Hemochromatosis

Learning Objectives:
• Briefly outline the management of hemochromatosis.
• Describe the histologic findings of hemochromatosis.
• Describe the clinical features, diagnosis, and clinical course of hemochromatosis.
• Define and then compare and contrast the etiology and pathogenesis of primary and
secondary hemochromatosis.

How and Why Does Hemochromatosis Occur?

Hemochromatosis is the accumulation of iron within the body’s organs; if not treated promptly,
it leads to tissue damage and organ failure. The iron accumulates most readily in the liver and
the pancreas. It can also be deposited in the heart, skin, joints, and other endocrine glands.
So how does hemochromatosis occur? There are two ways:
• Inherited genetic mutations in iron-processing genes, called primary hemochromatosis
• Acquired through excess exposure to iron, called secondary hemochromatosis
Let’s take a closer look at these mechanisms.
Primary Hemochromatosis
In primary hemochromatosis, there is a defect in a gene that controls iron absorption from food.
The most common genetic loss of function mutation is found in the hereditary
hemochromatosis gene (HFE) on chromosome 6. This is inherited in an autosomal
recessive manner and results in the disordered production of hepcidin.
The liver produces hepcidin to help regulate iron levels in the body by balancing iron
absorption. Normally, hepcidin does the following:
• Inhibits the function of the ferroportin exporter on intestinal enterocytes and
macrophages, preventing iron in their cellular compartments from entering the portal
circulation
• Downregulates absorption of iron from the intestinal lumen
If hepcidin is reduced, or its function is inhibited, the “brakes” on dietary iron absorption are
released. The result is unregulated transport of iron in the portal circulation. Iron accumulates
in the liver and pancreas first because these organs are the first to receive portal blood from the
intestines.
Secondary Hemochromatosis
Secondary hemochromatosis is “acquired” from environmental insults. It can be generally
categorized as excess iron “input” or faulty iron processing and loading
onto hemoglobin (ie erythropoiesis/red blood cell production).
Iron can’t really be excreted from the body (aside from menstruation and the minimal amount
sloughed off with cells in the gastrointestinal tract). When we have too much iron, the solution
is usually to just absorb less from the diet.
We can become overloaded with iron by two major mechanisms:
• Frequent blood transfusions, which contain iron
• Breakdown of red blood cells (RBCs; hemolysis) and release of iron
Most cases of secondary hemochromatosis revolve around excess blood transfusions, so let’s
talk about some diseases that require transfusions.

Diseases of Ineffective Erythropoiesis Requiring Blood Transfusions

Transfusing patients who have ineffective erythropoiesis (production of RBCs) is a compounding
issue. Ineffective erythropoiesis leads to increased erythropoietin (EPO), a hormone that plays a
key role in production of RBCs. EPO drives the body to increase absorption of the ingredients of
RBCs, including iron. So patients with ineffective erythropoiesis will probably already
experience iron overload. They are frequently treated with transfusions (given effective RBCs),
which also contain iron, further overloading them with iron.
Myelodysplastic Disorders, Leukemias, and Hemolytic Anemias. In these conditions, there is
either disruption of blood cell formation or abnormal destruction of blood cells. Treatment
often involves frequent transfusions, which drive the development of secondary
hemochromatosis. The transfusions compensate for the inability to make healthy blood cells. At
the same time, excess iron accumulates because iron is regulated through intestinal absorption
and cannot be excreted if given intravenously.
In myeloid disorders and some leukemias, too many RBCs are produced, and absorption of iron
in the intestines is increased to accommodate the overproduction. In hemolytic anemias, RBCs
are destroyed and release iron into the blood. The body compensates for the anemia by
releasing erythropoietin to increase RBC production and lower hepcidin so more iron can be
absorbed from the intestines. Both of these further exacerbate the iron overload.
β-Thalassemia. In this blood disorder, iron binding is impaired due to a lack of β-globin chains.
Transfusions are required very early in life and are the driving force behind the development of
secondary hemochromatosis in these patients. As discussed above, anemia also causes a
feedback loop with EPO to block hepcidin and increase iron absorption. The major consequence
is that patients are transfusion dependent to compensate for the severe anemia. This, coupled
with the already increased iron stores, will likely result in secondary hemochromatosis.
What Are the Presentation, Diagnosis, and Prognosis for Hemochromatosis?
We have just covered the general pathology behind the problem. So what will a patient
experience? What, and who, will we see as clinicians?
Before we get into the details of the clinical features of hemochromatosis, let’s briefly review
why our bodies need iron. Our blood cells need hemoglobin to carry oxygen, and hemoglobin
needs globin chains and heme (iron). As teenagers, our bodies need more oxygen for our
growing size. But as we get into our 20s, our bodies stop building muscle, and muscle mass
begins to gradually decline. In men, the total amount of required iron begins to decline at this
point.
Clinical Features
Primary hemochromatosis is classically seen in middle-aged men (40s-50s) and slightly older
women (50s-60s). So why this split? Anywhere from 10%-20% of ingested iron is actually
absorbed, but a person who is homozygous for hemochromatosis can have two to four times
more absorption! Our bodies can control storage of iron, but the major method of control is
through absorption. So over 20 years, a man could store up to 20 g, which is why the disease is
often seen in men in their 40s.
In women, there is an added variable that balances the equation: menstruation. From their
early teens to mid-to-late 50s, women have menstrual cycles and lose up to 60-100 mL of blood
with each cycle. It would take 30-40 years for a woman to store 20 g of iron because iron lost
through menstruation balanced the excess iron absorbed. This gives us the classic 60-year-old
female patient with hemochromatosis.
Hemochromatosis is often characterized as a middle-aged man with the triad of
“bronze diabetes”: cirrhosis, diabetes, and darkened skin pigmentation.
• The iron absorbed through the intestines first passes through the liver where it can
accumulate and cause damage, scarring, and eventually cirrhosis.
• Overload within the β cells of the pancreas causes dysfunction in the body’s ability to
produce and regulate insulin levels.
• Deposition of iron along with melanin can darken the skin of a patient so it is
reminiscent of a bronze statue.
These symptoms are more classically seen during the late stage of the disease when the body’s
total iron content can be as much as 20 g. What is the more typical initial presentation?
• Abdominal pain: This results from dysfunctional bile and bicarbonate secretion from the
damaged liver and pancreas. It also occurs due to excess storage of iron in the
enterocytes, which causes cell death, cell shedding into the intestinal lumen, and
irritation.
• Arthritis: As iron accumulates in the joints, free radicals can form and calcium
pyrophosphate crystals can deposit, creating inflammation and giving the hallmark J-
shaped hook appearance from malformed osteophytes on x-ray.
• Cardiac dysfunction: Excess iron in cardiac myocytes leads to dilated
cardiomyopathy with hypertrophy, or restrictive cardiomyopathy secondary
to amyloidosis where amyloid prevents myocyte iron release, making the heart stiff.
Accumulation in the heart can also increase the susceptibility to arrhythmias.
• Fluctuations in glucose homeostasis: Pancreatic β-cell destruction from excess iron can
cause poor insulin balance and blood glucose imbalance.
 • Skin pigmentation: If iron deposits in the skin, it appears darker.
• Hypogonadism: As iron deposits in the testicles, they become dysfunctional, leading
to atrophy, sexual dysfunction, and possibly gynecomastia.
• Hepatomegaly: Iron deposits in the liver sometimes cause it to expand because of the
space that the iron “takes up.”

Diagnosis and Lab Studies

Diagnosing hemochromatosis is quite simple. Iron can be monitored by measuring the
following:
• Ferritin (protein that binds stored iron)
• Serum iron
• Total iron-binding capacity (TIBC)—all proteins available for binding mobile iron
• Transferrin saturation (the percentage of transferrin and other mobile iron-binding
proteins saturated with iron)
Serum iron, ferritin, and transferrin will all be elevated, but TIBC will be low. This makes sense:
there is elevated iron in the body (serum iron) and increased storage in macrophages and the
liver (ferritin), and circulating transferrin is fully saturated with no further capacity to bind more
iron (high transferrin saturation and low TIBC). These relationships are summarized in the table
below.

The most important of these markers is transferrin saturation. It has relatively

good specificity (the ability to correctly identify those with the disease) if saturation is more
than 60% in men or more than 50% in women. Liver biopsy can also help determine the state of
the disease but is used much less commonly because the ferritin tests and MRI can stage the
disease noninvasively.
Another important diagnostic tool is gene polymerase chain reaction (PCR)-based assays. As
discussed earlier, hemochromatosis presents as an autosomal recessive mutation of
the HFE gene on chromosome 6. More specifically, in the proband (diseased family member)
there is often a mutation at amino acid 282 (C282Y).
If a patient presents with hemochromatosis and is homozygous for the serotype C282Y (two
copies of the mutated gene, one from each parent), then the parents should be tested. In this
case, it is likely that the parents are each heterozygous (one copy of the mutated gene) for the
mutation, meaning 25% of their children will be homozygous for C282Y, 50% will be
heterozygous for C282Y, and 25% will not carry the C282Y mutation. Of course, this changes if
one of the parents is homozygous; then their offspring will be 50% homozygous and 50%
heterozygous for C282Y.

Prognosis
Hemochromatosis most often progresses to cirrhosis, and there is a risk for development
of hepatocellular carcinoma. Another common progression is cardiomyopathy and heart failure.
These are discussed in detail further below.

What Is the Histology of Hemochromatosis?

As we’ve discussed, iron begins to accumulate in the liver because an excess amount of ferritin
is being produced to store the iron. As iron builds up, ferritin complexes bind to iron and
form hemosiderin. So we would expect to see a lot of hemosiderin granules in the hepatocytes
on a histological cross-section.
As the iron storage becomes more severe, the Kupffer macrophage cells of the liver begin to
engulf the excess iron, resulting in hemosiderin-laden macrophages. Hemosiderin can also
become deposited in the epithelium of the bile duct canaliculi.
The figure below is composed of three images of liver. The image on the left is a lower
magnification and is stained with Prussian blue. This stain is specific for identifying iron and
hemosiderin, as it colors iron a deep blue, which we see here as dots/smudges inside most of
the hepatocytes. The image on the right is a high magnification of the middle image (medium
magnification). These are stained with hematoxylin and eosin (H&E). Note that with this stain,
hemosiderin is the brown material inside most of the hepatocytes

The development of fibrosis occurs because free iron is toxic to hepatocytes. Excess iron acts as
an electron donor and increases the free radicals within the cell that cause lipid peroxidation.
This means lipids become degraded by the free radicals, damaging the cell, and
stimulating extracellular matrix production and scar formation. This scar formation produces the
fibrotic nodes that can later lead to cirrhosis, and cells often have lipofuscin granules present as
by-products of lipid peroxidation.

CLINICAL CORRELATION
It is very important for patients with hemochromatosis to avoid excessive alcohol consumption.
Alcohol metabolism creates a lot of unstable free radicals, so when added to the excess iron
acting as an electron donor, there is an exponentially greater amount of membrane damage.

What Are the Complications and Treatment of Hemochromatosis?

Ultimately, untreated hemochromatosis leads to cirrhosis and liver failure, which carries a poor
prognosis. If caught earlier, however, patients can live a high-functioning life!
Possible complications of cirrhosis caused by hemochromatosis include hepatocellular
carcinoma and portal hypertension, which cause esophageal varices and ascites. So in some
aspects, treatment can be geared toward relieving symptoms even if the damage is irreversible,
like in the cirrhotic phase of hemochromatosis. Patients who are treated early and maintain
healthy iron levels will still have an increased risk for hepatocellular carcinoma (although
hepatocellular carcinoma is very rare in noncirrhotic hereditary hemochromatosis).
The degree of treatment revolves around the stage of the disease. If the liver is near failure,
treatment revolves around lessening symptoms. If the liver is still fully functional, then chelating
drugs and phlebotomy can be used.
Phlebotomy. The first-line treatment for hemochromatosis is to remove excess iron by removing
RBCs with phlebotomy.
Chelating Drugs. Iron-chelating drugs like deferasirox, deferoxamine, and deferiprone have a
high affinity to iron. Like a sponge to clean up a spill, they act by binding up free iron. In severe
cases, these drugs are used alongside phlebotomy. In patients with anemia, only chelating drugs
are used because these patients cannot spare the loss of RBCs by phlebotomy.
Throughout the treatment process, we monitor the responsiveness to treatment with ferritin,
serum iron, and transferrin saturation.
Liver Transplant. Transplant can be an option for patients with hemochromatosis in end-stage
liver disease, but the course of that decision is similar to that in patients with cirrhosis.

Summary
• Hemochromatosis is the abnormal accumulation of iron in the body, causing deposition
of iron and disease in the liver, pancreas, heart, skin, joints, and gonads.
• Patients can inherit a mutation on the HFE gene, in an autosomal recessive fashion, or
acquire hemochromatosis through excess blood infusions, common treatment for β-
thalassemia and other anemias that cause ineffective erythropoiesis.
• The classic presentation of hemochromatosis is a middle-aged man with liver disease,
diabetes mellitus, and bronzing skin. Women show symptoms later in life because
menstruation blood loss slightly buffers the accumulation of iron from the disease.
• More commonly, the initial presentation is abdominal pain with varying glucose levels,
cardiac dysfunction, minor skin pigmentation, arthritis, and hypogonadism that may or
may not be accompanied by hepatomegaly.
• Diagnosis can be made with elevated iron, ferritin, and transferrin saturations of more
than 60% in men and 50% in women.
• On liver histology, hemochromatosis shows yellow-brown hemosiderin granules on H&E,
and the sensitive Prussian blue stain will light up the granules in a bright blue.
• Hemochromatosis is a chronic and progressive disease. Hemochromatosis leads to liver
failure, cardiomyopathy, and diabetes. When complications develop, they are often
irreversible.
• Treatment for hemochromatosis is centered on continuous phlebotomy until desired
iron content is obtained, followed by either maintenance phlebotomy or treatment with
deferasirox, deferoxamine, or deferiprone.
• If a patient with hemochromatosis presents before severe liver fibrosis occurs, then the
course of the disease can be widely reversed. If cirrhosis is present, the liver damage is
irreversible, and treatment is centered on taming complications.
• Hemochromatosis can cause end-stage liver disease, which may require transplantation.