Heme/Porphyrin Metabolism/Iron Homeostasis Flashcards
1
Q
generally describe porphyrin/heme/hemoglobin synthesis
A
starts in mitochondria, goes to cytoplasm, then goes back into the mitochondria where protoporphyrin IX is incorporated with iron (Fe2+), making heme. alpha2 and beta2 chains are made in the ribosomes and are incorporated with heme, making hemoglobin
2
Q
what is heme made of?
A
protoporphyrin IX and reduced Fe2+ (ferrous iron)
3
Q
what is hemoglobin made of
A
alpha2 and beta2 globin chains, and heme
4
Q
what is heme a prosthetic group for?
A
hemoglobin myoglobin cytochromes cyclooxygenase catalase cytochrome P450 containing enzymes
5
Q
where is heme degraded?
A
spleen and liver
6
Q
where is heme synthesis
A
de novo in all cells, bone marrow (erythroid progenitor cells) and liver
7
Q
what is reduced form of iron
A
Fe2+
8
Q
what is oxidized form of iron
A
Fe3+
9
Q
what can protoporphyrin IX bind?
A
Fe2+ and F3+
10
Q
what is hemin
A
protoporphyrin IX and oxidized iron Fe3+ (ferric), which cannot bind oxygen
11
Q
how is heme synthesis regulated?
A
heme acts as a negative feedback regulator to inhibit the rate limiting step delta-aminolevulinic acid synthase (delta-ALAS)
12
Q
how is iron incorporated into protoporphyrin IX?
A
ferrochelatase which requires ascorbic acid/vit C and cysteine as reducing agents
13
Q
what is the regulated/committed step of heme biosynthesis
A
when succinyl Coa and glycine are condensed by ALA synthase/B6/PLP to make delta ALA.
14
Q
what is the ALAS1 isoform?
A
delta ALA synthesis in non-erythroid cells (hepatocytes)
15
Q
what is the ALAS2 isoform?
A
delta ALA synthesis in erythroid cells (bone marrow)
16
Q
when is expression of ALAS1 increased?
A
in response to drugs and toxins
17
Q
describe what occurs upon activation of ALA1
A
heme synthesized in hepatocytes is incorporated in cytochrome P450 enzymes, therefore there is increased cytochrome p450 production in detoxification reactions
18
Q
describe activation of ALA2
A
heme made in erythroid cells is committed to hemoglobin synthesis
19
Q
when is expression of ALA2 increased?
A
hypoxia and erythropoietin increases heme synthesis
20
Q
what does what does ALAS2 mRNA contain?
A
iron responsive element in its 5’ untranslated region (UTR) and is responsive to intracellular availability of iron
21
Q
why would a B6 deficiency result in microcytic, hypochromic anemia?
A
B6 is needed for delta ALAS to make delta ALA, a precursor for heme. if delta ALA cannot function, heme cannot be made. therefore, hemoglobin is made with not enough heme, making the RBC small, and less oxygen binding
22
Q
what are acquired disorders of heme synthesis
A
iron deficiency anemia, lead poisoning, B6 deficiency
23
Q
what causes microcytic hypochromic anemia?
A
thassemia, lead poisoning, Vitamin B6 deficiency, iron deficiency - aka problems synthesizing heme
24
Q
what are congenital disorders of heme synthesis?
A
porphyrias (if any enzymes are wrong, no heme), (delta ALAS, ferrochelatase, uroporphyrin III cosynthase, etc)
25
pathophysiology of lead poisoning
lead (Pb2+) is a competitive inhibitor of Fe2+ but doesn't actually get inserted into protoporphyrin IX. therefore, Zn2+ is incorporated into PPIX instead, making zinc protoporphyrin ZnPP. lead also inhibits delta ALA dehydratase and ferrochelatase
26
what is an important indicator of lead poisoning/iron deficiency?
Zn PP (zinc protoporphyrin), bc in the absence of iron or blockage of iron binding, takes the place of iron in protoporphyrin, BUT MOSTLY DELTA ALA IN THE URINE
27
what would you expect to see in lead poisoning?
1. increase in zinc protoporphyrin 2. increase in delta ALA in urine d/t inhibition of delta ALAS - leading indicator of heavy metal poisoning 3. increase in protoporphyrin IX d/t inhibition of ferrochelatase 4. decreased heme synthesis 5. microcytic hypochromic anemia
28
what would you expect to see in B6 deficiency?
won't see increase in delta-ALA, because delta ALA dehyratase is not inhibited, delta ALA synthase is inhibited, so delta ALA won't be made. just decreased heme and microcytic hypochromic anemia.
29
what causes acute intermittent porphyria (AIP)?
dominantly inherited deficiency of uroporphyrin I synthase aka porphobilinogen deaminase aka hydroxymethylbilane synthase
30
prevalence of acute intermittent porphyrin
only 10% of individuals with genetic trait show clinical manifestations, and they are usually late onset.
31
clinical manifestations of AIP
1. excruciating abdominal pain (esp. menstruating women)
2. constipation
3. muscle weakness
4. CV abnormalities
5. agitation, seizures, mental derangement (hallucinations, paranoia, insomnia, anxiety, disorientation)
6. DARK URINE = PORPHYROBILINOGEN IN URINE
symptoms last few days - months.
32
what proteins would be accumulated with AIP?
1. ALA
2. porphobilinogen
IN BLOOD AND CSF
33
what occurs if a person with AIP is treated with sedatives?
this increases cytochrome p450 synthesis via delta ALAS, which depletes the pool of free unbound heme, causing delta ALAS to be unrepressed (active), making the buildup of porphobilinogen`
34
how would a person with AIP be treated?
withdrawal of offending drugs, infusion of hematin (a stable derivative of heme), which represses delta ALA synthase
ALSO carb rich diet bc it represses synthesis of ALA synthase
35
what is the most common porphyria
porphyria cutanea tarda
36
what causes porphyria cutanea tarda?
1. deficiency in uroporphyrinogen decarboxylase
2. alcoholism or liver damage
37
why is iron overload important in porphyria cutanea tarda?
uroporphyrinogen decarboxylase is sensitive to inhibition by iron salts.
38
symptoms of porphyria cutanea tarda
cutaneous photosensitivity - common in older men during summer - sunlight hits uroporphyrinogen III and becomes a free radical
39
what is the difference between acute intermittent porphyria and porphyria cutanea tarda?
AIP produces neurological and abdominal symptoms.
PCT only produces decreased heme and cutaneous sensitivity to light.
40
how is porphria cutanea tarda treate
avoid sunlight, abstinence of alcohol, phlebotomy to reduce iron overload
41
lifespan of RBC
120 days, then degraded by liver and spleen
42
where does most heme come from?
1. RBC
2. turnover of heme containing proteins - cytochrome p450 enzymes, catalase, myoglobin
43
what is heme broken down into?
bilirubin and Fe2+
44
what is the initial reaction of heme catabolism?
cleavage of porphyrin ring by heme oxygenase, producing bilverdin (yellow-green) and CO, and releases oxidized Fe2+
45
what breaks down biliverdin?
biliverdin is broken down into bilirubin by biliverdin reductase in the macrophages (red-orange)
46
how is bilirubin transferred to the liver?
binds to albumin
47
why is bilirubin transported to the liver?
only the liver converts insoluble bilirubin to water soluble bilirubin conjugates by UDP-glucuronyl transferase
48
how is unconjugated bilirubin conjugated in the liver?
diglucuronide to increase water solubility, and allows the conjugated bilirubin to be excreted in urine or bile
49
describe the process of bilirubin breakdown in the liver
1. bilirubin-albumin complex is broken down to bilirubin diglucuronide by UDP-glucuronate in the liver
2. bilirubin diglucuronide (conjugated bilirubin) is excreted into the intestine and is broken down into bile by bacteria
3. bile is broken down into urobilinogen
4. urobilinogen is excreted in the urine or broken down to stercobilin
5. stercobilin is excreted in feces
50
describe breakdown of heme starting in RBC to liver
1. senescent RBC are broken down to release heme
2. reticuloendothelial system (tissue macrophages, spleen and liver) breaks down heme to unconjugated bilirubin
3. unconjugated bilirubin is picked up by albumin and travels through the blood to the liver
4. albumin-bilirubin complex is taken up by facilitated diffusion in the liver, conjugated by UDP-glucuronate (glucuronic acid)
5. conjugated bilirubin is secreted into bile and then the intestine
6. in intestine, bacteria removes glucuronic acid, making urobilinogen
7. some urobilinogen is reabsorbed and enters portal blood.
7b. some urobilinogen participates in enterohepatic urobilinogen cycle.
7c. rest of urobilinogen is transported to kidney, converted to yellow urobilin
8. urobilinogen is oxidized by bacteria to make brown stercobilin
51
what makes urine its yellow color
urobilin
52
what makes feces brown
stercobilin (degraded urobilinogen via bacteria)
53
what causes jaundice (general)
hyperbilirubinemia
54
what would you expect to see in prehepatic jaundice?
increased unconjugated and conjugated bilirubin, caused by hemolysis
55
what would you expect to see with intrahepatic jaundice?
1. pale stool
2. decreased urobilinogen
3. decreased stercobilin
4. decreased conjugated bilirubin
5. increased unconjugated bilirubin
6. increased ALT/AST
56
what would you expect to see in posthepatic jaundice
1. increased conjugated bilirubin in the blood that spills over into the urine
2. decreased stercobilin and biliverdin
3. dark urine and pale stool
4. not making urobilinogen
57
causes of prehepatic jaundice
autoimmune problems, abnormal hg
58
what could cause intrahepatic jaundice?
1. infections like Hep A, B, C
2. chemical/drugs like acetaminophen or alcohol
3. genetic errors in bilirubin metabolism
59
what could cause posthepatic jaundice
1. intrahepatic bile duct problems like drugs, primary biliary cirrhosis, cholangitis
2. extrahepatic bile duct problems like gallstones, pancreatic tumors, or cholangiocarcinoma
60
what genetic conditions could cause increased hemolysis that might cause prehepatic jaundice?
sickle cell anemia, hereditary spherocytosis, beta thalssemia; aka increases in free radicals and RBC destruction
61
what errors of metabolism would cause prehepatic jaundice?
insufficient quantities of pyruvate kinase or G6PD
62
what environmental factors could cause prehepatic jaundice
infections, certain drugs, autoimmune reactions, posions
63
diagnosis of hemolytic jaundice?
1. low levels of haptoglobin - excess Hg binds to haptoglobin and removes haptoglobin from circulation
2. increased unconjugated and conjuugated bilirubin (bc increased hemolysis, increased heme degradation, increased bilirubin production, liver can't handle more than 3000mg/day
64
major cause of hepatocellular (intrahepatic jaundice)
impaired liver function, bilirubin cannot be conjugated, see increase in unconjugated bilirubin
65
explain symptoms of intrahepatic jaundice
bilirubin cannot be conjugated in the liver, so unconjugated bilirubin increases in the blood. cannot secrete unconjugated bilirubin into the bile, so don't see urobilinogen in urine (less yellow pee), and no stercobilin in the stool (pale stools). also increased ATL/AST because liver damage.
66
describe Gilbert's syndrome
1. benign, inherited
2. decreased UDP-glucuronyl transferase activity (not completely deficient)
3. symptoms onset 20's, 30's.
4. minor jaundice, maybe incindental finding
67
treat gilbert's syndrome
small doses of phenobarbital to stimulate UDP glucuronyl transferase activity
68
what causes posthepatic jaundice
obstruction of bile duct due to tumor or bile stones
69
what occurs in posthepatic jaundice?
backup of conjugated bilirubin due to blockage results in abnormal spillage of conjugated bilirubin into blood and excretion into the urine. urine turns dark d/t increase in conjugated bilirubin.
70
symptoms of posthepatic jaundice?
1. increased conjugated bilirubin in blood and urine (dark urine)
2. GI pain and nausea
3. liver damage (late stage)
4. increased unconjugated bilirubin
5. decreased sercobilin, so pale light stools
71
how is total bilirubin measured?
check total bilirubin vs conjugated (direct) bilirubin and subtract the two and that equals unconjugated(indirect) bilirubin.
72
why do some newborn babies accumulate bilirubin?
1. late expression of bilirubin glycuronyl transferase
2. breakdown of fetal Hg as it is replaced by adult Hg
3. hemolytic diseases associated with blood group incompatibilities between mother and child
73
why do premature infants often develop more severe jaunice?
hepatic immaturity, bc of late onset of bilirubin glycuronyl transferase
74
when does glucuronyl transferase reach max expression? (adult levels)
4 weeks
75
why is buildup of unconjugated bilirubin dangerous for baby
is toxic for newborn, because it is hydrophobic so can cross BBB and cause mental retardation called kernicterus
76
what is kernicterus
buildup of unconjugated bilirubin in newborn that crosses BBB and causes mental retardation
77
how is neonatal jaundice treated?
blue fluorescent light that converts bilirubin to more polar compound that can be excreted in the bile without conjugation
78
how do we excrete iron?
men: the shedding of intestinal epithelial cells, feces, sweat
women: menstruation
79
what iron is readily absorbed?
Fe2+ reduced state
80
why is nonheme iron found in plants more difficult to absorb?
this iron is in Fe3+ (oxidized form) and needs vit C to reduce to absorb into our GI tract
81
describe the difference betwen iron absorbed and transported through the body
iron must be absorbed in the ferrous state Fe2+, and then is oxidized by ferroxidase/ceruloplasmin to be able to transport (Fe3+)
82
describe the absorption of dietary iron
1. 10-15mg/day of iron is eaten in diet.
2. apotransferrin binds Fe3+ and becomes transferrin
3. transferrin-Fe3+ carries Fe3+ to cells
4. transferrin-Fe3+ is taken up into the cell by binding to transferrin receptors
5. Fe3+ is stored as ferritin in liver and RBC
6. excess iron is stored as hemosiderin in liver and RBC
83
is ferritin in plasma?
iron in storage form is found in small amounts in plasma, is directly proportional to intracellular iron stores
84
what is the level of ferritin in children and menstruating women?
close to 0g
85
how much ferritin is stored in older men?
sometimes more than 1g
86
what is abnormal accumulation of iron/hemosiderin?
hemosiderosis
87
why is iron transported by transferrin and stored in ferritin/hemosiderin?
it cannot be in a free form since it is very reactive
88
how is iron homeostasis regulated?
controls transferrin receptor and ferritin levels through regulating transcription/translation = aka regulates uptake
89
what occurs when iron stores are low?
liver cell translates transferrin receptor but not the ferritin receptor. this allows iron to be absorbed by the intestine and taken up from blood, but not to be stored, to make available for heme biosynthesis
90
how is transferrin mRNA regulated?
binding of apo-IRP to IRE in the 3'-UTR region STABILIZES the transferrin receptor mRNA and protects it from degradation = HIGH LEVELS OF TRANSFERRIN RECEPTOR EXPRESSION
91
how is ferritin mRNA regulated?
binding of apo-IRP to IRE in the 5'-UTR region of the ferritin mRNA inhibits initiation of translation = decreases ferritin synthesis and expression
92
what occurs when intracellular iron is high?
iron uptake is inhibited
1. downregulation of transferrin receptor
2. increased storage of iron as ferritin
93
what state is IRP bound to iron in? (active or inactive)
inactive
94
what enzyme in heme synthesis is regulated by iron levels?
ALA synthase mRNA is regulated by iron levels. low iron levels increase transcription of ALA synthase. low iron levels decrease expression of ALA synthase so protoporphyrin intermediates don't build up in the blood
95
how can iron deficiency happen
inadequate intake or loss of iron
1. acute massive hemorrhage
2. chronic blood loss (peptic ulcer, hemorrhoids, blood sucking intestinal parasites, tumors)
3. growth
4. pregnancy and lactation
96
what happens to iron levels during pregnancy?
250-300mg of iron is transferred to the fetus during pregnancy
97
what happens to iron levels during childbirth?
80-400mg is lost in the placenta, umbilical cord, and blood loss at birth.
98
what happens to iron levels during lactation?
100-180mg is lost
99
what tests are used to measure iron levels?
1. serum iron
2. serum ferritin
3. transferrin level or TIBC
4. transferrin saturation
100
explain serum iron test
measures amount of iron in blood. however, level in blood may be normal even though amt of iron in body is low. do other tests.
101
explain serum ferritin
since ferritin helps store iron, this could help measure how much of the stored iron has been used. useful in hemochromatosis .
102
explain tranferrin level/TIBC
since transferrin carries iron in the blood, TIBC measures how much of the transferrin is not carrying iron. if iron deficiency anemia, there will be a high level of transferrin that has no iron. HELPFUL FOR IRON DEFICIENCY ANEMIA
103
which 2 tests are most effective for determining iron deficiency?
serum iron levels and TIBC tests to calculate transferrin saturation. (TS = serum iron/TIBC x100)
104
normal Hg in men
13.5 - 17.5 g/dL
105
normal Hg in women
11.5 - 15.5 g/dL
106
what causes microcytic hypochromic anemia
impaired Hb synthesis
107
what could cause microcytic hypochromic anemia
thalassemia, lead poisoning, vitamin B6 or iron deficiency
108
what causes macrocytic normochromic anemia?
impaired DNA synthesis
109
wjat could cause macrocytic normochromic anemia
folic or B12 deficiency, erythroleukemia
110
what causes normocytic normochromic
red cell loss
111
what could be a cause of red cell loss
acute bleeding, sickle cell defects, red cell metabolic defects, red cell membrane defects
112
what is hereditary hemochromatosis (HH)?
autosomal recessive disease, accumulation of excess iron in cells.
113
clinical hallmarks of hereditary hemochromatosis?
1. cirrhosis
2. diabetes
3. cardiac failure
4. bronzing of skin
5. hemosiderin deposits in the liver, pancreas, skin, joints (stores excess iron)
114
where is the mutation for hereditary hemochromatosis
loss of function of HFE (high iron gene) means that there is an increase of absorption of iron by the liver. increases iron uptake by intestine into blood
115
what happens in a normal HFE gene?
HFE binds to transferrin receptor and reduces affinity of receptors for transferrin, this way iron is not transported to the liver or tissues.
116
when would hereditary hemochromatosis express itself?
late onset in the 30's, mostly males. females after menopause.
test ferritin levels
