Hereditary Hemochromatosis (HH) is a genetic disorder where the body absorbs and stores too much iron from the diet. This excessive iron accumulates in organs like the liver, heart, and pancreas, potentially leading to serious complications. While elevated ferritin (the iron storage protein) has long been the primary indicator of iron overload, evidence shows that individuals can carry the genetic mutations for HH and begin iron accumulation even if ferritin levels remain normal. This is common in early stages and requires looking beyond ferritin at other markers of iron metabolism.
Defining the Key Iron Markers
A comprehensive picture of iron status requires measuring three main components in the blood: serum iron, ferritin, and transferrin saturation. Serum iron measures the amount of iron circulating in the bloodstream at a given moment. This value can fluctuate throughout the day, which is why it is often measured as part of a fasting blood panel.
Ferritin is a protein that acts as the primary storage vessel for iron inside cells throughout the body. The amount of ferritin found in the blood generally reflects the total amount of iron stored in the body, with higher levels indicating greater iron stores. In a typical diagnostic scenario, an abnormally high ferritin level is the classic sign that a significant iron overload has occurred.
The third important marker is Transferrin Saturation (TSAT), which calculates the percentage of the transferrin transport protein that is currently bound to iron. Transferrin is responsible for shuttling iron from the gut and storage sites to cells that need it. Normal TSAT usually falls between 20% and 50%, indicating a healthy balance between iron transport capacity and the amount of iron being carried.
Transferrin Saturation as the Early Indicator
In the initial development of hereditary hemochromatosis, the body begins absorbing an inappropriate amount of iron from the digestive tract. This excess iron first overwhelms the transport system before it significantly increases the overall storage capacity. As a result, the iron-carrying protein, transferrin, becomes saturated with iron much sooner than the ferritin stores begin to swell.
This mechanism makes an elevated TSAT, typically above 45% or 50%, the earliest biochemical sign of developing HH. Even while the body’s total iron stores (reflected by ferritin) remain within the normal range, the transport system is already overloaded. Fasting TSAT is therefore a more sensitive indicator for detecting the condition in its preclinical or early stages.
A persistently high TSAT reading suggests the body is continually releasing too much iron into the bloodstream from the gut, keeping transferrin molecules heavily occupied. This elevated reading signals an upstream problem in iron regulation long before the downstream storage protein (ferritin) becomes grossly abnormal. A persistently high TSAT should prompt immediate further investigation for hemochromatosis, irrespective of whether the ferritin level is high.
Why Ferritin Levels Can Be Misleading
While ferritin is an excellent measure of iron stores under normal circumstances, its utility as a standalone screening tool for hemochromatosis is limited because it functions as an acute phase reactant. This means that ferritin levels can rise in response to inflammation, infection, or tissue damage, independent of the body’s iron status. Conditions like acute or chronic infections, certain cancers, and autoimmune disorders can all cause ferritin to elevate artificially.
Furthermore, liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and chronic hepatitis, are common causes of elevated ferritin. Since iron overload is often associated with liver damage, distinguishing between iron-related and inflammation-related ferritin increases can be challenging.
Conversely, a person can have a high ferritin level due to inflammatory conditions but have a normal or low TSAT, which often rules out HH. This distinction highlights why relying solely on ferritin can be deceptive; a normal ferritin level does not exclude early HH, and a high ferritin level does not automatically confirm it. The ratio of transport iron (TSAT) versus storage iron (ferritin) provides a much more specific indicator of the genetic iron loading characteristic of hemochromatosis.
Confirming Hemochromatosis Through Genetic Testing
When a patient presents with an elevated Transferrin Saturation but a normal Ferritin level, the next logical step in the diagnostic pathway is genetic testing. This testing is necessary because the presence of the genetic anomaly is the definitive confirmation of hereditary hemochromatosis. The most common form of HH is linked to mutations in the HFE gene, specifically the C282Y and H63D variants.
If a patient is found to have two copies of the C282Y mutation (homozygous) or is a compound heterozygote (one C282Y and one H63D), the diagnosis of HH is genetically confirmed. This confirmation is made regardless of the current ferritin value, as the genetic status indicates the lifelong potential and mechanism for iron accumulation. Genetic testing clarifies the cause of the abnormal TSAT and determines the risk for future iron-related organ damage.
In complex cases, or for individuals with extremely high ferritin, physicians may use non-invasive imaging techniques like MRI to measure the iron concentration in the liver. Liver iron concentration provides a direct assessment of tissue iron burden, which helps determine the risk of developing fibrosis or cirrhosis. However, for most patients with high TSAT and an HFE mutation, genetic testing confirms the diagnosis, even when ferritin is normal.