L53: Diseases of Heme Synthesis and Degradation Flashcards
(32 cards)
What does vitamin B6 deficiency lead to?
Decreased activity of ALAS [1] activity and microcytic hypochromic anemia
What does lead toxicity lead to?
ALA dehydratase [2] and ferrochelatase [8] are affected. delta-aminolevulinic acid (ALA) and Zn protoporphyrin IX accumulate
What is cause of porphyrias?
Defect in enzyme of heme biosynthesis
Describe classification of porphyrias based on site of heme precursor accumulation
Hepatic type - liver; rapid onset of neuropsychiatric symptoms
Erythropoietic type - bone marrow, RBCs, cutaneous photosensitivity
Describe porphyria cutanea tarda
Uroporphyrinogen decarboxylase [5] defects Hepatic type Most common type; usually caused by liver damage Skin symptoms (due to reactive oxygen species generated by photoactivated porphyrinogens) Uroporphyrins accumulate in liver, plasma, urine, stool
Describe acute intermittent porphyria
Porphobilinogen deaminase [3] mutations
Hepatic type
Neurological symptoms, can be severe
Lacks skin disease (porphyrinogens not made)
ALA and porphobilinogen in plasma, urine (darkens on standing)
Describe erythropoietic protoporphyria
Ferrochetelase mutation
Most common erythropoietic type
Mainly skin symptoms
Protoporphyrin accumulates in bone marrow, RBCs, plasma, liver and bile rather than in urine (it is insoluble)
What enzyme converts heme to biliverdin?
Heme oxygenase uses NADP to create biliverdin, releasing iron and CO in the process
Where are bile pigments created?
RES cells: spleen, liver, marrow
What are the differences b/w the heme oxygenases?
HMOX 2 is constitutively expressed. HMOX 1 is rate-limiting and induced by heme, heavy metals, and stress (hypoxia)
What enzyme converts biliverdin to bilirubin?
Biliverdin reductase
What are the 3 forms of bilirubin?
Free - insoluble
Bound - soluble
Conjugate - very soluble
What does bilirubin bind with and where?
With albumin in circulation (in blood)
What is bilirubin conjugated w/ and where?
Conjugated w/ 2 glucose molecules to form bilirubin diglucuronide. Occurs in the liver
What causes dark color in feces?
Stercobilin
What causes yellow color of urine?
Urobilin
What is portal circulation?
Circulation back from intestine to liver
What is taken up by portal circulation?
Urobilinogen
What are the 3 general causes of jaundice?
Pre-hepatic: excessive RBC lysis
Hepatic: impaired or inadequate liver function
Post-hepatic: bile duct obstruction (inadequacy of draining from liver to intestine)
What products increase in pre-hepatic jaundice?
Everything increases since there is increased amount of heme products. Urine is more yellow than normal since higher urobilin content. Stool is darker than normal since higher stercobilin content.
What is hepatic jaundice caused by?
Impaired bilirubin conjugation: neonatal jaundice, Crigler-Najjar and Gilbert sydromes
Impaired deficient transport of conjugated bilirubin: Dubin-Johnson and Rotor syndromes
Both: wide-scale liver damage; liver cirrhosis, viral hepatitis
What is neonatal jaundice caused by?
Developmental impaired bilirubin conjugation
What are Crigler-Najjar and Gilbert syndromes caused by?
Genetic deficiencies of bilirubin UDP-glucuronyl transferase and thus impaired bilirubin conjugation
How are degradation products redistributed in hepatic jaundice?
Since bilirubin diglucuronide can escape into circulation from the liver, feces is paler since less stercobilin is produced. Urine is dark because bilirubin diglucuronide makes its way into the kidneys from circulation and bilirubin diglucuronide itself makes its way into the urine. Urobilin is also higher (why tho?).
