1. PORPHYRIN AND HEME METABOLISM
Porphyrins metal and protein
Hemoproteins
Heme
Hemoglobin
Iron
Globin chains
Protoporphyrin III (IX)
Heme synthesis issues: porphyrias
Heme breakdown issues: jaundice
Iron in the hemoglobin structure can be reused.
The heme group is removed after use. This is referred to as protoporphyrin III (IX).

2. PORPHYRINS NOMENCLATURE Types of substituents Symmetry I or III
Oxidation between rings
Methylene -CH2-
Methene -CH=
Synthesis starts with the formation of a pyrrole ring. Two double bonds and a nitrogen. These are derived from two common precursors: succinate (part of Krebs cycle) and glycine.
When we assemble this, we take four of these rings and make a large organic structure with iron sitting in the center. 8 different substituent possibilities. But only three actually attach to the Cs opposite the N. If the groups attached to the outside of the ring are symmetrical, this is Type I symmetry, Type III is asymmetrical.
The four pyrrole rings are linked by a carbon link. Different names for a methylene or methene connection.

3. Heme Fig.44.2 Page 836 Protoporphyrin III
In this case, there are three different side groups.
Type I and Type III difference in this case – there aren’t evenly arranged CH3.
Always single or double ONLY connections.

4. Reactions for Protoporphyrin IX Fig. 44.3 Page 837
Succinate (activated as a CoA ester) and glycine starts things off. The final product, heme, has a predecessor called protoporphyrin IX. Why isn’t this III? When this work was first begun and they realized that the heme group had three substituents, they didn’t know how they were arranged. A chemist drew out all possibilities and the ninth one he drew was the right one. Thus the IX. At right are the rare, inborn errors of metabolism that can happen at each of these steps.
Here: the final product is a feedback inhibitor for the first step in the process. If final product is not produced, the process keeps pumping along. But in these porphyrias, the wrong stuff is produced and builds up. Nastiness follow. Could be behavioural, too. Color urine, skin lesions.
Most common: porphyria cutanea tarda. They get blisters, may be sensitive to UV light, have prolific hair growth. Werewolf legend: may be a person who had porphyria.

5. Synthesis of d-amino levulinic acid Fig. 44.4 837
Step 1
Synthesis of d-amino levulinic acid
Fig. 44.4
837
Mitochondrial location
Rate limiting
Pyridoxal phosphate (decarboxylase)
Regulation of enzyme levels by iron and protohemin
Heme synthesis occurs in bone marrow. That’s where reticulocytes arise so this is logical. Cells need good, healthy mitochondria for this process to begin. Glycine comes in through a transporter or can be derived from serine.
Need PLP as a cofactor. Rate limiting based on whether or not the protein is there. There is a fast turnover (minutes) – the body is always making ALA when we need it and not making it when we do not.
PLP- metabolism – facilitates decarboxylation in formation of deltaaminolevulinic acid.
Regulated by how much iron is in the cells as well as by how much protohemin end product is about. Fe stimulates synthesis of this. Protohemin: slows/shuts down this cellular machinery.

6. Synthesis of porphobilinogen Fig. 44.5 Page 838
Step 2
Synthesis of porphobilinogen
Fig. 44.5
Page 838
Also called porphobilinogen synthase
Zinc-dependent
Site of lead toxicity
Next step: take two delta-ALA and condense them. Called delta-ALA dehydratase (removes two waters). It relies on Zn. This forms the actual pyrrole ring. Two things stick out –acetate and proprionate. Also, there is a methylene carbon and a nitro group. Porphobilinogen.
Pb toxicity kills this step.
Next: four porphobilinogens are connected.

7. Further Reactions Step 3 Tetrapyrrole formation
synthesis of hydroxymethylbilane
synthesis of uroporphyrinogen III
Step 4 Conversion to protoporphyrin III
uro to copro
copro to proto
porphyrinogen to porphyrin
Step 5 Protoheme synthesis
insertion of ferrous iron
site of lead toxicity
Uro = only acetate and propionate side groups. Done in cytoplasm.
Uro-copro - ?
Copro-proto: get vinyl groups.
After the vinyl groups added, back to mitos. Then the four carbons that hold stuff together are oxidized and the iron is added to make heme from protoheme.
Second lead-tox site is where an enzyme adds the iron.

8. 1 2 3 3 4
Lead poisoning: get delta-aminolevulinic acid buildup. If you see this, there is possibly lead poisoning. ALA cannot condense and spills out into the urine.
If all works well, though, we get porphobilinogen.
Uroporphyrinogen synthase: allows for closure of the ring. Symmetry switch at this point.
Two-groups = copro. Then to mitos.
If more protoheme is needed than is needed for heme synthesis, it accumulates. And then some bad stuff happens.
Ferrochelatase adds the iron, forming protoheme. Protoheme from heme is that protoheme is not yet associated with any kind of a protein (myoglobin, cytochrome, hemoglobin). 4 5

9. Heme Proteins Protoheme (or heme) + globin ~ hemoglobin
Protohemin formation -- formation of superoxide
If too much protoheme is there, sometimes an electron will go from iron to iron III, forming superoxide. Product of this is protohemin. Hemin contains Fe+3. There’s an excess of heme biosynthesis going. This (hemin or protohemin) is our feedback inhibitor
Heme is used in lots of places and in many variations. In protoheme, there’s nothing other than four pyrrole rings around the iron. But other things have different attachments. Cyt C = all six positions are always fixed. Some cases have a +2 (ferrous) or +3 (ferric) iron.
Some cases the side chains have covalently attached side chains, sometimes they just are hydrophobically attached to a pocket.
Variations in heme
Fe ligands 4, 5, or 6
Ferrous or Ferric
Protoporphyrin III attachment to protein

10. Cyt. C = methionine reside attaches the heme to a protein.
Cyt. Oxidase; heme A has a different connection.
Heme b Heme c Heme a

11. Iron-IRE
Iron-IRE (iron regulatory element). In 5’ untranslated region of the gene, iron binding protein binding to this determines whether or not this is translated. Negatively regulated by protohemin accumulation. It represses transcription of the delta-ALA synthase gene. But Iron-IRE stimulates its formation.
Protohemin disinhibits formation of globin from amino acids.
Hydroxymethylbilane synthase (takes single pyrrole to tetrapyrrole) is regulated by production of erythropoietin. This comes from the kidney. People with renal dysfunction have severe anemia due to loss of erythropoietin. So it is give as a supplement at times.

12. Porphyrias Treatment Hematin (hemin hydroxide)
How would you treat somebody with this issue? Maybe treat with the feedback product.
Lesch-Nyhan: failure to use purines properly. To treat, give something that stops biosynthesis of purines.
In this case, give hematin (hemin hydroxide) to slow ALA synthase and the entire pathway.
Colored boxes: one step removed from one another yet the phenotypes are crazily different. Red: irritated skin. Green: from CNS stuff – skipped for now.

13. 1 2 3 3 4 4 5

15. Heme Degradation Fig. 44.7 Page 839
After 120 days, the RBC bites the dust. Taken out of circulation at the spleen. This is the way we want to get rid of RBCs if we don’t want craziness to follow. Otherwise Fenton chemistry could occur.
Bilirubin complexes with albumin, which is further metabolized in the LIVER. Liver disease – there are issues metabolizing heme. Next step: bilirubin diglucuronide: solubilized. This chemical is stored in the gall bladder and excreted into the gut. Thus goeth the heme. Microorganisms in the intestines take this product, fiddle with it and…
Some pigments are reabsorbed back into the blood supply and lost through the urine. This gives our urine color.
Dark brown of feces? Derived from heme breakdown.
Jaundice: yellow from buildup of heme.

16. Reactions Fig Page 840
ONLY PLACE WE ACTUALLY MAKE CO IN METABOLISM!!!!!!
Next: linear tetrapyrrole. Very highly pigmented (dark green).
Biliverdin reductase uses NADPH to produce bilirubin.
Bilirubin: not as conjugated, more orangey-brown.

17. Spleen Macrophages Blood Liver Heme oxygenase Biliverdin reductase
Serum albumin
GSH S-transferase
Bilirubin UDP-glucuronyl transferase
Spleen Macrophages
Blood
Liver
Albumin/bilirubin complex percolates along, reaches the liver, and a series of abundant glutathione-S-transferases act upon the complex. 4-5% of total protein in a liver. VERY abundant. There are ~7 different genes that code for these proteins. Around as homodimers. Two binding sites: hydrophobic things and heme-related stuff. If the bound thing can bind the glutathione, they bond and form an adduct. This is akin to leukotriene biosynthesis. This is another pathway to get rid of drugs. Bromobenzene – would form an adduct, the bromine would be displaced, and detox would follow. Their endogenous nature would be, maybe, healthy liver removing hydrophobic compounds from the blood. Years back, to check liver function something was added to the blood and it was seen how fast the liver cleared it via this pathway. But the MAIN goal of this is to remove bilirubin from albumin and bring it into the hepatocyte.
Spleen macrophages produce biliverdin, then bilirubin.
Blood- transport w/ albumin to liver.
Liver: GSH-transferase sequesters it from blood, and other enzyme conjugates to diglucuronide for removal. Liver not working? There’s an issue with bilirubin metabolism.
Now we need to make it more water soluble. We take hydrophobic bilirubin, and add polar groups to it with B-UDP-G-T. Then it is shipped to the gall bladder and released from there. Tis’ a diglucuronide. Not ALL of it goes to the gall bladder. Indirect reacting fraction: ?????????????????

18. Heme Degradation Features Blood Proteins Reactions Jaundice
hemolytic
obstructive
Neonate kernicterus
liver disease
Gilbert’s disease
Blood Proteins
serum albumin
haptoglobin
hemopexin
Hemolytic: RBCs bust prematurely. Could be Vit. E deficiency.
Obstructive: spleen and liver work, but gall bladder cannot empty. Cholestasis.
Diglucuronide = due to block, not from failure of excretion. One of few cases where there would be high diglucronide.
Indirect reacting: albumin-associated
Direct reacting: free?
Some believe that bilirubin is a potent antioxidant. But in infants, it screws with CNS function. Neonatal jaundice: caused by one of two things – lack of UDP glucuronyl transferase or, more importantly, the fact that neonates have a very high cells (polycythemia) – and have PILES of RBCs switching from fetal to adult hemoglobin. Normally treated by UV light, which breaks up some of the bilirubin, making it more soluble.
Gilbert’s disease: genetic, high fasting bilirubin. Due to a limitation in UDP-glucuronyl transferase. Will show up as a possible liver problem but don’t actually have one.
Crigler-Nager: more sever forms of this Gilbert’s disease. In one case, UDP-glucuronyl transferase is absent. Other form is partial loss of this.
Blood proteins: serum albumin. Critical role in delivering bilirubin to the liver for metabolism. Indirect fraction of bilirubin because you have to extract it inorder to get it it. But the glucuronide reacts directly. Albumin can also bind the heme group if it were to escape, somehow. The Fe would spontaneously oxidize to +3. Must be inisde of cell in a high reducing environment to remain as +2. Binds both bilirubin and hemin.
Haptoglobin: alpha 2 globulin, an acute phase reactant, Lots of IL-6 raise this crazily. Important protein for protecting in event that an RBC breaks open. As soon as hemoglobin present in a RBC is exposed to environment, it forms methemoglobin. Haptoglobin binds methemoglobin readily. And macrophages of liver degrade this stuff.
Hemopexin: like albumin, is able to bind the hemin group. Only hemopexin and hemin bind even tighter. If heme group gets away from protein, this stuff is able to grab right onto that hemin where there is a hemopexin receptor which clears the hemin from circulation. Protects against Fenton issue.

19. Blood So Far Plasma Erythrocyte Hemoglobin Globin chains
Protoporphyrin III
Iron

20. Iron Balance
We have ~4 gm Fe as males, 2.5 grams in females. There are two iron pools. Non-heme (all but heme) and the heme pool (MOSTLY associated with hemoglobin).
Stored in hepatocytes and Kupffer cells. Males typically have 1 g. of Fe in the liver, but females have ~400 mg.
There is some in muscle in the cytochromes and myoglobin (but is not mobile).

21. IRON METABOLISM Fig. 44.6 Page 838
From textbook. To be absorbed, must be absorbed through mucosa of the gut – this is highly regulated. It is bound to transferrin in the blood and is the major plasma iron protein. It delivers Fe to cells that need iron. Transferrin receptor is upregulated when there is an immune response. Transferring also delivers iron to the marrow for hematopoiesis.
If 4 g of Fe in an adult male, there is very, very little in the plasma at any given time.

22. Iron Absorption Low but regulated Ferrous iron conversion needed
Heme iron by separate pathway
Reducing agents aid uptake-vitamin C
Factors in breast milk facilitate uptake (lactoferrin)
We regulate iron level mainly at the level of iron absorption. Other than phlebotomy, we cannot really get rid of it. Other metals (Cu, Zn) have a bile cycle that keeps stuff around. This isn’t true for Fe, and thus we only want to absorb it when we need it. An intricate mechanism controls this.
Daily Fe absorption: 10% of the iron consumed. Chromium – we only absorb 1% of what we take in; this is not because of regulation, however – that’s inherent. But iron taken in is very carefully regulated.
Things that favor formation of Iron II facilitate uptake. We also take up heme iron in a separate, unidentified pathway. Heme iron is more bioavailable than free iron.
Vitamin C (reducing agent) favors ferrous iron and more uptake.
During the life cycle, there are important exceptions to low uptake of iron. Babies can absorb lactoferrin readily. Greater bioavailability. These lactoferrin receptors disappear.
Last two trimesters of pregnancy – the mother ups her iron uptake greatly so that the baby can form.

23. Promoters and inhibitors of non-heme iron absorption
Ascorbic acid
Meat
Citric Acid
Some spices
-carotene
Alcohol
Inhibitors:
Phytic acid
Polyphenols
Tannins
Calcium
Phytic acid is also a zinc antagonist. In some cultures with a bunch of phytate in the dies, they are anemic.
Tannins in tea.
Adapated from Paul Sharp Kings College UK

24. Duodenal iron transport
Fe3+
DRA
Dcytb e-
Fe3+
ferritin e- Tf
Fe3+
Fe2+
DMT1
Fe2+ HO
LIP
Fe2+ Hp
IREG1
heme
DMT1 – divalent metal transporter 1. Pretty specific for iron but can transport others. It is a symtransporter (iron and a proton). The pH in upper small intestine is around Cell cytoplasm is more like 7 – so there is more lumenal hydrogen. HCP-1 is a heme carrier protein. There is something that gets heme from the diet across the barrier into the cell. Once the heme is inside the cell, it is metabolized (heme oxygenase, same stuff as in splenic macrophages that destroys heme) – Fe2+ is released.
Divalent metal transporter A can convert from 3 to 2.
Dcytb: upregulated in iron deficiency – converts from 3 to 2. Same as dietary reducing agents.
Key to regulating iron biology is to regulate all of the above crazy quilt of stuff. Most of the regulation is at the level of feroporetin (IREG-1).
Once iron enters the enterocyte: excreted or stored. If stored, stored as ferritin. This is a large protein comprised ¼ as FeOH. Ferritin can be used in electron microscopy to pick up signals because it is so electron dense. Iron is stored as Fe3 in ferritin. But if the iron really needs to get to the bone marrow immediately, it enters the labile iron pool (LIP) –
DMT1, Dcytb, IREG1 were discovered on the same screen. IREG-1 is known as ferroporetin. It is transports iron outside of these duodenal cells. It is on the basolateral membrane of the absorptive enterocyte. Without it, we cannot get iron to cross the gut. Humans without this become VERY iron deficient. However, it is also know that to get iron COMPLETELY available in the blood plasma requires something other than these. That, shown here, is Hp. Hephaestin (X-linked) Sex-linked anemia is from an issue with this. This protein is highly homologous to ceruloplasmin, a copper enzyme. The function of this protein is dependent on copper. Copper deficiency hinders iron absorption. Hp works as a feroxidase (iron 2 to iron 3 – needs to be in 3 form to be picked up by transferrin in the plasma).
Duodenal cytochrome B.
HCP1
Plasma
Gut lumen
Adapated from Paul Sharp Kings College UK

25. Hepcidin Master Regulator
Liver-produced antimicrobial peptide
Lowers iron absorption by binding to ferroportin, resulting in internalization, and degradation
Expression is COMPLEX and related to liver iron mediated by TfR2 (Iron induces).
Expression increased by IL6
Hemochromatosis is the most abundant genetic disease in caucasians. 1/10 carry. Why do people with this not regulate iron absorption? They don’t eat an iron-high diet but absorb way too much iron. To the point, at times, that they need a liver transplant. The molecule responsible for this is Hepcidin. HEPCIDIN IS THE KEY. Binds to ferroportin, causing ferroporetin to be internalized and degraded. Iron absorption is slowed. So we need to make sure that there is an appropriate level of functional Hepcidin. If iron deficient, we should be able to block Hepcidin formation. It is also the key to getting iron out of our iron stores. It blocks iron mobilization from the RES system (macrophages). Hepcidin – if levels are high, plasma iron drops a lot.
Hepcidin levels are regulated by how much iron there is present in the blood. How do we sense the plasma iron pool? By TfR2 (transferring receptor 2). TfR1 is the most common (lymphocytes, neurons, erythropoietic cells) and brings iron into those tissues. TfR2 is ONLY in the liver and can differentiate between different levels (high, low, medium) of plasma iron. TfR1 will take in ANY iron that it encounters and thus is not a good sensor. TfR2 however is a good sensor. Another one is the hemochromatosis gene, HFE. The hemochormatosis gene is HFE and causes production of hepcidin to be deregulated. This HFE gene is also very similar to the MHC antigen. In addition to its signal being regulated by these other factors, it requires beta2 microglobulin and its specific receptor to function. If beta 2 microglobulin does not work, there is iron overload disease. Expression of this is upregulated by IL-6, a potentiator of inflammaiton. Helps produce PILES of hepcidin. Lots of IL-6 – become iron-deficient anemic. This is cause of the “anemia of chronic disease – moderated by IL-6 and hepcidin. So we should be able to distinguish between anemia and anemia of chronic disease.
Fe, Zn, Cu – present in traces in the plama. All three combined, 100 micrograms/dL. 1 microgram/ml. It is the same for all three of them. But there is way more iron in the human. 4 g Fe, 2 g Zn, .1 g Cu. During an infection, if there is lots of IL-6, the body changes these concentrations of Fe, Zn, and Cu. Zn and Fe go WAY DOWN. Cu spikes up.
Why does copper go up? Because most of copper in plasma is in ceruloplasmin (an acute phase protein) – IL-6 induces transcription of ceruloplasmin genes. Ups 2-3 fold. This may/may not mean anything.
Zn and Fe precipitously drop. Makes sense because both of these are essential to microbes. This starves the microbes. Good to drive them from blood into cells. IL-6 activates a pump (Zip-14) that moves Zn into liver (stored as metallothionine). But what about the iron? Zip-14 may transport iron, too (non-transferrin iron).

26. Iron transport
Steap3
Iron has moved from the enterocyte to transferrin. It is a beta-globulin, weighs 80,000 MW. It only binds two Fe3+. Transferrin either has no iron bound, one iron bound, or two irons bound. If all transferrin is saturated with iron, the blood would have “no iron binding capacity”. Or if there was PILES of iron in the blood w/ free transferrin, that blood has high iron binding capacity. % transferrin saturation is the topic here.
Transferrin in this case is shown with two atoms of bound iron. It meets a plasma membrane receptor called a transferrin receptor. After binding, the complex is taken up into an endosome via receptor mediated endocytosis. Then the vesicle is acidified, and the Fe dissociates from the transferrin. The transferrin can recycle to the surface without being degraded. Released as apotransferring (transferrin with no iron bound). This is how iron gets into bone marrow and other places. The amount of transferrin receptor on the cell surface is very highly regulated. TrR1 has a HIGH affinity for transferrin.
But now we have Fe3+ in this acidic compartment. How does it get to the rest of the cell, including the mitos? It is pumped out of the endosome by divalent metal transporter I (DMT-1) which is found here, not only in the enterocyte! But this thing has an absolute requirement for Iron II. How does it get to Iron III? There is another gene in this process called Steap3, a reductase in this endosome which reduces the Iron so that it can get out via DMT-1.
Succinate dehydrogenase needs some iron, too. Non-heme iron.

28. Iron Storage Ferritin Serum ferritin Hemosiderin
Ferritin: most common in liver but also found in the spleen.
Some can be released into blood where it is known as serum ferritin. This concentration is low compared to that associated with transferrin. Serum ferritin concentration is indicative of the actual total body iron stores. In adult male, 1,000 mg ferritin storage and 400 mg in females. Serum ferritin level is directly proportional to the body ferritin storage levels.
Bad news is that it is an acute phase protein. Serum ferritin is not helpful if there is an infection going on, would not be a good measure for somebody chronically ill.
Hemosiderin: Only made when iron concentration is VERY high. It is 36% by weight iron. Chronic iron overload diseases like hemochromatosis have hemosiderin around.

29. Iron Utilization Heme synthesis Non-heme iron proteins
Iron mobilization is dependent on copper ferroxidases
Ribonucleotide reductase uses iron.
Copper (imagine that) is necesser for stuff like Hephaestin to operate. And other ferroxidases.

30. Iron Mobilization
Shows iron metabolization in a macrophage. We may take in 1 mg from our diet each day, but go through PILES more each day that is recycled. And this is mobilized by splenic macrophages or Kupffer cells that destroy and recycle red blood cells. Iron is broken down by HO, enters labile iron pool and goes either of two ways.
There is no Hephaestin in macrophages. But there is Ferroportin1 that allows the iron to leave. Human beings lacking ceruloplasmin end up with liver iron accumulation disease. Get iron in brain, pancreas.
Ceruloplasmin oxidizes iron from Fe2+ to Fe3+ so it can be transported by ferritin.

31. TfR and Ferritin Posttranscription Regulation Fig. 16. 21 16
TfR and Ferritin Posttranscription Regulation Fig Page 290
Additional
IRE containing
mRNA transcripts
Include :
DMT1
ALA synthase
Ferroportin
Others
Too much iron is toxic to a cell, and it is only brought in when needed. Any extra leftover iron is stored in the cell because free iron is bad. We have an elegant genetic machinery that regulates intracellular iron biology. This is a mechanism where iron can determine whether a transcribed message is translated or not. In a number of genes, there is an RNA stem loop structure referred to as the Iron regulatory element (IRE). In 5’ untranslated region, the IRE is found. If there is low Fe in the cell, the RNA is occupied by IRE-binding protein. The occupancy of the RNA by this binding protein blocks the message from being translated. Low iron- no reason to make ferritin! Makes sense. Conversely, low iron is a reason to bring iron in. This is done by receptor mediated endocytosis, and transferrin receptor is needed. In the same low-Fe situation, IRE is on the 3’ untranslated of the transferrin receptor RNA, and Fe presence allows the transferring receptor RNA to be translated.
In presence of Fe, IRE binds to Fe and it falls off of the ferritin RNA, and the RNA is translated. Fe bound to IRE on transferrin receptor causes it to fall off, allowing that mRNA to be degraded and not translated.
DMT-1, ALA synthase, and ferroprotin have control like this posttranscriptional mechanism, too.

32. Iron Imbalance Excretion Deficiency Toxicity Hemochromatosis
Seconday effects (genetic and environmental)
Excretion of iron is nil. To get rid of it? Phlebotomy. Give blood.
Deficiency can be cause by lots of different things: diet, excessive bleeding, parasites, genetic stuff. Fe deficiency has MAJOR consequences for neonates.
Toxicity:
Thallasemias: hemoglobin is weird and RBCs degrade at the wrong time. Sickle cell anemia is like this, too.
It is rare for a person to have a diet high enough in iron to cause issues.
Certain cultures cook food in cast iron skillets – food with lots of carbohydrates and get lots of iron intake. Or blood eaters and vampires.

33. Ferroportin Hephaestin
Dcytb
Steap 2
DMT1
Ferritin
Ferroportin Hephaestin
Heme Carrier Protein1
Heme Oxygenase
Transferrin
Hepcidin
HFE
(b-microglobulin)
(transferrin receptor)
This is a review of what we’ve talked about today already. To bring iron across the apical enterocyte surface, we need a variety of different transport proteins, incloding duodenal cytochrome B and something else (Steap2, different from Steap 3). DMT-1 brings stuff across.
Ferroportin and Hephaestin work to get Fe out of the basal enterocyte.
There is also stuff for heme moving across.
In blue are some master regulators of iron absorption. Hepcidin fiddles with ferroportin expression.

34. Nutritional Issues-Iron
Deficiency
Causes
Diagnosis
Consequences
Supplementation
Toxicity

35. Causes of Iron deficiency
Pathological blood loss - hookworm
Low bioavailability of iron in food
Infection: more prevalent in developing countries 58% of females in Asia vs 10% of Western females are iron deficient
Being female
Pregnancy
Adapated from Paul Sharp Kings College UK
Hookworm is the most prevalent, or so JoePro made it sound.

36. Consequences of Iron Deficiency
Poor pregnancy outcomes
Increased perinatal morbidity
Defective psychomotor development
Impaired educational performance
Impaired work capacity
Adapated from Paul Sharp Kings College UK
Irreversible if not dealt with during infancy.

37. How do we diagnose iron deficiency
How do we diagnose iron deficiency? The circles show plasma iron concentration.
Triangle = iron binding capacity.
Chronic liver disease – IBP levels are low.

38. Adapated from Paul Sharp Kings College UK
Akin to the previous slide.
Serum ferritin: to distinguish between anemia of chronic disease and iron-deficiency anemia. KNOW THIS.
Some transferrin receptor is released into the blood as a soluble transferrin receptor. In iron deficiency anemia (but not anemia of chronic disease) there is a lot of this on membranes, and thus there is a good amount in the serum.
If, in practice, we order a hemoglobin analysis – frequency distrubution looks like a normal bell curve. But if a histogram was made of iron deficient people, the diagram would be shifted to the left a little bit (less hemoglobin). If a patient comes in with minor hemoglobin deficiency, how do you know they’re not at the low point of their normal range? Give them an iron supplement to see if their hemoglobin goes up. If it does, they were iron deficient. But if their hemoglobin does not go up with supplement, they’re just at the low end of the regular bell curve. This is important in a woman who is thinking of having a family.
Adapated from Paul Sharp Kings College UK

39. Micronutrients-Iron Dietary Recommended Intakes (DRI)
RDAs are gender specific
UL = 40 mg
Male is lower than female.

40. Self-explanatory.

41. Iron Absorption Adapts
Explains the discrepancy between recommendations that are out there in the public health service. (but I don’t know what that means).
Some say there’s no need for iron supplements because the body knows when we should take in more iron.
But women still may need more iron while pregnant.
18 mg is the dietary recommended intake. Some say just make sure women have a diet with enough iron. If supplements are given, hopefully the body just drops the percent absorption to accommodate. 24
Post Delivery
Weeks of Gestation
Barrett et al., 1994

42. Micronutrients-Iron Food Sources Toxicity Concerns
Supplementation Needed?
Iron is found in anvils, railroad rails, nails, and hammers, meatloaf, Dr. Prohaska’s glasses frame, among other things.

43. Not much iron in cow’s milk.

44. Key of this is shown up top
Key of this is shown up top. There is some elusive thing that enhances iron availability when ingested in the heme form. There’s some “meat factor” that enhances availability of the iron. If you’re a strict vegan, you know you need iron supplements.

45. Young Women Iron Zinc Copper EAR, mg 8 6.8 0.7 Age 14-18 % Below EAR16 26
Age 19-30 15 13 11
National health and nutrition education surveys (NHANES, not associated with undergarments).
EAR = estimated annual requirement. Not recommended intake, but the requirement. Recommended intake is greater than this. For example, needed copper is .7 but recommended is .9.
A fair number of women are below the EAR.
Zn/Cu/Fe – may have issues with neurological damage if we don’t get enough (but I didn’t hear if this is important for adults, too).

46. Supplements Necessary?
Has iron and extra zinc. But they forgot copper. So says Prohaska.
High levels of Fe and Zn antagonize copper. So remember this.
Some review questions: