Iron Deficiency Anemia: This is the most common cause of high Total Iron-Binding Capacity (TIBC) and low Transferrin Saturation (TSAT). In iron deficiency anemia, the body has a decreased amount of iron available for binding to transferrin, leading to a low TSAT. The liver responds by increasing the production of transferrin, which in turn increases TIBC.

Chronic Disease: Certain chronic diseases, such as chronic infections, inflammatory conditions, or malignancies, can lead to an increase in hepcidin levels. Hepcidin reduces iron absorption and increases iron sequestration in macrophages, resulting in a low TSAT. TIBC may be normal or slightly increased due to the body's attempt to increase iron transport.
Pregnancy: Pregnancy can cause an increase in TIBC due to increased transferrin production, which is necessary to meet the increased iron demands of the fetus. However, if iron intake is not sufficient, TSAT may be low.

Hemochromatosis with Iron Deficiency: Although hemochromatosis typically presents with high iron levels, in early stages or with concomitant iron deficiency, TSAT may be low, and TIBC may be elevated. Missing this diagnosis could lead to delayed treatment of a potentially serious condition.
Thalassemia Major: This condition can present with low TSAT and high TIBC due to ineffective erythropoiesis and increased transferrin production. It is crucial not to miss this diagnosis due to its significant implications for patient management and prognosis.

Atransferrinemia: A rare genetic disorder characterized by the absence or severe deficiency of transferrin, leading to a low TSAT. However, TIBC is typically low or undetectable, making this diagnosis less likely in the context of high TIBC.
Hypoplastic Anemia: Certain forms of hypoplastic anemia, such as Diamond-Blackfan anemia, can present with abnormalities in iron metabolism, including low TSAT and potentially elevated TIBC. These conditions are rare and would require specific diagnostic testing for confirmation.