Hemochromatosis Imaging

Updated: Mar 11, 2024
  • Author: Katherine Anne Zukotynski, MD, PhD, PEng, FRCPC, FACNM, FSNMMI; Chief Editor: John Karani, MBBS, FRCR  more...
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Practice Essentials

Hemochromatosis is characterized by a progressive increase of total body iron, with abnormal iron deposition in multiple organs, commonly the heart, pancreas, and liver. [1] It can be primary or secondary.

Primary hemochromatosis is a genetic disorder typically due to a loss of function or mutation in the genes involved in the regulatory components of hepcidin synthesis. [2] Brissot et al have proposed that the term "hemochromatosis" be reserved for entities in which iron overload is related to hepcidin deficiency or hepcidin resistance. [3] However, relatively recent advances in our understanding of hemochromatosis have highlighted that it is caused by mutations of multiple genes, including the homeostatic iron regulator (HFE) gene and non-HFE related genes (the latter of which are quite rare). [2, 4] A 2022 classification of hemochromatosis suggested by the International Society for the Study of Iron in Biology and Medicine (BIOIRON) is HFE-related, non-HFE-related, digenic (HFE and/or non-HFE), and molecularly undefined. [5] Hereditary hemochromatosis (HH), an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals, is the most commonly inherited disorder of systemic iron overload. [6] Secondary hemochromatosis can be the result of a variety of disorders, most commonly chronic hemolytic anemias. [1, 7, 8, 9, 10]

A diagnosis of hemochromatosis is made on the basis of a clinical examination, blood studies, and, when possible, magnetic resonance imaging (MRI)

Symptoms vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to the development of chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), among other conditions. [6] Although interest in excessive brain iron deposition has increased, a paucity of evidence shows changes in brain iron exceeding that in healthy individuals. [11]

Phlebotomy remains the current mainstay of treatment. [2, 10]

Imaging modalities

Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment of hemochromatosis. MRI has emerged as the reference standard imaging modality for detection and quantification of hepatic iron deposition. Quantitative MRI for iron deposition is not available at many institutions as calibration of each MR scanner is required. [12, 13, 14, 15] Ultrasonography (US) and computed tomography (CT) scanning are less helpful because the findings are often indeterminate. Although these imaging modalities may be helpful to assess the late sequelae of hemochromatosis, (eg, cirrhosis), if detected and treated early, disease progression may be altered significantly. [6]

See the images below.

Hemochromatosis Imaging. T2-Weighted gradient echo Hemochromatosis Imaging. T2-Weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.
Hemochromatosis Imaging. Noncontrast computed tomo Hemochromatosis Imaging. Noncontrast computed tomography scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently resulting in fetal loss or neonatal death. Most cases of neonatal hemochromatosis are believed to be caused by gestational alloimmune liver disease (GALD), with neonatal hemochromatosis representing a phenotype of GALD rather than a disease process. Extrahepatic siderosis in the pancreas, myocardium, thyroid, and minor salivary gland is a characteristic feature of neonatal hemochromatosis. Chavhan et al indicate that in the pancreas and the thyroid, neonatal hemochromatosis can be detected on MRI multiecho radient echo (GRE) T2*-weighted sequence within hours after birth. [16] This approach can allow clinicians to expedite treatment with intravenous immunoglobulin and exchange transfusion, thereby improving survival. Similarly, in a systematic review and analysis, Staicu et al found that MRI could detect iron overload in the liver as well as extrahepatic siderosis. [17] They suggested a prenatal diagnosis algorithm when neonatal hemochromatosis is suspected in the first affected pregnancy.

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Computed Tomography Scanning

Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs, including the joints, leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJs). Heilmeier et al reported that high-resolution peripheral quantitative computed tomography (HR-pQCT) scanning and its joint space width (JSW) quantification algorithm can be used to quantify in vivo three-dimensional (3D) joint morphology. [18] The invesigators analyzed hand-joint space morphology in patients with HH and found that HR-pQCT-based JSW quantification in the MCPJ is feasible and allows determination of the microstructural joint burden in patients with HH.

Patients with increased hepatic iron demonstrate diffuse increased attenuation of the liver, usually greater than 75 Hounsfield units on noncontrast examination. The liver vasculature appears particularly prominent because of increased contrast between vessels and the high-attenuation liver. Hepatomegaly also may be seen on CT scan. [19] Dual-phase (arterial and venous) CT scanning can help detect hepatocellular carcinoma (HCC) in patients with cirrhosis.

MRI is more sensitive and specific than CT scanning for the detection of abnormal hepatic iron deposition (see the image below).

Hemochromatosis Imaging. Noncontrast computed tomo Hemochromatosis Imaging. Noncontrast computed tomography scan in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse increased attenuation of the liver, representing abnormal iron deposition. The spleen is small and calcified from autosplenectomy.

Other abnormalities that can cause increased attenuation of the liver on CT scanning include amiodarone toxicity, use of Thorotrast (a previously used radiocontrast agent whose radioactivity had oncologic effects), [20] glycogen storage disease, gold therapy, and Wilson disease.

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Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is the gold standard for iron assessment in patients with hemochromatosis. This imaging modality is a valuable noninvasive technique for detecting and quantifying iron overload in multiple organs, including the liver, kidney, pancreas, heart, spleen, and pituitary gland, among others. [21]

Two advanced methods are used to measure liver iron concentration (LIC) quantitatively, as follows [22] :

  • Relaxometry: quantitative evaluation of MRI signal loss due to predominant shortening of T2-weighted and T2*-weighted relaxation times
  • Signal intensity ratio (SIR) method: technique based on measuring the SIR between the liver and paraspinal muscles

MRI can detect and quantify increased iron evels in the liver. Note that iron causes magnetic susceptibility artifact, which leads to spin dephasing (T2*-related signal loss) and results in decreased signal intensity on MRIs. [12, 13, 14, 23]  

Keep in mind that there is variability despite the best techniques and postprocessing tools for hepatic iron quantification; thus, local expertise and appropriate equipment and software remains key. [24, 25]

See the images below.

Hemochromatosis Imaging. T2-Weighted gradient echo Hemochromatosis Imaging. T2-Weighted gradient echo axial image in a patient with hemochromatosis demonstrates diffuse abnormal low signal intensity of the liver. The pancreas and spleen appear normal.
Hemochromatosis Imaging. T2-Weighted spin echo axi Hemochromatosis Imaging. T2-Weighted spin echo axial image in a 4-year-old boy with thalassemia demonstrates abnormal low signal intensity of the liver, spleen, and pancreas.
Hemochromatosis Imaging. T2-Weighted gradient echo Hemochromatosis Imaging. T2-Weighted gradient echo axial image in a 24-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse abnormal low signal intensity of the liver and spleen.
Hemochromatosis Imaging. T2-Weighted spin echo axi Hemochromatosis Imaging. T2-Weighted spin echo axial image in the same patient as in the previous image demonstrates diffuse abnormal low signal intensity of the liver and spleen. Signal abnormality is less apparent on this spin echo image, and the liver is only slightly lower in signal intensity than the paraspinal muscles.
Hemochromatosis Imaging. T1-Weighted spin echo axi Hemochromatosis Imaging. T1-Weighted spin echo axial image in the same patient as in the previous two images fails to demonstrate abnormal low signal intensity of the liver and spleen.
Hemochromatosis Imaging. T2-Weighted spin echo axi Hemochromatosis Imaging. T2-Weighted spin echo axial image in a 40-year-old man with alpha-thalassemia demonstrates diffuse, abnormal low signal intensity of the liver, spleen, and pancreas.
Hemochromatosis Imaging. T1-Weighted spin echo axi Hemochromatosis Imaging. T1-Weighted spin echo axial image in the same patient as in the previous image demonstrates diffuse abnormal low signal intensity of the liver, spleen, and pancreas. Although T1-weighted images are less sensitive than many other pulse sequences at detecting abnormal iron deposition, they still may demonstrate this abnormality.
Hemochromatosis Imaging. T1-Weighted spin echo ima Hemochromatosis Imaging. T1-Weighted spin echo image in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse, abnormal low signal intensity of the liver.
Hemochromatosis Imaging. T2-Weighted spin echo ima Hemochromatosis Imaging. T2-Weighted spin echo image in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse, abnormal low signal intensity of the liver.
Hemochromatosis Imaging. T2-Weighted gradient echo Hemochromatosis Imaging. T2-Weighted gradient echo image in a 47-year-old man with sickle cell disease who had undergone multiple transfusions demonstrates diffuse, abnormal low signal intensity of the liver. Magnetic susceptibility artifact obscures the upper pole of the left kidney because of dense splenic calcification.
Hemochromatosis Imaging. Magnetic resonance imagin Hemochromatosis Imaging. Magnetic resonance imaging demonstrates abnormal low signal intensity of the liver on this T2-weighted gradient echo image in a 37-year-old male. The spleen and pancreas are normal. These findings indicate abnormal iron deposition in the liver with sparing of the spleen and pancreas. This distribution is typical of hemochromatosis before the onset of cirrhosis.

T2-weighted gradient echo (GRE) images are most sensitive to magnetic susceptibility artifact and thus are the best sequences for detecting increased iron in the liver. T2-weighted GRE images can be performed as breath-hold images on most scanners. [26] On a 1.5-T scanner, an echo time (TE) of at least 10 milliseconds and a flip angle of less than 30° should be used. Recovery time (TR) is less important and should be selected based on the number of slices to be obtained and the duration of the breath hold.

Although less sensitive than T2-weighted gradient echo sequences, spin echo (SE) sequences also may demonstrate decreased signal intensity of the liver in patients with increased hepatic iron concentration. SE pulse sequences with a long TE (T2-weighted sequences) are more sensitive than those with a short TE.

In determining whether the signal intensity of the liver is abnormally low, skeletal muscle can be used as a control. If the liver shows signal intensity equal to or less than that of skeletal muscle, such as the paraspinal muscles on either T2-weighted GRE or T2-weighted SE images, increased iron accumulation in the liver can be diagnosed.

Most patients with primary hemochromatosis do not have involvement of the spleen; iron deposition in primary hemochromatosis occurs in the parenchymal cells of the liver (hepatocytes), not in the reticuloendothelial system (Kupffer cells and spleen). Therefore, splenic signal intensity is usually normal in these patients.

In patients with primary hemochromatosis, iron deposition can occur in the pancreas. Pancreatic involvement is uncommon in patients without cirrhosis. Most cirrhotic patients with primary hemochromatosis have pancreatic involvement and may have type 1 diabetes mellitus. Patients with pancreatic involvement usually show low signal intensity of the pancreas, regardless of whether they have diabetes.

Many types of anemia require multiple blood transfusions, resulting in abnormal iron deposition in the reticuloendothelial system. Patients show MR evidence of iron overload in the liver and spleen with low signal of both organs, particularly on T2-weighted GRE images. If the reticuloendothelial system becomes saturated with iron from too many transfusions, iron may be deposited in the parenchymal cells of the liver, pancreas, and heart, leading to low signal in the liver, spleen, and pancreas. [1, 8, 27, 28]

Studies have shown that patients with primary and secondary hemochromatosis can have subclinical left ventricle dysfunction with abnormalities on strain imaging. Byrne and coworkers performed baseline cardiac MR (CMR) at 3 T in 19 patients with newly diagnosed hereditary hemochromatosis (HH) and elevated serum ferritin levels and then repeated the testing after completion of a treatment course with venesection. [29] Patients with HH had normal T2* values in the presence of subclinical left ventricle dysfunction, which the authors determined can be detected by abnormal radial and circumferential strain.

Patients with thalassemia who have not undergone transfusions may have increased iron in the liver with a similar appearance to that in patients with primary hemochromatosis. If these patients are transfusion dependent, low signal may be noted in the liver and spleen and possibly in the pancreas.

Several types of MRI LIC measurement have been described in the literature. Straightforward GRE shows signal loss at the later echo time but is only qualitative and is easily confounded by the presence of hepatic steatosis. Quantitative approaches include SIR measurement and SE relaxometry. [30]

Utilizing the liver-to-muscle SIR on differently weighted MRIs allows easy and free calculation of the LIC by entering regions-of-interest (ROI) values in an online tool. A major limitation is its upper limit of detection of 350 µmol/g (equal to 20 mg/g). A significant number of affected patients present with an LIC above this threshold. [31]

SE relaxometry relies on the calculation of tissue relaxation rates (R2 and R2*, the inverse of relaxation times T2 and T2*), which increase as iron accumulates and are sensitive to changes in LIC values, with an upper limit of 769 µmol/g (43 mg Fe per g dry liver tissue)—well above the SIR threshold. [31] The commercially available St Pierre method (FerriScan) is based on T2* analysis of SE data. It is approved by the US Food and Drug Administration (FDA) and meets the quality requirements for clinical use, but data must be transferred for data analysis. In addition to cost, limitations include the need for scanner calibration and long measurement times. Alternative free-of-charge approaches are available for R2 via free breathing or respiratory-triggered SE MRI and for R2* via single breath-hold GRE MRI. [30]

Quantitative measurement of hepatic iron content by MRI has the advantage of sampling the entire liver, whereas liver biopsy samples only a small area of liver parenchyma. In addition, MRI quantitative measurement of hepatic iron avoids the risks inherent in percutaneous liver biopsy. However, a meta-analysis found that although T2 SE and T2* GRE MRI sequences accurately identified patients without liver iron overload (liver iron concentration >7 mg Fe/g dry liver weight) (negative likelihood ratios 0.10 and 0.05, respectively), they are less accurate in establishing a definitive diagnosis of liver iron overload (positive likelihood ratios 8.85 and 4.86, respectively). [32]

Although MRI is sensitive for detecting abnormal hepatic iron, particularly if performed with optimized technique for this purpose, it may not always reveal the etiology of abnormal iron deposition based on its distribution. However, this is typically not a difficult problem clinically, as the patient's history usually confirms the etiology.

Brain iron dyshomeostasis is increasingly being recognized as an important contributor to neurodegeneration. Sethi et al reported that both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in individuals with hereditary hemochromatosis relative to control subjects. [11] They concluded that quantitative susceptibility mapping and R2* can be acquired in a single MRI sequence and are complementary in quantifying deep gray matter iron.

Verberckmoes et al reported that iron deposition in the pituitary glands of patients with primary and secondary hemochromatosis results in T2- and T2*-signal loss on MRI. Other brain structures in which iron deposition can be seen include the choroid plexus and, sporadically, the circumventricular organs (eg, the pineal gland). [33]

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