Describe the general principles of diagnosis in hemochromatosis.
Diagnosis is often incidental.
Iron overload can progress slowly over decades.
Patients with significant iron overload may be asymptomatic.
Genetic testing confirms hereditary hemochromatosis.
Describe the laboratory diagnosis of iron overload.
↑ Serum ferritin
≥ 200 ng/mL for premenopausal patients
≥ 300 ng/mL for all other patients
↑ Transferrin saturation (≥ 45%)
↑ Serum iron
↓ Total iron-binding capacity
When is genetic testing (HFE gene) indicated?
unexplained iron overload and/or first-degree relative with hereditary hemochromatosis
What are findings of genetic testing?
Homozygous C282Y, homozygous H63D, or heterozygous C282Y/H63D mutation in the HFE gene confirms the diagnosis.
List additional studies.
↑ Hepatocellular enzymes (e.g., AST, ALT)
CBC may identify iron-loading anemia (e.g., sideroblastic anemia).
Which imaging studies should be optained?
MRI abdomen (without contrast)
—> Used to estimate hepatic iron concentration (HIC)
List additional imaging studies.
based on symptoms
Echocardiogram, cardiac MRI, and/or X-ray chest to evaluate for cardiac manifestations (e.g., cardiomyopathy)
Plain radiography to evaluate for joint manifestations (e.g., arthritis of the second and third MCPs)
MRI abdomen (liver; a: T2-weighted gradient echo; b: Express; axial plane)
The liver is hypointense on both the gradient echo and Express sequences, with signal intensities of 33 and 158, respectively. These values are lower than those of the paraspinal musculature (394 and 307). Paraspinal musculature does not accumulate iron. Lower hepatic signal is consistent with hemochromatosis.
MRI can identify excessive hepatic iron accumulation and estimate iron concentration. A signal intensity ratio (liver to muscle) can be used to determine hepatic iron concentration.
When is a liver biopsy indicated?
Homozygous HFE C282Y mutation plus either of the following:
Serum ferritin level > 1000 ng/mL
Additional risk factors for cirrhosis
All other patients: if needed to stage fibrosis or investigate an alternative cause of liver disease
List histology findings of liver biopsy.
Concentration and distribution pattern of hepatic iron
Hemosiderin (normally golden yellow on microscopy) appears blue with the Prussian blue stain.
Pattern of hereditary hemochromatosis: pronounced parenchymal siderosis (accumulation of hemosiderin within the tissue) in hepatocytes and bile duct epithelium
Pattern of secondary iron overload: Kupffer cells (specialized macrophages) containing hemosiderin
Presence and degree of hepatic fibrosis
Hemochromatosis
Photomicrograph of a liver tissue sample (Prussian blue stain)
Prussian blue stains the iron deposits dark blue (green arrows) and the nuclei bright red. A portal triad (P; green overlay) is visible in the lower left corner.
Photomicrograph of a liver biopsy specimen (H&E stain, high magnification)
Deposits of coarse granular brown pigment (examples indicated by green overlay) are visible within the hepatocytes. Further deposits also appear in portal tract macrophages.
These deposits stained positive with the iron stain (prussian blue stain; not shown here), confirming the diagnosis of hemochromatosis.
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