Chapter 21: Disorders of Haem Metabolism: Iron and the Porphyrias

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Welcome to the Deep Dive.

If you are feeling maybe a little overwhelmed by your clinical biochemistry notes right now.

Which is completely normal, by the way.

Oh, the right place.

Our mission today is basically a one on one last minute tutoring session.

Yeah.

We are covering chapter 21 of clinical biochemistry and metabolic medicine, the eighth edition,

specifically everything you need to know about the incredibly intricate world of ham and iron metabolism.

It's a big topic.

It is.

We're going to look at how these microscopic systems function normally and what happens in the clinic when they fail.

And we are covering some fascinating ground today.

We will be exploring everything from why a specific tiny enzyme deficiency might have caused the historical madness of King George III.

Which is a wild story.

Right.

To exactly how a modern clinician tracks down hidden gastrointestinal bleeding just by looking at a very specific set of laboratory values.

I was looking through this material earlier and the sheer number of ways these physiological systems can break down is, well, it's terrifying, but also kind of brilliant once you see the patterns.

It really is.

We're going to break down these complex pathways into easily digestible aha moments.

So you can walk into your exam or your clinical rotation feeling completely confident.

So grab a coffee, get comfortable, and let's get started with the foundation.

Normal ham metabolism.

They're good.

First things first, where and how does our body actually make ham?

So it happens in a few key places.

In the bone marrow, ham is synthesized and incorporated into hemoglobin, which is the iron -containing pigment carrying oxygen from your lungs to your tissues.

And in your muscles.

In your muscles.

It gets incorporated into myoglobin.

And quantitatively, the liver is the major organ outside the bone marrow that produces ham.

It uses it to synthesize cytochromes for the electron transport chain.

But there is a massive critical rule for ham's oxygen -carrying ability, right?

The iron inside it absolutely must be in the ferrous state.

Exactly.

F2 plus 6.

That ferrous state is non -negotiable for carrying oxygen.

And eventually, those red blood cells reach the end of their lifespan and are broken down by the reticular endothelial system.

Mostly in the spleen.

Yes.

The body is incredibly efficient here.

The globin peptide chain just goes back into the general protein pool to be reused.

Oh, nice.

Yeah.

And the ham ring itself is split open by an enzyme called hame oxidase to form a linear molecule called biliverdin.

The iron is released and recycled, while that biliverdin is reduced into lipid -soluble bilrubin.

Okay, let's unpack this biosynthesis pathway.

Because understanding how the body builds hame from scratch is essential for understanding the crazy diseases we will talk about later.

Definitely.

Think of this process like a precarious factory assembly line.

It starts simply enough.

Glycine and succinate condense to form 5 -aminolivulic acid, or ALA for short.

That very first step on the assembly line is the most important one to remember.

It requires pyridoxal phosphate and is catalyzed by an enzyme called ALA synthase.

You want to highlight this in your brain.

ALA synthase is the rate -limiting step of the entire synthetic pathway.

It's the boss of the factory.

Exactly.

Because it sets the pace, it is heavily regulated by negative feedback from the final product, hame itself.

So if the body has enough hame, it sends a signal back to ALA synthase to slow down.

Spot on.

And if hame levels drop, that break is released, and ALA synthase goes into absolute overdrive to make more.

So the factory line speeds up or slows down based on demand.

Once we have ALA, the line keeps moving.

Two molecules of ALA condense to form a molecule called porpobalinogen, or PBG.

Right.

Then four molecules of PBG combine to form a ring called europorpharinogen.

And just a quick note, the body forms a couple of different isomers, but the major pathway uses the type 3 isomer to create this structure.

Right.

The type 3 isomer.

This leads to coproporpharinogen, then protoporpharin, and in the very last step, an Fe2 plus iron ion is dropped right into the center of the ring to finally form hame.

Take four of those hame molecules, link them covalently to four polypeptide chains, and boom, you have a functional hemoglobin molecule.

But the problem arises when there's a bottleneck on that factory line.

Excess intermediate molecules have to go somewhere, and how they exit the body gives clinicians massive visual clues.

How so?

Well, the early precursors, ALA and PBG, are water soluble, so they are flushed out in the urine.

Normally they are completely colorless.

However, PBG can spontaneously oxidize when exposed to air and light to form europorpharin, which is dark red.

Wait, so a patient could provide a urine specimen that looks completely normal yellow, but if a nurse leaves it sitting on a well -lit benchtop, it will literally turn blood red over time.

It is a stunning visual, and it is a massive clinical clue that intermediates are backing up in the hame pathway.

That is wild.

Now, before we move off of hame, I saw a lot of notes on hemoglobin variants.

Sometimes other things bind to hemoglobin, or the iron changes state, ruining the oxygen carrying capacity.

Carbon monoxide is the famous one, creating carboxyhemoglobin.

Why is it so lifeful to this process?

Hemoglobin actually has a much greater affinity for carbon monoxide than it does for oxygen.

It essentially hijacks the molecule.

Wow.

Yeah, the blood turns a distinct cherry red, and consciousness is lost when about 50 % of the oxyhemoglobin is replaced by it.

Then there is methemoglobin.

That's when the iron oxidizes, right?

Exactly.

The iron in the center is oxidized from that crucial F2 plus state into the ferric F3 plus state.

It turns brown, and it simply cannot carry oxygen.

This can be triggered by common drugs like sulfonamides or nitrates, causing severe tissue hypoxia and a bluish tint to the skin called cyanosis.

There is a really dangerous clinical trap here regarding pulse oximeters, right?

A vital one to remember.

A standard pulse oximeter will misleadingly read about 85 % oxygen saturation in a patient with high methemoglobin, regardless of how little oxygen is actually reaching their tissues.

Oh, wow.

You cannot rely on that basic monitor if you suspect this condition.

Good to know.

We also have methemalbumin, which is also brown.

It forms during severe intravascular hemolysis, or acute hemorrhagic pancreatitis, when the normal protein that binds free hemoglobin haptoglobin is totally overwhelmed.

Correct.

Then there is sulfhemoglobin, caused by certain drugs interacting with hydrogen sulfide in the gut, which permanently damages the molecule.

Finally, there is myoglobin.

It's normally safely tucked inside your muscles, but if muscle cells are crushed in a trauma or damaged in a heart attack, myoglobin dumps into the plasma.

Because it's a very small molecule, it's rapidly cleared by the kidneys.

So we know hemo super power comes from that single iron atom dropped into its center.

But how does the body actually manage its supply of that iron?

This brings us to the iron banked account.

The human body holds about 50 to 70 millimoles, roughly three to four grams, of total iron.

But free iron is highly toxic.

It acts like a wrecking ball, generating dangerous free radicals.

So the body keeps it strictly bound to proteins.

It's tightly controlled.

Very.

Think of your total iron like your financial portfolio.

About 70 percent is your active checking account, constantly circulating in your erythrocyte hemoglobin.

Up to 25 percent is locked away in your savings account within the spleen and bone marrow.

This savings is stored as either ferritin or hemocytorin.

And pathologists actually use a potassium ferrocyanide stain, the Prussian blue reaction, to visually assess these hemocytorin iron stores.

Right.

Finally, there is the tiny amount of cash in your wallet, the transit pool.

Only about point one percent of your total body iron is circulating in the plasma at any given moment, bound to a transport protein called transferrin.

Controlling that entire bank account relies entirely on absorption of the door, not excretion.

We absorb iron via an active process in the duodenum.

To keep the club safe from free iron toxicity, the gut uses a system of bouncers and locked doors.

I love that analogy.

Free V2 Plus enters the gut cells via a transporter called DMT1 and hand -bound iron enters via HCP1.

Once inside the intestinal cell, that iron wants to enter the bloodstream.

It has to exit through a cellular doorway called ferroportin.

But the body doesn't just leave that door wide open.

Not at all.

There's a master regulator, a bouncer protein called hepcidin.

Hepcidin actively inhibits ferroportin.

Oh, okay.

When your body's iron stores are fully stocked, hepcidin levels rise, locking the ferroportin doors and forcing the iron to stay in the gut cell until it's naturally shed.

Another protein, HFE, acts like the club manager, helping to regulate this hepcidin production.

And keeping with the financial analogy, the daily transactions are incredibly small.

We only absorb about one milligram of iron a day, which is maybe 10 % of the iron in our diet.

That tiny amount is the loose change in your pocket and it perfectly replaces the one milligram of loose change we lose daily just from the natural shedding or disclamation of skin and intestinal cells.

Exactly.

Because we don't have a dedicated excretion pathway for iron and our storage accounts are so vast, you can't go bankrupt in a day.

If you went on a striply zero iron diet today, it would take you about three years to actually become iron deficient from that daily one milligram loss alone.

Once it does get absorbed, iron is transported through the plasma in the Fe3 plus form attached to transferrin.

Normally transferrin is only about one third saturated with iron.

What is highly relevant for clinical testing is how wildly that plasma iron concentration can fluctuate.

It is so noisy.

Plasma iron is generally higher in men than women.

It fluctuates wildly from day to day due to stress or diet.

It even has a circadian rhythm, peaking much higher in the morning than in the evening.

Because of all this physiological noise, simply ordering a plasma iron lab test is a pretty terrible way to diagnose iron deficiency.

To really see what's going on, clinicians rely on a specific set of lab markers.

When we measure plasma transferrin, we often look at the total iron binding capacity, or TIBC.

If a patient has simple iron deficiency, the body is desperate, so it manufactures more transferrin to catch any available iron.

That means the TIBC goes up while the actual plasma iron is low.

Then we look at ferritin, the main storage protein.

A normal plasma ferritin is around 100 micrograms per liter.

If it drops below 10, that definitively proves the iron savings account is entirely empty.

You have iron deficiency.

Here's where it gets really interesting.

There is a massive trap with ferritin.

It is an acute phase protein.

That means if a patient has any underlying inflammation, an infection, malignancy, or liver disease, their ferritin levels will shoot up defensively, even if their actual iron stores are completely empty.

The inflammation perfectly masks the deficiency.

So how does a clinician tiebreak a chronically ill patient who might also be iron deficient?

You look at the soluble transferrin receptor, or TFR.

Cells that are starving for iron put out more of these receptors on their surface to catch whatever transferrin floats by.

Unlike ferritin, TFR does not rise with the acute phase inflammatory response.

So if TFR is high, the cells are truly iron -starved, giving you a clear answer regardless of what the inflammation is doing to the ferritin.

So what does this all mean for an actual patient sitting in an exam room?

Let's look at what happens when these systems break down, starting with iron overload.

Take the first clinical case.

A 46 -year -old man in the hepatology clinic presents with abnormal liver function tests and newly diagnosed type 2 diabetes.

His lab results come back, and his ferritin is a staggering 2343 micrograms per liter.

His transfer and saturation is maxed out at 95%.

If we connect this to the bigger picture, this is a classic presentation

of primary or hereditary hemochromatosis.

This is most commonly caused by a genetic mutation in that HFE club manager gene we mentioned, specifically the C282Y mutation.

Because HFE is mutated, the hepcidin bouncer isn't regulated properly, the ferroportin doors stay wide open, and the gut just absorbs iron continuously for decades.

And because it's a primary overload, the iron deposits differently than in other conditions.

It causes parenchymal iron overload, flooding the actual functional cells of the organs, it damages the pancreas causing the diabetes, it deposits in the skin causing a grayish bronze pigmentation, which is why it historically was called bronze diabetes, it shreds the liver causing cirrhosis, and deposits in the heart causing cardiomyopathy.

And the treatment for this modern genetic disorder feels incredibly medieval.

We literally prescribe bloodletting.

It is essentially medicinal bleeding called venus section.

Each 500 milliliter unit of blood removed takes about 250 milligrams of iron out of the body.

You just keep drawing blood regularly until their ferritin drops below 100.

We do have contrast this with secondary iron overload, which you see in patients with conditions like salicemia major.

They get overloaded because they require constant life -saving blood transfusions.

For them, you absolutely cannot do venus section because they're already profoundly anemic.

That makes sense.

Instead, you have to use an iron chelating agent like dysphoriaxamin to bind the iron so it can be excreted.

You can also see dietary iron overload in very specific circumstances, famously in populations brewing traditional beer and iron drums, though that primarily deposits in the reticulo endothelial storage system rather than destroying parenchymal cells.

Let's look at the other extreme, investigating iron deficiency.

We have a 64 -year -old woman presenting with weight loss, tiredness, and loose stools.

Her hemoglobin is low at 9 .0.

Her mean crepuscular volume, or MCV, is 70, meaning her red blood cells are microcytic, are visibly too small.

Her mean crepuscular hemoglobin is 23, so they are hypochromic, appearing pale under a microscope.

Her ferritin is 7, and her TIBC is elevated at 60.

That ferritin of 7 micrograms per liter definitively proves her iron stores are depleted.

She has iron deficiency anemia.

But the most critical lesson for any future clinician looking at these labs is never just prescribe an iron pill and send them home.

You must ask why a 64 -year -old woman is completely drained of iron.

We established earlier with our loose change analogy that it takes years to deplete iron stores just from a poor diet alone.

You have to find the source of the hidden bleeding.

For this patient, fecal occult blend tests were positive.

A subsequent colonoscopy revealed a carcinoma at her descending colon.

The iron deficiency wasn't just a nutritional quirk, it was the physiological alarm bell for her cancer.

Once you address the root cause, you treat the deficiency with oral iron supplements.

You generally avoid parenteral or intravenous iron unless absolutely necessary because it carries a real risk of severe anaphylaxis.

We've seen what happens when the iron bank account goes haywire, but what about when that Haem factory assembly line we talked about earlier completely breaks down?

That brings us to the rare and fascinating world of the porphyrias.

These are a group of rare disorders caused by a deficiency in one of the specific enzymes in the Haem biosynthesis pathway.

Here's the mechanism you need to understand.

Because there is an enzyme block, the factory can't produce enough Haem.

Because Haem levels drop, that negative feedback break on the boss, ALA synthase, is lifted.

So ALA synthase goes into overdrive, desperately trying to make more Haem.

This causes a massive toxic overproduction and accumulation of all the precursor molecules that occur before the enzyme block, spilling out onto the factory floor.

Clinically, we divide these into two main groups, the acute porphyrias and the cutaneous non -acute porphyrias.

The acute porphyrias are almost all autosomal dominant genetic conditions.

They include acute intermittent porphyria, or AIP, hereditary copra porphyria, and variegate porphyria.

Patients usually have latent phases where they feel completely fine.

Interrupted by acute phases where the biochemical buildup becomes highly toxic.

Let's look at a clinical presentation.

A 17 -year -old woman comes to the hospital with severe colicky abdominal pain.

The surgeons suspect appendicitis, they do a laparotomy, but find absolutely nothing wrong in her abdomen.

But post -operatively, her blood pressure spikes massively to 170 over 120.

They screen her urine and her PBG is a massive 213 micromoles per liter.

What happened here?

This is a textbook acute porphyric attack, specifically acute intermittent porphyria, caused by a deficiency in the enzyme PBG -diminase.

The symptoms are primarily neurological and abdominal, caused by the direct toxic effects of massive amounts of ALA -BBG circulating in the nervous system.

What's terrifying is that the surgery itself acted as the trigger.

Because of the anesthesia.

Exactly.

Certain drugs, particularly barbiturate anesthetics given during surgery,

powerfully induce ALA synthase activity.

The doctors unwittingly threw gas on the fire.

Other common triggers include alcohol, acute infections, or changes in estrogen levels.

The treatment protocol here is to immediately stop any provoking drugs and administer hame arginate intravedously.

This provides the external hame the body is desperately trying to make, thereby restoring the negative feedback loot and shutting down that out of control ALA synthase.

Then we have the cutaneous porphyrius, where the symptoms manifest on the skin.

The most common of all the porphyrias is porphyria cutanea tarta, or PCT.

In PCT, a later enzyme, uroporphyrinogen decarboxylase, is deficient.

The classic presentation is a patient whose skin is incredibly sensitive to minor trauma, specifically developing intense blistering on the sun -exposed backs of their hands.

And while it can be genetic, it's usually acquired, triggered by liver -stressing factors like alcohol abuse, high -dose estrogens, or hepatitis C.

Their urine uroporphyrins will be highly elevated.

Yes.

Congenital erythropoietic porphyria is incredibly severe, causing massive photosensitivity and hemolytic anemia.

And because of the specific chemistry of porphyrins, they actually deposit in the bones and teeth.

Wait, their teeth literally glow pink.

They do.

Under ultraviolet light, the accumulated porphyrins cause the teeth to strongly fluoresce pink.

Another variant, protoporphyria, causes a much milder skin photosensitivity without the dramatic fluorescence.

Now, if you are suspecting an acute porphyria because a patient has sudden abdominal pain and neuropathy, you also have to rule out heavy metal poisoning.

Lead actually inhibits PBG synthase and ferricelatase on that same assembly line.

It mimics an acute porphyria attack perfectly, causing high ALA levels, but notably PBG levels usually aren't elevated in lead poisoning.

When you are sending lab investigations for suspected porphyria, there is a golden rule.

You must protect the samples from light.

Remember how PBG oxidizes and turns dark red in the light?

You don't want the ambient room light to ruin the biochemical state of the sample before it's tested.

That makes total sense.

The lab will usually request urine, feces, and blood.

Because these precursor molecules react to light, labs can literally shine an ultraviolet light on the plasma and the different types of porphyria will glow at slightly different emission wavelengths, giving you an exact specific diagnosis without needing to sequence genes.

And we absolutely cannot talk about porphyria without mentioning the most famous suspected case in history, King George III.

Historically, he was plagued by mysterious debilitating bouts of colicky abdominal pain alongside profound neurological and psychiatric symptoms, the famous madness of King George.

Right.

While it hasn't been categorically proven with modern DNA testing, it is widely thought by medical historians that he suffered from an acute porphyria.

His royal symptoms perfectly match the toxic buildup of ALA and PBG we just described.

This raises an important question, and it's something I want you to mull over as you finish up your studying.

We saw how a tiny genetic error in the HFE gene causes the massive iron overload of hemochromatosis, a condition we currently treat with the ancient medieval practice of vena section.

But as we move into an era of CRISPR and advanced gene editing, we might soon be able to simply rewrite that faulty club manager code in the patient's DNA.

It makes you wonder how soon will the practice of manually bleeding patients join leeches as a bizarre historical footnote in clinical medicine replaced entirely by microscopic genetic corrections?

That is a brilliant point to end on and a wild thought for the future of medicine.

You now have the physiological foundation, the lab values, and the clinical correlations for ham and iron metabolism completely decoded.

A huge thank you for joining us from the Last Minute Lecture Team.

You've got this.