Hemochromatosis Imaging

Major advances in our understanding of genetic iron overload have led to clarification in terminology of related diseases. Brissot et al have proposed that the term “hemochromatosis” should be reserved for entities in which iron overload is related to hepcidin deficiency or hepcidin resistance. Diagnosis of hemochromatosis is noninvasive and is based on clinical examination, blood studies, and, when possible, magnetic resonance imaging. Phlebotomy is the mainstay of treatment, but in the future, new therapeutic approaches should become available both as an adjunct to bleeding in the induction phase and as its replacement in the maintenance phase. ^[1]

Hereditary hemochromatosis (HH) is the most commonly inherited disorder of systemic iron overload. Although interest in excessive brain iron deposition is increasing, a paucity of evidence shows changes in brain iron exceeding that in healthy individuals. ^[2] Hemochromatosis is characterized by a progressive increase in total body iron stores, with abnormal iron deposition in multiple organs. ^[3] Primary hemochromatosis is a genetic disorder, whereas secondary hemochromatosis can be the result of a variety of disorders, most commonly chronic hemolytic anemias. ^{[3, 4, 5, 6, 7]}

Hereditary hemochromatosis is an autosomal recessive disorder that occurs in approximately 1 in 200-250 individuals. Mutations in the HFE gene lead to excessive iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is taken up by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ^[8]

Imaging modalities

Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. Magnetic resonance imaging (MRI) has emerged as the reference standard imaging modality for detection and quantification of hepatic iron deposition. Ultrasound (US) is unable to detect iron overload, and computed tomography (CT) findings are nonspecific and are influenced by multiple confounding variables. If caught and treated early, disease progression in HH can be altered significantly. ^[8]

MRI is the best imaging examination to evaluate abnormal iron deposition in the liver. CT scanning is less sensitive than MRI but can demonstrate increased iron if it is severe. Although quantification of iron deposition in the liver is possible with MRI, calibration of each MR scanner is necessary. Therefore, quantitative MRI for iron deposition is not available at many institutions. ^{[9, 10, 11, 12]}  Iron deposits in the liver usually do not alter liver echogenicity. If ultrasonographic liver abnormalities are present, they are usually secondary to cirrhosis. An echogenic pancreas has been described with iron deposition.

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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. In the pancreas and the thyroid, neonatal hemochromatosis can be detected on MRI multiecho GRE T2*-weighted sequence within hours after birth, according to Chavhan et al. This approach can allow clinicians to expedite treatment with intravenous immunoglobulin and exchange transfusion, thereby improving survival. ^[13]

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. ^[14] Dual-phase (arterial and venous) CT can help detect hepatocellular carcinoma in patients with cirrhosis. 

MRI is more sensitive and specific than CT scanning for detection of abnormal hepatic iron deposition.

Other abnormalities that can cause increased attenuation of the liver on CT scanning include amiodarone toxicity, use of Thorotrast, glycogen storage disease, gold therapy, and Wilson disease.

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Hereditary hemochromatosis causes unbalanced iron deposition in many organs, including the joints, leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJs). A study by Heilmeier et al reported that high-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm can be used to quantify in vivo 3D joint morphology. They 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. ^[15]

 

MRI has become a valuable noninvasive technique for quantifying hepatic iron overload, as long as it is performed in a properly controlled and validated manner. MRI also allows assessment of iron load in the pancreas, heart, spleen, and pituitary gland.

Two advanced methods used to measure liver iron concentration (LIC) quantitatively include the following ^[16] :

• Relaxometry—quantitative evaluation of MRI signal loss due to predominant shortening of T ₂-weighted and T ₂*-weighted relaxation times.
• Signal intensity ratio (SIR) method—technique based on measuring the signal intensity ratio between liver and paraspinal muscles.

Increased iron in the liver can be detected and quantified by MRI. Iron causes magnetic susceptibility artifact, which leads to spin dephasing (T2*-related signal loss). This dephasing results in decreased signal intensity on MRI scans. ^{[9, 10, 11, 17, 18]}

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T2-weighted gradient echo images are most sensitive to magnetic susceptibility artifact and thus are the best sequences for detecting increased iron in the liver. T2-weighted gradient echo images can be performed as breath-hold images on most scanners. 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 chosen 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 sequences also may demonstrate decreased signal intensity of the liver in patients with increased hepatic iron concentration. Spin echo 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 gradient echo or T2-weighted spin echo 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 gradient echo 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. ^{[3, 5, 19, 20]}

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 magnetic resonance (CMR) at 3 T in 19 patients with newly diagnosed HH and elevated serum ferritin levels and repeated the testing after completion of a course of treatment with venesection. 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. ^[21]

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.

Bantu siderosis, a condition found in parts of Africa, causes abnormal iron deposition in the liver. This disorder occurs in patients who drink large amounts of locally brewed beer, which is iron-laden. In addition, patients have a genetic predisposition for increased iron absorption and have abnormal iron deposition in parenchymal cells (hepatocytes) and in the reticuloendothelial system (Kupffer cells). Bantu siderosis may cause decreased signal intensity in the liver and spleen from abnormal iron deposition in these organs. 

Several types of MRI liver iron content (LIC) measurement have been described in the literature. Straightforward gradient echo (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 signal intensity ratio (SIR) measurement and spin echo (SE) relaxometry. ^[22]

Utilizing the liver-to-muscle SIR on differently weighted MRI scans 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 actually present with an LIC above this threshold. ^[23]  

Spin echo (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. ^[23] The commercially available St. Pierre method (FerriScan) is based on T2* analysis of SE data. It is FDA approved 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 gradient-recalled echo sequence (GRE) MRI. ^[22]

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, quantitative measurement of hepatic iron by MRI avoids the risks inherent in percutaneous liver biopsy. However, a meta-analysis found that T2 SE and T2* GRE MRI sequences accurately identified patients without liver iron overload (liver iron concentration greater than 7 mg Fe/g dry liver weight) (negative likelihood ratios 0.10 and 0.05, respectively) but are less accurate in establishing a definitive diagnosis of liver iron overload (positive likelihood ratios 8.85 and 4.86, respectively). ^[24]

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. Hereditary hemochromatosis is the most commonly inherited disorder of systemic iron overload. Sethi et al reported that both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in individuals with hereditary hemochromatosis compared to controls. 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. ^[2]

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). ^[25]