A Primer on Hereditary Hemochromatosis for the Overworked Fellow

I was reviewing charts on the hemochromatosis protocol during my transfusion medicine fellowship when I came across a patient with iron overload severe enough to require ongoing therapeutic phlebotomy — and a completely wild-type HFE panel. No C282Y. No H63D. No S65C. Just normal.

I had just finished writing the service guide, which included a brief section on HFE alleles and genotypes. I had written a sentence about this exact scenario: “Occasionally you will see patients with iron overload and a WT HFE locus. This probably means they have another type of HH.” I had written that sentence and moved on. I had no idea what it actually meant.

So I went down the rabbit hole. What I found reframed everything I thought I knew about hemochromatosis — and I think it’ll do the same for you.

Hemochromatosis Is a Hepcidin Story

Here is the reframe: hereditary hemochromatosis is not, at its core, a story about HFE. It’s a story about hepcidin.

Hepcidin is a small peptide produced by hepatocytes, and it is the master regulator of iron homeostasis. The mechanism is elegant. Hepcidin binds to ferroportin — the only known iron exporter in the human body — and tags it for internalization and degradation. When hepcidin is high, ferroportin disappears from the cell surface. Iron stays trapped inside enterocytes, macrophages, and hepatocytes. When hepcidin is low, ferroportin is abundant. The gut absorbs iron without restraint.

In hereditary hemochromatosis, regardless of the gene involved, the unifying pathophysiology is hepcidin deficiency relative to iron burden. The iron accumulates because the hormone that should be putting the brakes on iron absorption isn’t doing its job. HFE is not hepcidin. HFE is one of several upstream signals that tell the liver to make hepcidin in the first place. And that distinction explains everything.

The Sensing Circuit

Think of hepcidin production as the output of a sensing circuit. The liver is constantly asking: how much iron is out there? The answer comes from multiple inputs, and several proteins are involved in integrating those signals.

HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV) all participate in sensing transferrin saturation and stimulating hepcidin expression. HJV acts as a BMP co-receptor, and both HFE and TFR2 modulate downstream BMP/SMAD signaling. Mutations in any of them produce the same functional consequence: the liver underestimates iron burden, hepcidin production is insufficient, and ferroportin runs unchecked.

HAMP is the gene that encodes hepcidin itself. Mutations here skip the sensing problem entirely — you’re not impairing the signal circuit, you’re eliminating the signal.

SLC40A1 encodes ferroportin. Mutations here operate at the other end of the pathway entirely, at the effector rather than the sensor. And as we’ll get to, ferroportin disease is its own special category.

The Four Types, and Why They’re Not All the Same

Type 1 — HFE

This is the one we learn in medical school and then assume is the whole story. HFE mutations are the most common cause of HH, with C282Y homozygosity the genotype most strongly associated with clinical disease. Onset is typically in late adulthood, often amplified by additional iron-loading exposures like alcohol use or chronic ineffective erythropoiesis. Menstruating individuals are partially protected by blood losses until menopause. Penetrance is lower than we historically believed — many C282Y homozygotes never develop symptomatic disease.

Compound heterozygosity (C282Y/H63D) causes milder disease. H63D homozygosity milder still. S65C, the least common of the HFE alleles, is associated with mild to moderate iron overload when homozygous, and a single copy is generally not enough on its own to cause clinically significant disease. A single copy of any HFE allele typically isn’t sufficient.

Type 2 — HJV or HAMP

Here is where things escalate. Type 2, also called juvenile hemochromatosis, presents in the first or second decade of life. Type 2A involves HJV, Type 2B involves HAMP. Both are autosomal recessive, both are rare, and both are aggressive.

Because iron accumulation begins in childhood, end-organ damage — particularly cardiac and endocrine — accumulates early. Without treatment, fatal cardiomyopathy by the third decade of life is not a hypothetical. This is not a disease you find incidentally on routine iron studies in a 50-year-old.

A fellow who has only ever managed Type 1 may not be thinking about HH in a young patient with unexplained iron overload, elevated transferrin saturation, and a normal HFE panel. That blind spot can have real consequences.

Type 3 — TFR2

Type 3 HH is caused by mutations in TFR2 — one of those upstream sensors feeding into the hepcidin circuit — and is intermediate in severity and onset, typically presenting in early adulthood. It is autosomal recessive and rare, with most reported cases from Mediterranean populations. Clinically it resembles Type 1 more than Type 2, though it tends to present earlier. If Type 1 is the late-night slow burn, Type 3 is the same fire with an earlier start time.

Type 4 — SLC40A1 (Ferroportin Disease)

Type 4 is the most mechanistically interesting, and the one most likely to trip you up.

Type 4A is a loss-of-function mutation in ferroportin. Iron accumulates preferentially in macrophages rather than parenchymal cells, because ferroportin is how macrophages export the iron they’ve scavenged from senescent red blood cells. When ferroportin doesn’t work, that iron is trapped. Serum ferritin can be markedly elevated — because ferritin leaks from iron-laden macrophages — while serum iron and transferrin saturation are low. This is the opposite pattern from classic HH. Patients may also become anemic with phlebotomy more quickly than expected, because their macrophages can’t release stored iron to support erythropoiesis.

Type 4B is a gain-of-function mutation that makes ferroportin resistant to hepcidin. The brake exists; the car just doesn’t respond to it. This behaves more like classic HH: elevated transferrin saturation, parenchymal iron loading, and good response to phlebotomy.

Both subtypes are autosomal dominant — which means a family history may be easier to elicit than in the recessive types, and a single pathogenic allele is enough.

Back to the Wild-Type

When you encounter iron overload with a normal HFE panel, the differential isn’t just “secondary causes.” Depending on the clinical picture — especially the patient’s age, the pattern of iron deposition, and family history — it’s worth asking whether you’re looking at Type 2, 3, or 4. Extended genetic testing panels exist. A hematologist or geneticist may be a useful colleague.

And then there’s the patient I encountered who had wild-type results across the full panel — not just HFE, but HJV, HAMP, TFR2, and SLC40A1 as well. No known pathogenic variant anywhere in the circuit. Just iron overload that didn’t have a name we could give it yet. The most likely explanation is a mutation in a gene we haven’t characterized — which is to say, the circuit we’ve described is probably not complete.

The bigger takeaway, though, is the same one that started this post. Hemochromatosis is a disease of hepcidin deficiency. Once you see it that way, the genetics stop feeling like rote memorization and start feeling like variations on a theme.

HFE, HJV, HAMP, TFR2, SLC40A1 — they’re all part of the same story. Some are upstream sensors, one is the signal itself, one is the effector. The iron accumulates because somewhere in the circuit, the brake is broken.

A wild-type HFE result doesn’t mean there’s no hemochromatosis. It means you need to look upstream, downstream — or possibly somewhere we haven’t mapped yet.