6

The synthesis of vitamin B6 and mutations in the ALAS2 gene can cause what?

Answer 6

X-linked sideroblastic anemia

Question 7

Out of ALAS1 and ALAS2, which is erythroid specific and which one is ubiquitous?

Answer 7

ALAS1 is ubiquitous, ALAS2 is erythroid-specific

Question 8

Where is ALAS2 expressed?

In which chromosome is it located?

When is it activated and what regulates its activation?

Answer 8

ALAS2 is expressed in RBC precursors. It is located in chromosome X

Expression is induced only during active heme synthesis. Iron availability regulates it, which prevents the accumulation of porphyrin intermediates

Question 9

What are sideroblasts?

Answer 9

They are abnormal nucleated erythroblasts

Question 10

What is the treatment for X-linked sideroblastic anemia?

Answer 10

Pyridoxine (vitamin B6), which is a cofactor of ALA-synthase

Question 11

What is the function of PGC-1α?

Answer 11

It is a coactivator of nuclear receptors and transcription factors, regulates mitochondrial biogenesis and oxidative metabolism.

It induces the synthesis of enzymes involved in FA oxidation and gluconeogenesis. Insulin and glucose inhibit PGC-1α synthesis because of the decreased demand in cytochromes required for the production of ATP in the liver

Question 12

This disease is due to mutations in ALAD gene

Answer 12

ALAD porphyria

Question 13

This disease leads to the accumulation of succinylacetone, which is a potent competitive inhibitor of ALAD

Answer 13

Hepatorenal tyrosinemia

Question 14

This disease leads to anemia and accumulation of δ-ALA

Answer 14

Lead poisoning

Question 15

What is the action of lead?

Answer 15

It inhibits ALAD activity by displacing zinc atoms from the enzyme

Question 16

What happens in elevated levels of δ-ALA?

Answer 16

Elevated levels of δ-ALA is neurotoxic that can affect both central and peripheral nerve systems, resulting in memory loss and confusion. It can cause hypertension and hyponatremia via increased production of ADH

Question 17

How is hydroxymethylbilane (HMB) produced? What catalyzes the reaction?

Answer 17

HMB is produced by condensation of four porphobilinogen molecules

The reaction is catalyzed by PBG-deaminase (PBGD)/HMB synthase

Question 18

What happens to the final step of the production of protoporphyrin IX? What enhances the reaction?

Answer 18

Introduction of Fe2+. It occurs spontaneously, but very slow. The reaction is enhanced by ferrochelatase

Question 19

This recessive disease is caused by a deficiency of ALA dehydratase in RBC

Answer 19

ALA dehydratase porphyria

Question 20

This disease is caused by the gain of function mutation in ALAS2 gene

Answer 20

X-linked dominant protoporphyria

Question 21

This disease is the most subtype of porphyria. Patients often develop photosensitivity, cutaneous sensitivity is caused by accumulationo f porphyrins under skin, which become phototoxic upon activation by light

Answer 21

Porphyria Cutanea Tardea (PCT)

Question 22

What are the precipitating factors of porphyria?

Answer 22

Illicit drugs: barbituates, sulfa-containing antibiotics, some antiepileptic drugs, progestogens, and synthetic estrogens

Excessive alcohol consumption, heavy exercise schedule, infections, reproductive hormones, smoking, and severe calorie restriction or fasting

Question 23

What is the function of haptoglobin?

Answer 23

Hemoglobin-haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss iron in urine

Question 24

What is the function of hemopexin?

Answer 24

Binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin

Question 25

What happens when there is an imbalance between production and excretion of bilirubin?

Answer 25

It results in its increased plasma concentrations (>3 mg/dL) -- jaundice

Question 26

What can cause jaundice?

Answer 26

Jaundice can be caused by an excessive hemolysis is due to trauma or infection. A failure of liver to transport, store, or conjugate bilirubin. Deficiencies of enzymes involved in bilirubin metabolism. Cirrhosis or hepatitis.

Question 27

What can cause neonatal jaundice?

Answer 27

A combination of two factors: excessive intravascular hemolysis, underdeveloped liver

Question 28

What can cause prehepatic (hemolytic) jaundice?

Answer 28

This can result from excessive hemolysis (beyond the liver’s ability to conjugate it. Excessive RBC lysis can be a result of — autoimmune disease, hemolytic disease of the newborn, structurally normal RBCs (sickle cell disease). High plasma concentrations of unconjugated bilirubin

Question 29

Intrahepatic jaundice

Answer 29

Can be caused by impaired uptake, conjugation, or secretion of bilirubin, reflects a general liver (hepatocyte) dysfunction. In this case, hyperbilirubinemia is usually accompanies by other abnormalities in liver function, it can be caused by viruses, toxins, or genetic errors

Question 30

What can cause posthepatic jaundice? How is it characterized?

Answer 30

Can be caused by an obstruction of the biliary tree. It leads to an increased level of plasma conjugated bilirubin and other biliary metabolites (bile acids). It is characterized by pale colored stools (absence of fecal bilirubin or urobilin). Dark urine is caused by an increased levels of conjugated bilirubin in urine. In a complete obstruction, urobilin is absent from the urine. It can be caused by gallstones or tumors

Question 31

What is hyperbilirubinemia?

Answer 31

Hyperbilirubinemias are inherited disorders in bilirubin metabolism associated with high plasma levels of unconjugated or conjugated bilirubin

Question 32

What is the difference between conjugated and unconjugated hyperbilirubinemia?

Answer 32

Unconjugated — insufficient conjugation due to enzyme deficiency, excessive hemolysis Conjugated hyperbilirubinemia — conjugated bilirubin is more water soluble, conjugated hyperbilirubinemias are less severe in their symptomology than unconjugated

Question 33

What is the disease that has a relatively mild condition characterized by periods of elevated levels of bilirubin in the blood (hyperbilirubinemia) — episodes are usually caused by dehyration, fasting, or illness, usually is recognized in adolescence but 30% have no symptoms

Answer 33

Gilbert syndrome

Question 34

What are the differences between Gilbert syndrome's two inheritance patterns?

Answer 34

It can show two different inheritance patterns — mutations in promoter region — autosomal recessive inheritance while a missense mutation in UGT1A1 gene — autosomal dominant inheritance

Question 35

What disease is a more severe condition of Gilbert syndrome? How is it treated?

Answer 35

Cringer-Najjar Syndrome It can be treated with phototherapy (10-12 hrs/day), liver transplant by the age of 5

Question 36

This disease has an autosomal recessive inheritance — a mutation in both UGT1A1 genes It is characterized by a complete absence or marked reductionin bilirubin conjugation. A severe unconjugated hyperbilirubinemia that usually presents at birth and affected individuals are at a high risk for kernicterus

Answer 36

Cringer-Najjar Syndrome

Question 37

What are the similarities between Dubin-Johnson and Rotor syndromes?

Answer 37

Both disorders are characterized by impaired biliary secretion of conjugated bilirubin, there is a presence of conjugated bilirubin in the blood

Question 38

This disease results from mutations in the ABCC2 gene coding for bile canalicular multispecific organic anion transporter The transporter is involved in the excretion of many non-bile organic anions by an ATP-requiring process Lysosomal accumulation of pigment causes the liver to turn black. It is inherited in an autosomal recessive pattern

Answer 38

Dubin-Johnson syndrome

Question 39

What is the difference between dubbing-johnson syndrome and rotor syndrome?

Answer 39

In the rotor syndrome, the liver cells are not pigmented

Question 40

This disease is caused by mutations in the SERPINA1 gene that can leads to a shortage (deficiency) of protein and lack of control of neutrophil elastase Autosomal codominant 10% of infants develop liver disease, jaundice, adults develop liver damage (cirrhosis — swollen abdomen, feet, or legs, and jaundice) due to the formation of scar tissue in the liver Individuals with A1AD are also at risk of developing a type of liver cancer called hepatocellular carcinoma

Answer 40

Alpha-1 antitrypsin deficiency

Question 41

What causes the majority of neonatal jaundice and why is it especially dangerous?

Answer 41

lysis of large number of RBCs after birth OR immaturity of the enzymes involved in bilirubin conjugation (UDP-glucuronyltransferase) High levels of unconjugated bilirubin are toxic to the newborn because it can cross the not fully developed BBB and damage the brain in infants by increased levels of bilirubin

Question 42

Why is phototherapy effective? How does it work?

Answer 42

Because phototherapy converts unconjugated bilirubin to a move water-soluble, non-toxic form A blue light (420-470nm) converts bilirubin into two other compounds called lumirubin and isolumirubin, which are isomers of bilirubin that can be removed from the body without conjugation

Question 43

What is phenobarbital used for?

Answer 43

Phenopbarbital is often administered to the mother prior to an induced labor of a premature infant. Drug crosses the placenta and induces the synthesis of UDP glucuronyl transferase