Diagnostic Criteria

When transferrin saturation (TS) is ≥ 45 % and HFE testing shows C282Y homozygosity, patients with ferritin < 1000 µg/L and normal liver enzymes should be started on prophylactic phlebotomy without a preceding liver biopsy – this approach targets true iron overload while avoiding unnecessary invasive testing. 1
If ferritin is > 1000 µg/L or liver enzymes are abnormal, a liver biopsy is recommended to stage fibrosis before initiating phlebotomy – biopsy guides treatment intensity in patients with more advanced disease. 1
In individuals with TS < 45 %, elevated ferritin frequently reflects liver disease (e.g., hepatitis C, alcoholic liver disease, NAFLD) rather than iron overload – these conditions should be investigated as the primary cause of hyperferritinemia. 1

Initial Depletion Phase (Hereditary Hemochromatosis)

Remove approximately 500 mL of blood each week or every two weeks until serum ferritin reaches 50–100 µg/L – this schedule achieves safe iron removal in most patients. 2
Each unit of blood removes ~200–250 mg of iron; severe overload (>30 g total body iron) may require 2–3 years of phlebotomy to achieve target ferritin – duration depends on baseline iron burden. 2
Check hemoglobin before every phlebotomy; discontinue phlebotomy if hemoglobin falls below 11 g/dL and reduce frequency when hemoglobin is 11–12 g/dL – prevents iatrogenic anemia. 2
Do not allow a drop of more than 20 % in hemoglobin or hematocrit from baseline – safeguards against excessive blood loss. 2
Monitor ferritin after every 10–12 phlebotomy sessions (≈ every 3 months) during the depletion phase – ensures the target range is approached without overshoot. 2

After depletion, schedule phlebotomy every 1–4 months to keep ferritin within 50–100 µg/L – maintains iron balance long‑term. 2
Some patients reaccumulate iron slowly and may need only 1–2 units per year – individualized frequency based on serial ferritin trends. 2

Avoid vitamin C supplementation during phlebotomy therapy because it accelerates iron mobilization and may precipitate toxic iron levels. 2
Patients with cardiomyopathy or arrhythmias should receive a slower phlebotomy schedule to reduce the risk of sudden cardiac death from rapid iron mobilization. 2
Raw shellfish should be avoided because iron‑overloaded patients are at heightened risk for Vibrio vulnificus infection. 2
Dietary iron restriction is unnecessary; a single phlebotomy removes 200–250 mg of iron, far exceeding the 2–4 mg/day absorbed from food. 2

In chronic hepatitis C, phlebotomy lowers alanine aminotransferase (ALT) but does not improve viral clearance and is not recommended for mild secondary iron overload. 1
For alcoholic liver disease, there is no evidence that phlebotomy provides clinical benefit. 1

When hereditary hemochromatosis is treated before cirrhosis develops, patient survival becomes comparable to that of the general population. 2
Achieving iron removal before cirrhosis eliminates the risk of hepatocellular carcinoma (HCC). 2
Patients report improvement in fatigue, malaise, abdominal pain, and skin hyperpigmentation after successful phlebotomy. 2
Cardiac function and glycemic control in diabetic patients improve with iron depletion. 2
Approximately 30 % of treated individuals experience reversal of hepatic fibrosis. 2
In established cirrhosis, phlebotomy does not reverse advanced fibrosis, and HCC risk persists despite iron removal, necessitating ongoing surveillance. 2
HCC accounts for about 30 % of deaths related to hereditary hemochromatosis, while complications of cirrhosis contribute roughly 20 %. 2

The American Association for the Study of Liver Diseases recommends measuring transferrin saturation (TS) to properly evaluate iron status in patients with elevated ferritin, and if TS ≥45%, proceed with HFE genetic testing for C282Y and H63D mutations 3, 4
The American Association for the Study of Liver Diseases suggests that if TS <45%, focus on non-iron overload causes of elevated ferritin, such as inflammatory conditions or metabolic syndrome 3, 4

A ferritin level of 255 μg/L is mildly elevated for a female, indicating possible iron overload or inflammation, according to the American Association for the Study of Liver Diseases 4
Elevated ferritin with normal hematologic parameters is most commonly due to inflammatory conditions (90% of cases in outpatients), as stated by the American College of Gastroenterology 5

The American College of Gastroenterology notes that elevated ferritin with normal hematologic parameters can also be due to metabolic syndrome or non-alcoholic fatty liver disease 5
The American Association for the Study of Liver Diseases states that early iron overload disorders, such as hereditary hemochromatosis, can also cause elevated ferritin 3, 4

The American Association for the Study of Liver Diseases recommends therapeutic phlebotomy to achieve ferritin <50 μg/L in patients with confirmed hereditary hemochromatosis and elevated TS 6
The American College of Gastroenterology suggests treating the underlying condition rather than focusing on the elevated ferritin in cases of secondary causes, and monitoring ferritin levels periodically to assess response 7