Heme Metabolism Flashcards
Heme Synthesis Step 1
•mitochondria
- succinyl CoA + glycine —> delta aminolevulinic acid (ALA)
- catalyzed by aminovulinate synthase (ALA synthase) RATE LIMITING
- pyridoxal phosphate - B6 derived prosthetic cofactor
Heme Synthesis Step 2
•ALA is transported from the mitochondria to the cytosol
- 2 ALA dimerized —> porphobilinogen (PBG)
•ALA dehyratase aka porphobilinogen synthase
Heme Synthesis Step 3
•cytosol
- 4 PBG condensed —> hydroxymethylbilane
•PBG deaminase aka uroporphinogen I synthase
Heme Synthesis Step 4
•cytosol
4a. hydroxymethylbilane —> uroporphyrinogen I
•spontaneous reaction
4b. hydroxymethylbilane —> uroporphyrinogen III
•uroporphyrinogen III synthase
Heme Synthesis Step 5
•cytosol
5a. uroporphyrinogen I —> coproporphyrinogen I
5b. uroporphyrinogen III —> coproporphyrinogen III
•uroporphyrinogen III decarboxylase
Heme Synthesis Step 6
•coproporphyrinogen III transported into mitochondria
- coproporphyrinogen III —> protoporphyrin IX
Heme Synthesis Step 7
•mitochondria
protoporphyrin IX —> heme
•ferrochelatase incorporates Fe2+
Rate Limiting Step of Heme Synthesis
- The rate-limiting and regulated step in heme synthesis is ALA synthase whose activity is inversely related to the concentration of heme and hemin (ferric Fe3+ as the metal ion).
- Additionally, hemin inhibits the synthesis of the enzyme as well as the transport of the enzyme from the cytosol, where it is synthesized, into the mitochondria.
Heme Synthesis - Lead Poisoning
- The ferrochelatase, ALA dehydratase, and ALA synthase enzymes are all sensitive to the toxic effects of lead, especially ferrochelatase.
- Consequently, primarily protoporphyrin will accumulate in patients subjected to lead poisoning.
- Additionally high levels of coproporphyrinogen III may be found.
- General symptoms include microcytic anemia due to reduced production of hemoglobin as well as GI and kidney disease.
- In children, exposure to lead typically results from consuming lead paint chips and leads to mental deterioration.
- In adults, exposure is typically environmental and is associated with headaches, memory loss and demyelination.
- Chelating agents to remove the lead are used for treatment.
Heme Synthesis - Acute Intermittent Porphyria
- AIP, an autosomal dominant disorder, is caused by defective PBG deaminase causing urinary PBG to become markedly elevated.
- Additionally urinary ALA can be increased.
- A major symptom is abdominal pain of unexplained origin.
-Healthcare personnel lacking knowledge of AIP have diagnosed acute abdominal emergency with unnecessary operation performed.
- Other presenting symptoms can include reddish brown urine due to porphobilin, polyneuropathy, itching, painful skin erythema, skin blisters and psychological disturbances.
- Patients may also exhibit hyponatremia, hypochloremia and azotemia (excessive amount of nitrogen-containing substances in the blood].
- The most effective treatment is IV therapy with hemin to inhibit the ALA synthase reaction.
- For very mild attacks [mild pain, no paresis or no hyponatremia], glucose therapy may be effective.
Heme Synthesis - Porphyria Cutanea Tarda
- A defect of uroporphyrinogen III decarboxylase (UROD) causes porphyria cutanea tarda, the most common porphyria, which is inherited as autosomal dominant.
- Uroporphyrin accumulates causing the urine to be tea-colored.
- The prevailing symptom is blistering cutaneous sensitivity especially of the hands and forearms.
- Additionally changes in hair growth and pigmentation may occur.
- The primary defense for photosensivity is avoiding exposure to sunlight.
- Alcohol consumption must be eliminated and ceasing tobacco smoking is highly recommended.
- Because of the adverse effects of estrogen on porphyrin metabolism, estrogen use should be discontinued with potential reinstitution if disease remission is achieved.
- Because iron stores can inhibit UROD especially in patients with a heavy iron burden, therapeutic phlebotomy may improve heme synthesis.
Heme Synthesis - ALA Dehydratase Deficiency Porphyria
- ALA dehydratase deficiency porphyria (ADP) is an autosomal recessive disorder unlike AIP, an autosomal dominant disorder.
- ADP is the least common of the porphyrias.
- Activity of ALA dehydratase [PBG synthase] is very low leading to markedly reduced production of porphobilinogen with excessive excretion of ALA.
- As with AIP, symptoms include abdominal pain and neurological symptoms.
- Measurement of urinary PBG allows one to distinguish between the two diseases, as this is only excreted with AIP.
Heme Synthesis - Congenital Erythropoietic Porphyria
- Congenital erythropoietic porphyria (CEP), also known as Gunter’s disease, is inherited as autosomal recessive and is extremely rare.
- The defective enzyme is uroporphyrinogen III synthase.
- A defect at this step increases the spontaneous formation of uroporphyrinogen I that is then decarboxylated to coproporphyrinogen I.
-Hence both of these unique porphyrins appear in the urine of these patients.
- Usually symptoms begin during infancy though with milder cases symptoms may not begin until adulthood.
- As with porphyria cutanea tarda, skin photosensitivity can be extreme leading to blistering, severe scarring and hair growth.
-Phototoxic damage can cause loss of facial features and fingers.
- Because synthesis of heme is diminished activity of ALA synthase is increased causing early intermediates to increase even more so.
- Blood transfusions and perhaps removing the spleen may reduce porphyrin production by the bone marrow
Heme Synthesis - Variegate Porphyria
- Variegate porphyria results from a defect in the enzyme that produces protoporphyrin, protoporphyrinogen oxidase.
- Like AIP it is inherited as autosomal dominant.
- It produces severe, acute but usually not long-lasting symptoms. Many patients with this disorder never exhibit symptoms.
- Acute attacks, as with AIP, are associated with abdominal pain along with vomiting, diarrhea or constipation.
-During an attack, the patient may exhibit muscle weakness, anxiety and even hallucinations.
•Signs and symptoms rarely begin in infancy or early childhood. Children with this disorder may have mental retardation.
Iron Absorption
•Iron is an essential trace metal in the diet due to its obligatory role in a variety of metabolic processes.
-In the diet, iron is present in different forms. These are generally heme iron from hemoglobin and myoglobin in animal tissues and non-heme iron, including ferric oxides and salts, ferritin and lactoferrin).
•Iron can be absorbed in either of these forms in the duodenum.
-Iron is absorbed in its reduced (Fe2+, ferrous state) in the duodenum.
- When nonheme iron is ingested in its oxidized ferric (Fe3+) state, ferric reductase first reduces it to the ferrous state.
- Absorption of the nonheme and heme forms occurs via the divalent metal transporter and endosomes or via the heme transporter, respectively.
- Heme oxygenase releases ferrous iron (Fe2+) from the heme moiety.
- The ferrous iron first can be oxidized to Fe3+ and bound to transferrin within the intestinal cell.
- Alternatively, the Fe2+ can be transported into the blood by ferroportin and hephaestin.
•In the blood the Fe2+ is oxidized to Fe3+ before binding to plasma transferrin. There may be a second minor absorption site near the end of the small intestine.
Disorders of Bilirubin Metabolism - Hemolytic Anemia
- Jaundice from hemolysis results from the accelerated destruction of red blood cells.
- Clinical examples include hereditary spherocytosis, sickle cell disease, or in hemoglobin turnover in newborns.
- Because of the increased catabolism of hemoglobin, the production of bilirubin markedly increases. Since there is no block in bilirubin conjugation and excretion, the amount of bilirubin diglucuronide excreted into the intestine increases.
- However, the amount of bilirubin produced far exceeds the conjugating capacity of the liver, especially in newborns, leading to a predominantly unconjugated hyperbilirubinemia.
- Production of bilirubin-UDP glucuronyltransferase is physiologically delayed in most newborn infants and results in the “physiologic jaundice” seen during the first week of life.
- Since unconjugated bilirubin is deposited in the skin, irradiation of jaundiced infants with blue light, which causes photolysis of unconjugated bilirubin to water soluble products, has proved to be therapeutically effective in lowering bilirubin levels.
- The capacity of the liver to conjugate bilirubin increases rapidly during the first few days of life and most infants are no longer jaundiced by the second week of life.
Disorders of Bilirubin Metabolism - Liver Damage (Hepatitis)
- With liver damage, there may be destruction of hepatocytes.
- Clinical examples include infectious hepatitis and acetaminophen (Tylenol) poisoning.
- Jaundice results from an impaired capacity to conjugate and secrete the bilirubin diglucuronide into the bile.
- The indirect van den Bergh reveals high levels of unconjugated bilirubin.
- There is, however, usually some residual hepatic capacity to conjugate bilirubin so a mixed hyperbilirubinemia is usually found depending on the degree of liver cell destruction.
-This occurs because not all of the conjugated bilirubin can be excreted by the damaged hepatocytes causing it to exit the cells into the blood.
Disorders of Bilirubin Metabolism - Obstruction of the Biliary Passage
- With bile duct obstruction, there is failure of bile to reach the lumen of the bowel.
- A clinical example would be a gallstone stuck in the lumen of the bile duct.
- In the early stages of this disease, while liver function remains normal, the liver secretes conjugated bilirubin resulting in a marked direct hyperbilirubinemia.
- Prolonged biliary obstruction results in liver damage, so that values obtained by the indirect as well as the direct assays are both elevated.
- Stools are clay-colored and conjugated bilirubin is excreted in the urine in large amounts darkening its color.
