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MR imaging of iron depositional disease
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MR IMAGING OF THE LIVER II: DISEASES
MR IMAGING OF IRON DEPOSITIONAL DISEASE Stuart Pomerantz, MD, and Evan S. Siegelman, MD
NORMAL PHYSIOLOGY To discriminate among the different causes of iron deposition in the liver, an understanding of the physiology of normal iron metabolism is helpful. Because of its capability to readily accept and donate electrons (alternating between ferric [Fe2] and ferrous [Fe3] states), iron serves as a useful component of cytochromes, the oxygen-binding molecules hemoglobin and myoglobin, and various enzymes. Iron overload, however, has the ability to damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that can induce oxidative damage to cellular membranes, proteins, and DNA. In some instances, the oxidative changes of iron overload can initiate and promote cancer growth.3, 10 Adult men normally have about 5 g of total body iron; approximately 70% of this iron is present within hemoglobin. An additional 10% to 15% of body iron is present within muscle fibers as myoglobin. The body can absorb 1 to 2 mg of iron daily, which is much smaller than the 20 mg daily requirement of hematopoietic tissue. Thus, in addition to the dietary iron absorbed by the duodenal enterocytes, iron must be efficiently recycled from
senescent erythrocytes. In a process known as extravascular hemolysis, red blood cells are ingested by reticuloendothelial (RE) macrophages. The RE cells catabolize hemoglobin for reusable iron, which is transferred and bound to the serum protein transferrin. Excess iron is bound to ferritin and hemosiderin within hepatic parenchymal cells (hepatocytes) and within the RE cells of the liver (Kupffer’s cells), spleen, and bone.3 The regulation of intestinal iron absorption is incompletely understood. Nevertheless, control at the absorption stage is critical because humans have no physiologic mechanism for iron excretion.3, 4 Iron absorption is modulated in at least three ways. A local limit on cellular absorption, previously known as a mucosal block, is modified based on the amount of iron recently consumed in the diet. Absorption may also respond to overall body stores of iron and is modulated by the iron saturation level of plasma transferrin. The third method of absorption involves the erythropoietic regulator, which increases or decreases iron absorption in response to requirements for erythropoiesis through an unknown mechanism.3 Iron overload within the body occurs by two distinct pathways: increased gastrointes-
From the Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
MRI CLINICS OF NORTH AMERICA VOLUME 10 • NUMBER 1 • FEBRUARY 2002
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tinal absorption or intravenous blood transfusion. The iron overload syndromes that result from increased gastrointestinal absorption cause excess parenchymal iron deposition and are best exemplified by genetic hemochromatosis (GH). This entity is a primary focus of this review because of its prevalence and the clinical importance of establishing an early diagnosis. Entities with similar pathologic mechanisms, such as erythropoietic hemochromatosis, are also discussed. In contrast, iron overload secondary to blood transfusions initially causes deposition within the RE cells of the liver, spleen, and bone marrow and results in different clinical and imaging findings.44
MR Imaging of Iron Overload Before evaluating the imaging features of specific iron overload entities, the physical properties that allow visualization of iron with MR imaging must be reviewed. Iron is a paramagnetic substance that acquires a strong magnetization when placed within a magnetic field. Intracellular iron (in the form of deoxyhemoglobin, methemoglobin, ferritin, or hemosiderin) results in focal hot spots of magnetic nonuniformity. Adjacent water protons lose phase coherence within these foci of magnetic nonuniformity, resulting in signal loss. The magnetic susceptibility effects of
iron thus result in areas of low signal intensity on MR images.8, 44 T2-weighted and heavily T2*-weighted sequences generate the most susceptibility to the paramagnetic effects of iron and are thus used in evaluating iron depositional disease. These sequences can provide both qualitative and quantitative measures of iron accumulation.45 T2*-weighted gradient-echo (GRE) images have been shown to have a greater sensitivity for mild degrees of hepatic iron than spin-echo T2 sequences (Fig. 1). Because GRE sequences lack the 180 ‘‘refocusing’’ pulses of standard spin-echo sequences, this loss of phase is allowed to accumulate, resulting in rapid loss of transverse magnetization and thus loss of signal intensity. A wide variety of GRE techniques can be used to qualitatively evaluate iron overload. At 1.5 T, we recommend a breath-hold T2*weighted GRE sequence. We select a repetition time (TR) of 100 to 300 milliseconds so we can image in a single breath-hold. The TR has less effect on the degree of T2* weighting than does the choice of echo time and flip angle. The authors of this article recommend a minimum echo time of 7 milliseconds and prefer 15 milliseconds or more. At lower field strengths, echo time should be increased appropriately. The flip angle can vary but ideally should be less than 30 to minimize the influence of T1 differences between tissues.43
Figure 1. MR demonstration of secondary hemochromatosis in a 36-year-old man with Thalassemia who has not had prior blood transfusions. A, Axial T1-weighted opposed-phase gradient-echo (GRE) image (TR 240, TE 2.1, flip angle 90) shows normal signal intensity of the liver (L) and spleen (S) and pancreas (arrow). B, In-phase image (same parameters except TE 4.2) shows greater loss of signal intensity in the liver compared with spleen. The pancreas remains normal signal intensity. C, Out-of-phase image obtained with a longer echo time (same parameters except TE 6.3) reveals that the liver is lower signal intensity than the spleen. Had not the shorter TE opposedphase image been performed, it may not have been possible to distinguish hepatic signal loss from iron deposition or steatosis. Thus, when attempting to diagnose intracellular lipid by chemical shift imaging, an opposed-phase image of shorter TE should be performed.48 Otherwise potential T2* shortening effects of hepatic iron could create a false-positive diagnosis of steatosis of the liver. Of potential greater clinical importance, a hemorrhagic adrenal mass could be mischaracterized as an adrenal adenoma by the same mechanism. D, Heavily T2*-weighted GRE image (TR 100, TE 20, flip angle 20) shows near signal void of the liver and only mild signal loss of the spleen. The pancreas remains of normal signal intensity. E, T2-weighted breath-hold fast spin-echo (FSE) image (TR infinite, effective TE 93) reveals pancreas (arrow) and spleen (S) signal intensity to be greater than that of paraspinal muscle (m) and liver (L) to be of lower signal intensity. Normal liver should have higher signal intensity than muscle of moderately weighted turbo or FSE sequences. Note the greater degree of signal loss within the liver on the heavily T2*-weighted image, (D), compared with this FSE image.
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Figure 1. See legend on opposite page
GENETIC HEMOCHROMATOSIS Genetics Hemochromatosis was originally described in the late nineteenth century by Trousseau, and the term hemochromatosis was first used by von Recklinghausen in 1889 to describe
the postmortem findings in patients who had died from bronzed diabetes.33, 37 In 1975, a genetic basis for hemochromatosis was established by human leukocyte antigen (HLA) linking, which revealed an autosomal recessive pattern. 37 This hereditary or primary form of hemochromatosis has come to be referred to as genetic hemochromatosis (GH) in
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distinction from other primary and secondary forms of iron overload. In 1996, Feder and colleagues14 described a novel gene termed HFE on the short arm of chromosome 6 containing 2 missense mutations.14 One mutation, C282Y, is homozygous in 83% of patients with GH. The second mutation, H63D, is not associated with the same degree of iron overload as the C282Y mutation. In 1998, an HFE gene knockout mouse was created, which has facilitated GH and iron metabolism research at the molecular level.2, 9
Pathophysiology The function of the HFE gene is not fully understood. The product of the HFE gene is a cell-surface protein that binds to transferrin and is expressed in all tissues except the brain. Its exact role in the regulation of iron transport and storage is unclear. Some have proposed a model in which the abnormal gene product primarily affects the role of duodenal crypt cells, which act as sensors for total body iron stores. If the levels of transferrin-bound iron in the serum cannot be sensed, the crypt cells will falsely register an iron-deficient state. This results in an increase in absorption of luminal iron by upregulating cell-surface transporter proteins.33 Others suggest that the effect of the HFE gene may be more systemic.30, 50 In patients with GH, RE cells have been shown to have early release of intracellular ferritin and are incapable of storing excess iron.1, 15, 16 This defect results in increased iron deposition in parenchymal cells of organs such as the liver, heart, and pancreas.43 This pattern of selective iron deposition results in suggestive abdominal MR imaging findings that are described below.
Epidemiology Advances in the epidemiology of GH have followed the recent genetic discoveries. Originally considered uncommon, GH is now recognized to be the most common genetic disorder among persons of northern European
ancestry.30 GH is also the most common genetic disorder among the white population in the United States, although it is less frequent among other groups of Americans. In the United States, 1 in every 250 to 300 persons is homozygous for the hemochromatosis mutation, and at least 1 in every 10 persons is a carrier for the mutation.9
Screening/Genetic Testing Issues Although the goal is to identify individuals at most risk for developing iron overload before they develop life-threatening conditions, a number of factors prevent consensus on guidelines for population screening. One complicating factor is the incomplete penetrance of the HFE gene mutations. The reported percentages of homozygous individuals who manifest clinical signs of GH vary from approximately 25% to 50%, with more severe sequelae (such as hepatic fibrosis or cirrhosis) developing in only about 10%.9, 31, 33, 36, 37, 50 Moreover, not all patients with a clinical presentation of GH are C282Y homozygotes, even those with end-stage symptoms. From 0.5% to 14% of patients with clinical signs and symptoms of GH are actually heterozygotes.36 The importance of HFE mutations other than C282Y is also controversial. Pooled data from US and European studies have shown an increased risk of end-stage disease in H63D homozygotes and an even larger risk in compound heterozygotes (those heterozygous for both C282Y and H63D alleles) compared with the general population. 9 Some groups, such as Italians and African-Americans, have a clearly higher proportion of patients with primary iron overload and typically do not carry any known HFE mutations.35, 37 Environmental factors and coexisting disease also play an important role in the expression of the hemochromatosis gene. Dietary intake of red meat varies from person to person and among cultures. Patients can promote iron overload with iron supplements. Additionally, vitamin C has been shown to increase iron absorption. Coexisting disease can be one of the most powerful cofactors
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affecting the penetrance of the hemochromatosis gene. Hepatitis, alcoholism, and porphyria cutanea tarda all increase hepatic iron stores and can accelerate organ damage, even in heterozygous patients. Conversely, the presence of undetected abnormal HFE alleles may in part explain why there is such variation in the degree of organ damage from common insults such as infectious hepatitis and alcoholism.9, 50 Although widespread population screening for HFE mutations may be premature at this time, genetic testing, which is commercially available, has a role in the evaluation of a patient with signs, symptoms, or MR image findings suspicious for the disease. Genetic testing is useful to resolve ambiguous cases as well as to confirm the diagnosis in younger patients with abnormal blood chemistry panels. This latter group is less likely to have accrued organ damage.36 Genetic testing is most useful for screening high-risk groups, such as siblings of an identified proband (who by definition have a 25% chance of being homozygous for GH) and possibly patients with diabetes or arthritis. Genetic identification also allows treatment (described below) to begin early, which is crucial for preventing irreversible sequelae of iron deposition.9, 33, 37
Clinical Features and Diagnosis of GH—5 physicians, 5 years Organ dysfunction results from iron deposition in the liver and subsequently in the pancreas, myocardium, pituitary gland, and synovium. Serologic abnormalities and mild symptoms may occur earlier in life, but the clinical signs and symptoms that cause patients to seek medical help generally do not appear until the fifth or sixth decade of life. These findings include lethargy, arthralgia, loss of libido, glucose intolerance, abdominal pain, and heart failure.33 Although GH is the most common primary iron overload disease and is more prevalent in the population than previously realized, it still remains underdiagnosed. This failure of diagnosis can be attributed to lack of aware-
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ness of GH, its long latency period, and nonspecific signs and symptoms. It has been estimated that the average patient with GH sees at least 5 physicians and waits 5 years between the initial onset of signs or symptoms and the time of diagnosis and treatment.38, 43 If untreated, patients with GH may progress to cirrhosis and liver failure. Hepatocellular carcinoma (HCC) occurs in up to 36% of cases and often is the cause of death. Diabetes appears in up to 80% of patients, with increasing insulin dependence occurring as pancreatic B-cell damage progresses. Cardiac abnormalities, including cardiomyopathy and arrhythmias, occur in 15% to 40% of patients.30, 32, 33 Women with GH tend to have less severe manifestations of the disease secondary to iron loss with menstruation and pregnancy. A minority of women, however, can still develop clinical disease, but more often at a later age than affected men.36 The site of earliest and heaviest iron deposition is in the liver in the form of ferritin and hemosiderin. The initial distribution of iron in the liver is within the periportal hepatocytes. If untreated, the liver disease progresses to perilobular fibrosis and ultimately to cirrhosis. Approximately 30% of cirrhotic patients with GH develop HCC, even years after phlebotomy therapy has reduced body iron stores.30 The relationship of iron to hepatic cirrhosis and neoplasia has not been fully clarified. Excess iron in hepatocytes may stimulate the release of profibrogenic substances that cause the liver to produce the collagen bundles characteristic of cirrhotic scarring. Iron may also result in lipid peroxidation, which promotes DNA damage and subsequent carcinogenesis.19, 33
Diagnosis of GH Screening tests for GH, including serum ferritin levels and transferrin saturation, are available as part of standard chemistry panels. They are useful for alerting clinicians to patients who may have GH. For definitive diagnosis and subsequent monitoring of hemochromatosis therapy, a reliable means of evaluating body iron stores would be ideal.
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Ferritin and transferrin saturation values may not accurately reflect the body iron store because of their lack of specificity and sensitivity. False-positive results are seen in alcoholism and infection because of the role of transferrin as an acute-phase reactant. Falsenegative results occur in young patients with hemochromatosis but very low levels of iron overload. 17 Thus, positive results of blood chemistry tests have in the past been confirmed with a liver biopsy. Liver biopsy has long been considered the gold standard for diagnosis of hemochromatosis because it allows both histologic evaluation and quantitative determination of hepatic iron concentration. The degree and distribution of iron overload confirm the presence of hemochromatosis. Histologic evaluation allows detection of hepatic cirrhosis. The presence and severity of cirrhosis are key determinants of prognosis and management, especially with regard to monitoring for hepatocellular carcinoma.36 Since the discovery of the GH gene, however, genetic testing is now possible in patients who are found to have an elevated serum ferritin or transferrin saturation. Patients with a positive genetic test may or may not be considered for a subsequent liver biopsy. Some physicians believe that asymptomatic patients with only minimally elevated serum markers or those with already known advanced cirrhosis30 could avoid biopsy and simply proceed to treatment (described below). Like those who have asked whether genetic testing could replace the need for liver biopsy, others have wondered if MR imaging could accomplish the same feat. Through the evolution of increasingly sophisticated MR imaging techniques, even very low levels of iron deposition are detectable in a qualitative and quantitative fashion on high-field systems.17 Because MR imaging does not generate absolute signal intensities, this type of analysis relies on comparison with an internal standard, such as fat or skeletal muscle. Skeletal muscle is a reliable internal standard because it has been shown to have no significant difference in T2 values over a wide range of
total body iron stores. In patients with GH, no change in muscle signal intensity was present with phlebotomy treatment. Thus, serial MR imaging examinations may be helpful to monitor the efficacy of phlebotomy therapy.43 The issue of whether MR imaging can replace biopsy is dependent on the necessity of knowing the liver iron concentration to confirm a diagnosis of hemochromatosis in patients without the HFE gene or a wild-type mutation35 or to assess treatment response. Unfortunately, a widely applicable quantitative analysis of iron stores by MR imaging has not yet been developed. Numerous investigators have succeeded in correlating T2 or T2* relaxation times with specific measures of liver iron content.5, 11, 12, 17, 34 Unfortunately, differences in background noise caused by radiofrequency tuning, field of view, matrix, and field strength, as well as numerous other system-dependent factors, exert an effect on the estimate of iron deposition. Consequently, this type of quantitation, though technically possible, may be feasible only at an institution where a large enough series of biopsy samples can be correlated with data from MR images to generate a best-fit equation. Even then, the same pulse sequence and imaging parameters must be performed on the same machine each time for the estimated iron concentration to have validity.17, 43 So, what is the role of MR imaging in the evaluation of GH now that a genetic test for the disease is readily available? In patients with known GH, MR imaging can noninvasively evaluate the distribution of iron in the body and reveals complications of the disease (Figs. 2 through 4). In the liver, MR imaging can reveal findings of cirrhosis or HCC (see Fig. 3). Iron overload of the pancreas is suggestive of advanced disease and could explain the cause of a patient’s diabetes. MR imaging of the pituitary gland can reveal low signal intensity on T2-weighted images secondary to iron deposition, which could explain a patient’s impotence or loss of libido.46 Finally, MR imaging has a role in the evaluation of myocardial iron deposition (see Fig. 4). Cardiac involvement is present in up to 15% of adults with GH; 30% of this progresses
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Figure 2. Genetic hemochromatosis (GH) in a 29-year-old man. A, Axial T1-weighted opposed-phase GRE image (TR 250, TE 1.8, flip angle 90) shows low signal intensity liver (L) and very low signal intensity pancreas (p). B, In-phase image (similar imaging parameters except TE 4.2) obtained at the same level shows marked loss of signal of the liver (L) and pancreas (p) secondary to iron overload. C, In-phase image (TE 4.2) obtained higher within the abdomen shows a near normal signal intensity of the spleen (S). This is the typical distribution of abdominal iron in advanced GH.
to cardiomyopathy, often complicated by arrhythmias.13, 36 The onset of cardiac failure is a very poor prognostic sign, with death occurring within 6 months in most cases.21, 33 In patients who present before 30 years of age, cardiomyopathy is much more frequent and is often the cause of death.21, 30, 36 Determination of cardiac involvement in cirrhotic patients with GH will influence whether the patient is a candidate for orthotopic liver transplant (OLT). Disappointing survival rates in GH patients who have undergone OLT have been partially attributed to iron-induced cardiomyopathy that often does not manifest until the post-transplantation period.13 MR image findings of iron overload of the heart may be a contraindication
for liver transplantation or may suggest the need for combined heart and liver transplantation.27, 47 The detection of cardiac iron overload is usually accomplished by right ventricle biopsy. In comparison, MR image detection of cardiac iron is noninvasive and may be more accurate than biopsy because of possible biopsy sampling error. The anatomic distribution of cardiac iron has been shown in tissue specimens to be either heterogeneous or concentrated in a subepicardial rather than subendomyocardial location.21 Therefore, up to 30% of right ventricular biopsies may yield false-negative results.7 In contrast, spin-echo and GRE sequences have been shown to be sensitive to cardiac iron deposition, and the
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Figure 3. GH and hepatocellular carcinoma in a 41-year-old man. A, Axial T1-weighted opposedphase GRE image (TR 150, TE 1.8, flip angle 60) shows lower signal intensity of the liver (L) than the spleen (S). On this opposed-phase image alone, it is difficult to determine whether the low signal intensity of the liver is secondary to the chemical shift effects of hepatic steatosis or to the magnetic susceptibility effects of hepatic iron overload. There is a subtle subcapsular mass of the right lobe of the liver (arrow). The mass is of higher signal intensity than surrounding liver and is isointense to spleen. B, Corresponding in-phase GRE image (similar parameters except TE 4.2) shows dramatic signal loss of the liver (L) and pancreas (p) secondary to the T2* effects that become more dominant with a longer TE. There is improved tumor-liver (arrow) contrast. Most hepatocellular carcinomas are relatively resistant to iron overload and thus are readily revealed on T2*- or T2weighted images in patients with hepatic iron overload. C, Axial T2-weighted FSE image (TR 3550, TE 88 milliseconds) obtained at a slightly different level through the liver shows abnormal low signal intensity of the liver (L) and pancreas (P) and normal signal intensity of the spleen (S). This is the typical distribution of abdominal iron in advanced GH.
Figure 4. MR demonstration of iron overload of the myocardium in a 51-year-old man with genetic hemochromatosis, cirrhosis, and liver failure who was being considered for liver transplantation. A, Heavily T2*-weighted GRE image (TR 100 millisecond, flip angle 90, TE 20 millisecond) through the level of the interatrial septum shows very low signal intensity myocardium (***) indicative of iron deposition within the myocardium. Lower images (not shown) revealed iron overload of the liver. Because of the presence of myocardial iron, the patient was no longer considered a candidate for a liver transplant without also a heart transplant. The patient died shortly after MR imaging. B, Gross photograph of the heart at autopsy shows marked iron overload within the right ventricle (arrow) stained with Prussian blue. The left ventricle (curved arrow) shows bronzed discoloration. The myocardium is both dilated and hypertrophied. C, Histologic section of the myocardium obtained at autopsy shows marked iron deposition (curved arrow) in the myocytes (Prussian blue original stain, magnification 40). Myocyte hypertrophy is present as evidenced by enlarged nuclei (long arrow), which normally should be only twice the size as an erythrocyte (short arrow).
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Figure 4. See legend on opposite page
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direct multiplanar capabilities of MR imaging allows demonstration of the entire myocardium.l8, 21, 49
Treatment of GH Once a diagnosis of GH has been made, treatment consists of a vigorous schedule of phlebotomy. Depletion of excess iron usually requires 50 to 150 phlebotomies over a 9to 24-month period. After this initial iron is removed, 4 to 10 additional phlebotomies per year are required to prevent excess iron reaccumulation. 6 30 If treatment is initiated in the early stages of the disease, patients can progress to a normal life expectancy. If left untreated, parenchymal deposition results in significant organ dysfunction and damage. Even patients with only mild to moderate organ damage benefit from phlebotomy, with decreased complications of portal hypertension and preservation of cardiac function. Impotence and arthropathy, however, tend to have a poor response to therapy. 26 30 Neonatal Hemochromatosis Neonatal hemochromatosis is a severe and usually fatal disease characterized by massive hepatic iron deposition with fulminant liver failure presenting in the perinatal period. Liver transplantation is the only effective treatment but often is unsuccessful. 3 Neonatal hemochromatosis reveals the same iron distribution as GH, with progressive parenchymal involvement of the liver, pancreas, and myocardium, and sparing of the spleen. MR imaging evaluation of extrahepatic iron overload may be of specific value because marked siderosis of the liver can be physiologic in the perinate. Therefore, liver biopsy alone may result in an erroneous diagnosis.l8
sions. Iron from transfused erythrocytes is accumulated within the RE cells of the liver, spleen, and bone marrow (Fig. 5). If the number of transfusions is low, this type of iron deposition is clinically insignificant. The iron storage capacity of the RE system is 10 g, which is the amount of iron contained in 40 U of blood. Patients who receive much more than 40 U of blood can exceed the iron storage capacity of the RE system and develop iron overload of parenchymal cells. 4 0 , 51 These patients with transfusion-dependent severe anemias are treated with iron chelation therapy to prevent the sequelae of parenchymal iron deposition, such as cirrhosis and diabetes. One group of investigators found that quantitative imaging was accurate in estimating liver iron in transfusion-dependent patients who were being treated with chelation therapy, provided there was no underlying cirrhosis. 5 Cirrhosis with Diffuse Liver Siderosis Diffuse iron deposition also occurs in the liver of patients who have non-GH-induced cirrhosis. The degree of deposition is usually mild and does not require treatment. The cause of the excess iron deposition is not well understood but may be related to anemia, pancreatic insufficiency, or decreased transferrin synthesis. Differentiation between patients with GH and those with diffuse iron deposition caused by cirrhosis alone can be difficult because they may have similar signs, symptoms, and laboratory values. Although liver biopsy or genetic testing can differentiate between the two in most cases, this can also be accomplished with a rapid MR scan. A cirrhotic patient with pancreatic iron overload most likely has GH (see Figs. 2 and 3). In contrast, the pancreas of most cirrhotic patients who do not have GH reveals normal signal intensity. The degree of hepatic signal loss caused by iron is also lower in cirrhotics without GH.41, 42
SECONDARY HEMOCHROMATOSIS Transfusional Iron Deposition Disease The other main route of excess iron into the body is through multiple parenteral transfu-
Erythrogenic HemochromatosisThalassemia without Transfusion In diseases of ineffective erythropoiesis, such as thalassemia major, erythropoietic tissues in the bone marrow increase the demand
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Figure 5. Iron overload secondary to multiple transfusions in a 51-year-old man with leukemia. A, Axial T1-weighted opposed-phase GRE image (TR ⳱ 235, TE ⳱ 2.1, flip angle ⳱ 90⬚) shows that whereas the liver (L) is higher signal intensity than the spleen (S), both these organs are of much lower signal intensity than pancreas (P) and paraspinal muscle (M). B, In-phase image (similar imaging parameters except TE ⳱ 4.2) obtained at the same level as Figure 5A shows moderate to marked loss of signal intensity of the liver (L) and spleen (S) indicating iron overload. C, Heavily T2*weighted GRE image (TR ⳱ 117, TE ⳱ 20, flip angle ⳱ 20⬚) shows liver and spleen signal intensity to be equal to background noise. The pancreas (p) is of minimally lower signal intensity than paraspinal muscle (m) and may reflect early saturation of the reticuloendothelial system by iron.
for iron, resulting in excess absorption. This hyperplastic response is referred to as erythropoietic or erythrogenic hemochromatosis and can also be present in sideroblastic and megaloblastic anemias.51 Interestingly, the MR images of appearance of patients with erythropoietic hemochromatosis who have not undergone transfusion can be the same as that of patients with GH (see Fig. 1). Excess iron is preferentially deposited in parenchymal cells of the liver, as in GH, but it is not deposited in RE cells because the latter are able to mobilize their iron to meet the patient’s erythropoietic needs. Thus, in patients with either GH or erythrogenic hemo-
chromatosis, there is marked signal hypointensity on MR images within hepatic or pancreatic parenchyma and normal signal intensity in the spleen and bone marrow.43 The subgroup of transfusion-dependent thalassemic patients like other patients with transfusional iron overload, also has decreased splenic signal intensity caused by excess RE iron.51 FOCAL ACCUMULATIONS OF IRON Siderotic Liver Nodules Patients with hepatic cirrhosis caused by GH have been shown to be at increased risk
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for developing hepatocellular carcinoma (HCC).3, 30, 32 In addition, hepatic iron deposition may be a possible risk factor for the development of HCC, even in the absence of GH.10, 20 Patients with cirrhosis can accumulate hepatic iron in two ways. One pattern is mild deposition diffusely throughout the hepatic parenchyma (Fig. 6). The other pat-
tern is focally within regenerative nodules (Fig. 7).28 The liver is believed to be especially vulnerable to the potentially toxic and mutagenic effects of excessive tissue iron.10 Some investigators have attempted to use MR imaging to help establish a causal relationship. Ito and colleagues20 reported that the frequency of
Figure 6. Segmental hepatic iron overload and mild diffuse increase in liver iron in a 42-year-old man with a history of cirrhosis from hepatitis C and prior splenectomy. A, Axial T1-weighted opposedphase GRE (TR ⳱ 180, TE ⳱ 2.1, flip angle ⳱ 90⬚) shows normal signal intensity liver (L) and an absent spleen. There is a very subtle wedge-shaped region of lower signal intensity in a subcapsular portion of the right lobe of the liver (arrows). Based on this image alone, distinguishing between segmental iron overload and focal hepatic steatosis is not possible. B, In-phase image (similar imaging parameters except TE ⳱ 4.2) obtained at the same level shows even lower segmental signal intensity (arrows). Had the low signal intensity on the opposed-phase image been secondary to steatosis, it may be expected that this region is isointense or hyperintense to the surrounding liver on this in-phase image. C, Heavily T2*-weighted GRE image (TR ⳱ 100, TE ⳱ 20, flip angle ⳱ 20⬚) shows moderate to marked segmental signal loss (arrows) indicating focal iron overload. The remainder of the liver is mildly hypointense relative to skeletal muscle (m) indicating mild iron deposition. Without the presence of the spleen, it is impossible to determine if the liver iron is secondary to chronic liver disease or prior transfusions based on the MR images alone. The small amounts of iron in the surrounding liver was not enough to result in demonstrable signal loss on the T1-weighted GRE images in A and B.
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Figure 7. Use of GRE images to reveal siderotic nodules in a 45-year-old man with cirrhosis secondary to hepatitis C. A, Axial FSE T2-weighted image (TR ⳱ 4500, TE ⳱ 102) shows several low signal intensity foci (arrows) within the posterior segment of the right lobe of the liver. It is difficult to distinguish a potential siderotic nodule from normal flow void within some of the central lesions. B, Corresponding heavily T2*-weighted GRE sequence (TR ⳱ 100, TE ⳱ 20, flip angle ⳱ 20⬚) shows a greater number of very low signal intensity siderotic nodules (white arrows) and high signal intensity within intrahepatic portal venous branches (curved arrow). The authors use heavily T2*-weighted sequences to qualitatively assess the degree of hepatic iron overload and to reveal siderotic nodules. It is the latter that often provides the best depiction of the nodular components of a cirrhotic liver. Siderotic nodules of the spleen (black arrows) (Gamna Gandy bodies) are better revealed on this sequence.
HCC in patients with siderotic regenerative nodules visible with MR imaging was significantly higher than that in patients without iron in such nodules. The presence of such nodules is not necessary for HCC development because some patients in their study had HCC without siderotic regenerative nodules. They suggest two possible mechanisms for the carcinogenetic effect of hepatic iron. The first is a direct one in which free cellular iron may induce mutations by generating reactive oxygen species. An indirect possibility is that excess hepatic iron may facilitate the persistence of chronic hepatitis B and C viral infections, which are major risk factors for the development of HCC.20 Chapoutot and colleagues 10 indirectly support this theory with their report that liver iron deposition was more common in hepatitis C–infected patients who developed HCC than in hepatitisC patients who did not. Krinsky and colleagues 24 showed no increase in HCC or dysplastic nodules in patients with siderotic nodules when they com-
pared these liver findings with explanted livers. By not performing explant sectioning, Ito and colleagues20 may have missed small foci of HCC in their non-HCC control group and thus overestimated the relationship between siderotic nodules and the presence of HCC. Even though it remains unclear whether iron-containing nodules are at risk for developing foci of dysplasia and hepatocellular carcinoma, MR imaging is useful for detecting and characterizing any foci of cancer that develop within iron-rich nodules. Because the cells that constitute HCCs tend to lose the ability to store excess iron, the tumors appear as bright nodules within a dark nodule on T2- or T2*-weighted images. This distinctive ‘‘nodule in a nodule’’ pattern should be considered HCC until proved otherwise.25 Longitudinal MR imaging studies of such lesions have demonstrated rapid interval growth, suggesting that aggressive treatment should be considered.39 We have found that heavily T2*-weighted images are also helpful
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Figure 8. Diffuse hepatocellular carcinoma and siderotic regenerating nodules in a 68-year-old man with alcoholic cirrhosis. A, Axial T2-weighted FSE image (TR ⳱ 4800, effective TE ⳱ 84) shows a nodular contour of the liver and ascites (A) in keeping with cirrhosis and portal hypertension. There is an infiltrating mass (M) of the left lobe of the liver with extension into the right lobe (arrow). B, Heavily T2*-weighted GRE image (TR ⳱ 100, TE ⳱ 9, flip angle ⳱ 20⬚) obtained at the same level provided better contrast between tumor (M and arrow) and surrounding cirrhotic liver. An additional nodule of hepatoma (small arrow) is better delineated in the right lobe. The cells, which comprise hepatoma, unlike hepatocytes that are not involved by tumor, tend to lose the ability to store excess iron. Thus, T2*-weighted images may show better tumor-liver contrast in patients with iron deposition of the liver.
in delineating the extent of infiltrating HCC in cirrhotic livers that contain iron. Any ironspared region of liver should be considered cancer (Fig. 8).
Segmental Iron Accumulation Reports on multiple patients have linked increased hepatic iron levels to alterations in portal flow. In cases of portal compression, thrombosis, and shunting, segmental or lobar regions of decreased signal intensity corresponded to increased hepatocyte iron at histologic examination. 22, 23, 29 Hepatocytes normally receive their iron supply from the portal flow. Therefore, it is likely that the abnormal accumulation in these cases was caused by a decreased release of iron secondary to metabolic disturbance rather than an increased accumulation. MR imaging can reveal these segmental areas of increased iron and exclude a diagnosis of an associated malignancy (see Fig. 6).
References 1. Adams PC, Flanagan PR, Chau L, et al: Monocyte membrane ferritin in hemochromatosis. Clin Invest Med 14:402–408, 1991 2. Anderson GJ, Powell LW: Of metals, mice, and men: What animal models can teach us about body iron loading [comment]. J Clin Invest 105:1185–1186, 2000 3. Andrews NC: Disorders of iron metabolism [published erratum appears in N Engl J Med 342:364, 2000; see comments]. N Engl J Med 341:1986–1995, 1999 4. Angelucci E, Brittenham GM, McLaren CE, et al: Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 343:327–331, 2000 5. Angelucci E, Giovagnoni A, Valeri G, et al: Limitations of magnetic resonance imaging in measurement of hepatic iron. Blood 90:4736–4742, 1997 6. Barton JC, McDonnell SM, Adams PC, et al: Management off hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 129:932– 939, 1998 7. Blankenberg F, Eisenberg S, Scheinman MN, Higgins CB: Use of cine gradient echo (GRE) MR in the imaging of cardiac hemochromatosis. J Comput Assist Tomogr 18:136–138, 1994 8. Bradley WG, Jr: MR appearance of hemorrhage in the brain [see comments]. Radiology 189:15–26, 1993 9. Brandhagen DJ, Fairbanks VF, Batts KP, Thibodeau SN: Update on hereditary hemochromatosis and the HFE gene. Mayo Clin Proc 74:917–921, 1999 10. Chapoutot C, Esslimani M, Joomaye Z, et al: Liver
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iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis. Gut 46:711–714, 2000 Clark PR, St. Pierre TG: Quantitative mapping of transverse relaxivity (1/T(2)) in hepatic iron overload: A single spin-echo imaging methodology. Magn Reson Imaging 18:431–438, 2000 Ernst O, Sergent G, Bonvarlet P, et al: Hepatic iron overload: Diagnosis and quantification with MR imaging [see comments]. AJR Am J Roentgenol 168: 1205–1208, 1997 Farrell FJ, Nguyen M, Woodley S, et al: Outcome of liver transplantation in patients with hemochromatosis. Hepatology 20:404–410, 1994 Feder JN, Gnirke A, Thomas W, et al: A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis [see comments]. Nat Genet 13:399–408, 1996 Fillet G, Beguin Y, Baldelli L: Model of reticuloendothelial iron metabolism in humans: Abnormal behavior in idiopathic hemochromatosis and in inflammation. Blood 74: 844–851, 1989 Flanagan PR, Lam D, Banerjee D, Valberg LS: Ferritin release by mononuclear cells in hereditary hemochromatosis. J Lab Clin Med 113:145–150, 1989 Gandon Y, Guyader D, Heautot JF, et al: Hemochromatosis: Diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology 193:533– 538, 1994 Hayes AM, Jaramillo D, Levy HL, Knisely AS: Neonatal hemochromatosis: Diagnosis with MR imaging. AJR Am J Roentgenol 159:623–625, 1992 Hennemeyer C, Sundaram M: Radiologic case study. Post-transfusional reticuloendothelial system iron overload of sickle cell disease, secondary hemochromatosis. Orthopedics 23:303, 398–400, 2000 Ito K, Mitchell DG, Gabata T, et al: Hepatocellular carcinoma: Association with increased iron deposition in the cirrhotic liver at MR imaging. Radiology 212:235–240, 1999 Jensen PD, Bagger JP, Jensen FT, et al: Heart transplantation in a case of juvenile hereditary haemochromatosis followed up by MRI and endomyocardial biopsies. Eur J Haematol 51:199–205, 1993 Kadoya M, Matsui O, Kitagawa K, et al: Segmental iron deposition in the liver due to decreased intrahepatic portal perfusion: Findings at MR imaging. Radiology 193:671–676, 1994 Kawamori Y, Matsui O, Kitagawa K, et al: Segmental hepatic iron deposition due to peripheral portal vein tumor thrombus: MR features. J Comput Assist Tomogr 15:1042–1044, 1991 Krinsky GA, Lee VS, Nguyen MT, et al: Siderotic nodules in the cirrhotic liver at MR imaging with explant correlation: No increased frequency of dysplastic nodules and hepatocellular carcinoma. Radiology 218:47–53, 2001 Mitchell DG, Rubin R, Siegelman ES, et al: Hepatocellular carcinoma within siderotic regenerative nodules: Appearance as a nodule within a nodule on MR images. Radiology 178:101–103, 1991 Morrison ED, Kowdley KV: Genetic liver disease in adults. Early recognition of the three most common causes. Postgrad Med 107:147–152, 155, 158–159, 2000 Mosimann F, Gardaz JP, Fontolliet C, Gillet M: Fatal cardiomyopathy after liver transplantation for genetic hemochromatosis. Transplant Proc 26:3635– 3636, 1994 Murakami T, Nakamura H, Hori S, et al: CT and MRI
29. 30. 31. 32. 33. 34.
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of siderotic regenerating nodules in hepatic cirrhosis. J Comput Assist Tomogr 16:578–582, 1992 Murphy FB, Bernardino ME: MR imaging of focal hemochromatosis. J Comput Assist Tomogr 10:1044– 1046, 1986 Niederau C, Erhardt A, Haussinger D, Strohmeyer G: Haemochromatosis and the liver. J Hepatol 30(suppl 1):6–11, 1999 Niederau C, Stremmel W, Strohmeyer G: Haemochromatosis. Ergeb Inn Med Kinderheilkd 55:117– 148, 1987 Niederau C, Stremmel W, Strohmeyer GW: Clinical spectrum and management of haemochromatosis. Baillieres Clin Haematol 7:881–901, 1994 Olynyk JK: Hereditary haemochromatosis: Diagnosis and management in the gene era. Liver 19:73–80, 1999 Papakonstantinou O, Kostaridou S, Maris T, et al: Quantification of liver iron overload by T2 quantitative magnetic resonance imaging in thalassemia: Impact of chronic hepatitis C on measurements. J Pediatr Hematol Oncol 21:142–148, 1999 Pietrangelo A, Montosi G, Totaro A, et al: Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 341:725–732, 1999 Powell LW, George DK, McDonnell SM, Kowdley KV: Diagnosis of hemochromatosis [see comments]. Ann Intern Med 129:925–931, 1998 Robson KJ, Merryweather-Clarke AT, Pointon JJ, et al: Diagnosis and management of haemochromatosis since the discovery of the HFE gene: A European experience. Br J Haematol 108:31–39, 2000 Rouault TA: Hereditary hemochromatosis. JAMA 269:3152–3154, 1993 Sadek AG, Mitchell DG, Siegelman ES, et al: Early hepatocellular carcinoma that develops within macroregenerative nodules: Growth rate depicted at serial MR imaging. Radiology 195:753–756, 1995 Siegelman ES: MR imaging of diffuse liver disease. Hepatic fat and iron. Magn Reson Imaging Clin North Am 5:347–365, 1997 Siegelman ES, Mitchell DG, Outwater E, et al: Idiopathic hemochromatosis: MR imaging findings in cirrhotic and precirrhotic patients. Radiology 188:637– 641, 1993 Siegelman ES, Mitchell DG, Rubin R, et al: Parenchymal versus reticuloendothelial iron overload in the liver: Distinction with MR imaging [see comments]. Radiology 179:361–366, 1991 Siegelman ES, Mitchell DG, Semelka RC: Abdominal iron deposition: Metabolism, MR findings, and clinical importance. Radiology 199:13–22, 1996 Siegelman ES, Outwater EK: Magnetic resonance imaging of focal and diffuse hepatic disease. Semin Ultrasound CT MR 19:2–34, 1998 Siegelman ES, Outwater EK: MR imaging techniques of the liver. Radiol Clin North Am 36:263–286, 1998 Sparacia G, Iaia A, Banco A, et al: Transfusional hemochromatosis: Quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism. Radiology 215:818–823, 2000 Surakomol S, Olson LJ, Rastogi A, et al: Combined orthotopic heart and liver transplantation for genetic hemochromatosis. J Heart Lung Transplant 16:573– 575, 1997 Tsushima Y, Dean PB: Characterization of adrenal
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masses with chemical shift MR imaging: How to select echo times. Radiology 195:285–286, 1995 49. Waxman S, Eustace S, Hartnell GG: Myocardial involvement in primary hemochromatosis demonstrated by magnetic resonance imaging. Am Heart J 128:1047–1049, 1994
50. Worwood M: Pathogenesis and management of haemochromatosis. Br J Haematol 105(suppl 1):16– 18, 1999 51. Yoon DY, Choi BI, Han JK, et al: MR findings of secondary hemochromatosis: Transfusional vs erythropoietic. J Comput Assist Tomogr 18:416–419, 1994 Address reprint requests to Evan S. Siegelman, MD Department of Radiology University of Pennsylvania Medical Center 3400 Spruce Street 1st Floor Silverstein Philadelphia, PA 19104–4283 e-mail: [email protected]
MR IMAGING OF THE LIVER II: DISEASES
MR IMAGING OF IRON DEPOSITIONAL DISEASE Stuart Pomerantz, MD, and Evan S. Siegelman, MD
NORMAL PHYSIOLOGY To discriminate among the different causes of iron deposition in the liver, an understanding of the physiology of normal iron metabolism is helpful. Because of its capability to readily accept and donate electrons (alternating between ferric [Fe2] and ferrous [Fe3] states), iron serves as a useful component of cytochromes, the oxygen-binding molecules hemoglobin and myoglobin, and various enzymes. Iron overload, however, has the ability to damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that can induce oxidative damage to cellular membranes, proteins, and DNA. In some instances, the oxidative changes of iron overload can initiate and promote cancer growth.3, 10 Adult men normally have about 5 g of total body iron; approximately 70% of this iron is present within hemoglobin. An additional 10% to 15% of body iron is present within muscle fibers as myoglobin. The body can absorb 1 to 2 mg of iron daily, which is much smaller than the 20 mg daily requirement of hematopoietic tissue. Thus, in addition to the dietary iron absorbed by the duodenal enterocytes, iron must be efficiently recycled from
senescent erythrocytes. In a process known as extravascular hemolysis, red blood cells are ingested by reticuloendothelial (RE) macrophages. The RE cells catabolize hemoglobin for reusable iron, which is transferred and bound to the serum protein transferrin. Excess iron is bound to ferritin and hemosiderin within hepatic parenchymal cells (hepatocytes) and within the RE cells of the liver (Kupffer’s cells), spleen, and bone.3 The regulation of intestinal iron absorption is incompletely understood. Nevertheless, control at the absorption stage is critical because humans have no physiologic mechanism for iron excretion.3, 4 Iron absorption is modulated in at least three ways. A local limit on cellular absorption, previously known as a mucosal block, is modified based on the amount of iron recently consumed in the diet. Absorption may also respond to overall body stores of iron and is modulated by the iron saturation level of plasma transferrin. The third method of absorption involves the erythropoietic regulator, which increases or decreases iron absorption in response to requirements for erythropoiesis through an unknown mechanism.3 Iron overload within the body occurs by two distinct pathways: increased gastrointes-
From the Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
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tinal absorption or intravenous blood transfusion. The iron overload syndromes that result from increased gastrointestinal absorption cause excess parenchymal iron deposition and are best exemplified by genetic hemochromatosis (GH). This entity is a primary focus of this review because of its prevalence and the clinical importance of establishing an early diagnosis. Entities with similar pathologic mechanisms, such as erythropoietic hemochromatosis, are also discussed. In contrast, iron overload secondary to blood transfusions initially causes deposition within the RE cells of the liver, spleen, and bone marrow and results in different clinical and imaging findings.44
MR Imaging of Iron Overload Before evaluating the imaging features of specific iron overload entities, the physical properties that allow visualization of iron with MR imaging must be reviewed. Iron is a paramagnetic substance that acquires a strong magnetization when placed within a magnetic field. Intracellular iron (in the form of deoxyhemoglobin, methemoglobin, ferritin, or hemosiderin) results in focal hot spots of magnetic nonuniformity. Adjacent water protons lose phase coherence within these foci of magnetic nonuniformity, resulting in signal loss. The magnetic susceptibility effects of
iron thus result in areas of low signal intensity on MR images.8, 44 T2-weighted and heavily T2*-weighted sequences generate the most susceptibility to the paramagnetic effects of iron and are thus used in evaluating iron depositional disease. These sequences can provide both qualitative and quantitative measures of iron accumulation.45 T2*-weighted gradient-echo (GRE) images have been shown to have a greater sensitivity for mild degrees of hepatic iron than spin-echo T2 sequences (Fig. 1). Because GRE sequences lack the 180 ‘‘refocusing’’ pulses of standard spin-echo sequences, this loss of phase is allowed to accumulate, resulting in rapid loss of transverse magnetization and thus loss of signal intensity. A wide variety of GRE techniques can be used to qualitatively evaluate iron overload. At 1.5 T, we recommend a breath-hold T2*weighted GRE sequence. We select a repetition time (TR) of 100 to 300 milliseconds so we can image in a single breath-hold. The TR has less effect on the degree of T2* weighting than does the choice of echo time and flip angle. The authors of this article recommend a minimum echo time of 7 milliseconds and prefer 15 milliseconds or more. At lower field strengths, echo time should be increased appropriately. The flip angle can vary but ideally should be less than 30 to minimize the influence of T1 differences between tissues.43
Figure 1. MR demonstration of secondary hemochromatosis in a 36-year-old man with Thalassemia who has not had prior blood transfusions. A, Axial T1-weighted opposed-phase gradient-echo (GRE) image (TR 240, TE 2.1, flip angle 90) shows normal signal intensity of the liver (L) and spleen (S) and pancreas (arrow). B, In-phase image (same parameters except TE 4.2) shows greater loss of signal intensity in the liver compared with spleen. The pancreas remains normal signal intensity. C, Out-of-phase image obtained with a longer echo time (same parameters except TE 6.3) reveals that the liver is lower signal intensity than the spleen. Had not the shorter TE opposedphase image been performed, it may not have been possible to distinguish hepatic signal loss from iron deposition or steatosis. Thus, when attempting to diagnose intracellular lipid by chemical shift imaging, an opposed-phase image of shorter TE should be performed.48 Otherwise potential T2* shortening effects of hepatic iron could create a false-positive diagnosis of steatosis of the liver. Of potential greater clinical importance, a hemorrhagic adrenal mass could be mischaracterized as an adrenal adenoma by the same mechanism. D, Heavily T2*-weighted GRE image (TR 100, TE 20, flip angle 20) shows near signal void of the liver and only mild signal loss of the spleen. The pancreas remains of normal signal intensity. E, T2-weighted breath-hold fast spin-echo (FSE) image (TR infinite, effective TE 93) reveals pancreas (arrow) and spleen (S) signal intensity to be greater than that of paraspinal muscle (m) and liver (L) to be of lower signal intensity. Normal liver should have higher signal intensity than muscle of moderately weighted turbo or FSE sequences. Note the greater degree of signal loss within the liver on the heavily T2*-weighted image, (D), compared with this FSE image.
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Figure 1. See legend on opposite page
GENETIC HEMOCHROMATOSIS Genetics Hemochromatosis was originally described in the late nineteenth century by Trousseau, and the term hemochromatosis was first used by von Recklinghausen in 1889 to describe
the postmortem findings in patients who had died from bronzed diabetes.33, 37 In 1975, a genetic basis for hemochromatosis was established by human leukocyte antigen (HLA) linking, which revealed an autosomal recessive pattern. 37 This hereditary or primary form of hemochromatosis has come to be referred to as genetic hemochromatosis (GH) in
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distinction from other primary and secondary forms of iron overload. In 1996, Feder and colleagues14 described a novel gene termed HFE on the short arm of chromosome 6 containing 2 missense mutations.14 One mutation, C282Y, is homozygous in 83% of patients with GH. The second mutation, H63D, is not associated with the same degree of iron overload as the C282Y mutation. In 1998, an HFE gene knockout mouse was created, which has facilitated GH and iron metabolism research at the molecular level.2, 9
Pathophysiology The function of the HFE gene is not fully understood. The product of the HFE gene is a cell-surface protein that binds to transferrin and is expressed in all tissues except the brain. Its exact role in the regulation of iron transport and storage is unclear. Some have proposed a model in which the abnormal gene product primarily affects the role of duodenal crypt cells, which act as sensors for total body iron stores. If the levels of transferrin-bound iron in the serum cannot be sensed, the crypt cells will falsely register an iron-deficient state. This results in an increase in absorption of luminal iron by upregulating cell-surface transporter proteins.33 Others suggest that the effect of the HFE gene may be more systemic.30, 50 In patients with GH, RE cells have been shown to have early release of intracellular ferritin and are incapable of storing excess iron.1, 15, 16 This defect results in increased iron deposition in parenchymal cells of organs such as the liver, heart, and pancreas.43 This pattern of selective iron deposition results in suggestive abdominal MR imaging findings that are described below.
Epidemiology Advances in the epidemiology of GH have followed the recent genetic discoveries. Originally considered uncommon, GH is now recognized to be the most common genetic disorder among persons of northern European
ancestry.30 GH is also the most common genetic disorder among the white population in the United States, although it is less frequent among other groups of Americans. In the United States, 1 in every 250 to 300 persons is homozygous for the hemochromatosis mutation, and at least 1 in every 10 persons is a carrier for the mutation.9
Screening/Genetic Testing Issues Although the goal is to identify individuals at most risk for developing iron overload before they develop life-threatening conditions, a number of factors prevent consensus on guidelines for population screening. One complicating factor is the incomplete penetrance of the HFE gene mutations. The reported percentages of homozygous individuals who manifest clinical signs of GH vary from approximately 25% to 50%, with more severe sequelae (such as hepatic fibrosis or cirrhosis) developing in only about 10%.9, 31, 33, 36, 37, 50 Moreover, not all patients with a clinical presentation of GH are C282Y homozygotes, even those with end-stage symptoms. From 0.5% to 14% of patients with clinical signs and symptoms of GH are actually heterozygotes.36 The importance of HFE mutations other than C282Y is also controversial. Pooled data from US and European studies have shown an increased risk of end-stage disease in H63D homozygotes and an even larger risk in compound heterozygotes (those heterozygous for both C282Y and H63D alleles) compared with the general population. 9 Some groups, such as Italians and African-Americans, have a clearly higher proportion of patients with primary iron overload and typically do not carry any known HFE mutations.35, 37 Environmental factors and coexisting disease also play an important role in the expression of the hemochromatosis gene. Dietary intake of red meat varies from person to person and among cultures. Patients can promote iron overload with iron supplements. Additionally, vitamin C has been shown to increase iron absorption. Coexisting disease can be one of the most powerful cofactors
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affecting the penetrance of the hemochromatosis gene. Hepatitis, alcoholism, and porphyria cutanea tarda all increase hepatic iron stores and can accelerate organ damage, even in heterozygous patients. Conversely, the presence of undetected abnormal HFE alleles may in part explain why there is such variation in the degree of organ damage from common insults such as infectious hepatitis and alcoholism.9, 50 Although widespread population screening for HFE mutations may be premature at this time, genetic testing, which is commercially available, has a role in the evaluation of a patient with signs, symptoms, or MR image findings suspicious for the disease. Genetic testing is useful to resolve ambiguous cases as well as to confirm the diagnosis in younger patients with abnormal blood chemistry panels. This latter group is less likely to have accrued organ damage.36 Genetic testing is most useful for screening high-risk groups, such as siblings of an identified proband (who by definition have a 25% chance of being homozygous for GH) and possibly patients with diabetes or arthritis. Genetic identification also allows treatment (described below) to begin early, which is crucial for preventing irreversible sequelae of iron deposition.9, 33, 37
Clinical Features and Diagnosis of GH—5 physicians, 5 years Organ dysfunction results from iron deposition in the liver and subsequently in the pancreas, myocardium, pituitary gland, and synovium. Serologic abnormalities and mild symptoms may occur earlier in life, but the clinical signs and symptoms that cause patients to seek medical help generally do not appear until the fifth or sixth decade of life. These findings include lethargy, arthralgia, loss of libido, glucose intolerance, abdominal pain, and heart failure.33 Although GH is the most common primary iron overload disease and is more prevalent in the population than previously realized, it still remains underdiagnosed. This failure of diagnosis can be attributed to lack of aware-
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ness of GH, its long latency period, and nonspecific signs and symptoms. It has been estimated that the average patient with GH sees at least 5 physicians and waits 5 years between the initial onset of signs or symptoms and the time of diagnosis and treatment.38, 43 If untreated, patients with GH may progress to cirrhosis and liver failure. Hepatocellular carcinoma (HCC) occurs in up to 36% of cases and often is the cause of death. Diabetes appears in up to 80% of patients, with increasing insulin dependence occurring as pancreatic B-cell damage progresses. Cardiac abnormalities, including cardiomyopathy and arrhythmias, occur in 15% to 40% of patients.30, 32, 33 Women with GH tend to have less severe manifestations of the disease secondary to iron loss with menstruation and pregnancy. A minority of women, however, can still develop clinical disease, but more often at a later age than affected men.36 The site of earliest and heaviest iron deposition is in the liver in the form of ferritin and hemosiderin. The initial distribution of iron in the liver is within the periportal hepatocytes. If untreated, the liver disease progresses to perilobular fibrosis and ultimately to cirrhosis. Approximately 30% of cirrhotic patients with GH develop HCC, even years after phlebotomy therapy has reduced body iron stores.30 The relationship of iron to hepatic cirrhosis and neoplasia has not been fully clarified. Excess iron in hepatocytes may stimulate the release of profibrogenic substances that cause the liver to produce the collagen bundles characteristic of cirrhotic scarring. Iron may also result in lipid peroxidation, which promotes DNA damage and subsequent carcinogenesis.19, 33
Diagnosis of GH Screening tests for GH, including serum ferritin levels and transferrin saturation, are available as part of standard chemistry panels. They are useful for alerting clinicians to patients who may have GH. For definitive diagnosis and subsequent monitoring of hemochromatosis therapy, a reliable means of evaluating body iron stores would be ideal.
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Ferritin and transferrin saturation values may not accurately reflect the body iron store because of their lack of specificity and sensitivity. False-positive results are seen in alcoholism and infection because of the role of transferrin as an acute-phase reactant. Falsenegative results occur in young patients with hemochromatosis but very low levels of iron overload. 17 Thus, positive results of blood chemistry tests have in the past been confirmed with a liver biopsy. Liver biopsy has long been considered the gold standard for diagnosis of hemochromatosis because it allows both histologic evaluation and quantitative determination of hepatic iron concentration. The degree and distribution of iron overload confirm the presence of hemochromatosis. Histologic evaluation allows detection of hepatic cirrhosis. The presence and severity of cirrhosis are key determinants of prognosis and management, especially with regard to monitoring for hepatocellular carcinoma.36 Since the discovery of the GH gene, however, genetic testing is now possible in patients who are found to have an elevated serum ferritin or transferrin saturation. Patients with a positive genetic test may or may not be considered for a subsequent liver biopsy. Some physicians believe that asymptomatic patients with only minimally elevated serum markers or those with already known advanced cirrhosis30 could avoid biopsy and simply proceed to treatment (described below). Like those who have asked whether genetic testing could replace the need for liver biopsy, others have wondered if MR imaging could accomplish the same feat. Through the evolution of increasingly sophisticated MR imaging techniques, even very low levels of iron deposition are detectable in a qualitative and quantitative fashion on high-field systems.17 Because MR imaging does not generate absolute signal intensities, this type of analysis relies on comparison with an internal standard, such as fat or skeletal muscle. Skeletal muscle is a reliable internal standard because it has been shown to have no significant difference in T2 values over a wide range of
total body iron stores. In patients with GH, no change in muscle signal intensity was present with phlebotomy treatment. Thus, serial MR imaging examinations may be helpful to monitor the efficacy of phlebotomy therapy.43 The issue of whether MR imaging can replace biopsy is dependent on the necessity of knowing the liver iron concentration to confirm a diagnosis of hemochromatosis in patients without the HFE gene or a wild-type mutation35 or to assess treatment response. Unfortunately, a widely applicable quantitative analysis of iron stores by MR imaging has not yet been developed. Numerous investigators have succeeded in correlating T2 or T2* relaxation times with specific measures of liver iron content.5, 11, 12, 17, 34 Unfortunately, differences in background noise caused by radiofrequency tuning, field of view, matrix, and field strength, as well as numerous other system-dependent factors, exert an effect on the estimate of iron deposition. Consequently, this type of quantitation, though technically possible, may be feasible only at an institution where a large enough series of biopsy samples can be correlated with data from MR images to generate a best-fit equation. Even then, the same pulse sequence and imaging parameters must be performed on the same machine each time for the estimated iron concentration to have validity.17, 43 So, what is the role of MR imaging in the evaluation of GH now that a genetic test for the disease is readily available? In patients with known GH, MR imaging can noninvasively evaluate the distribution of iron in the body and reveals complications of the disease (Figs. 2 through 4). In the liver, MR imaging can reveal findings of cirrhosis or HCC (see Fig. 3). Iron overload of the pancreas is suggestive of advanced disease and could explain the cause of a patient’s diabetes. MR imaging of the pituitary gland can reveal low signal intensity on T2-weighted images secondary to iron deposition, which could explain a patient’s impotence or loss of libido.46 Finally, MR imaging has a role in the evaluation of myocardial iron deposition (see Fig. 4). Cardiac involvement is present in up to 15% of adults with GH; 30% of this progresses
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Figure 2. Genetic hemochromatosis (GH) in a 29-year-old man. A, Axial T1-weighted opposed-phase GRE image (TR 250, TE 1.8, flip angle 90) shows low signal intensity liver (L) and very low signal intensity pancreas (p). B, In-phase image (similar imaging parameters except TE 4.2) obtained at the same level shows marked loss of signal of the liver (L) and pancreas (p) secondary to iron overload. C, In-phase image (TE 4.2) obtained higher within the abdomen shows a near normal signal intensity of the spleen (S). This is the typical distribution of abdominal iron in advanced GH.
to cardiomyopathy, often complicated by arrhythmias.13, 36 The onset of cardiac failure is a very poor prognostic sign, with death occurring within 6 months in most cases.21, 33 In patients who present before 30 years of age, cardiomyopathy is much more frequent and is often the cause of death.21, 30, 36 Determination of cardiac involvement in cirrhotic patients with GH will influence whether the patient is a candidate for orthotopic liver transplant (OLT). Disappointing survival rates in GH patients who have undergone OLT have been partially attributed to iron-induced cardiomyopathy that often does not manifest until the post-transplantation period.13 MR image findings of iron overload of the heart may be a contraindication
for liver transplantation or may suggest the need for combined heart and liver transplantation.27, 47 The detection of cardiac iron overload is usually accomplished by right ventricle biopsy. In comparison, MR image detection of cardiac iron is noninvasive and may be more accurate than biopsy because of possible biopsy sampling error. The anatomic distribution of cardiac iron has been shown in tissue specimens to be either heterogeneous or concentrated in a subepicardial rather than subendomyocardial location.21 Therefore, up to 30% of right ventricular biopsies may yield false-negative results.7 In contrast, spin-echo and GRE sequences have been shown to be sensitive to cardiac iron deposition, and the
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Figure 3. GH and hepatocellular carcinoma in a 41-year-old man. A, Axial T1-weighted opposedphase GRE image (TR 150, TE 1.8, flip angle 60) shows lower signal intensity of the liver (L) than the spleen (S). On this opposed-phase image alone, it is difficult to determine whether the low signal intensity of the liver is secondary to the chemical shift effects of hepatic steatosis or to the magnetic susceptibility effects of hepatic iron overload. There is a subtle subcapsular mass of the right lobe of the liver (arrow). The mass is of higher signal intensity than surrounding liver and is isointense to spleen. B, Corresponding in-phase GRE image (similar parameters except TE 4.2) shows dramatic signal loss of the liver (L) and pancreas (p) secondary to the T2* effects that become more dominant with a longer TE. There is improved tumor-liver (arrow) contrast. Most hepatocellular carcinomas are relatively resistant to iron overload and thus are readily revealed on T2*- or T2weighted images in patients with hepatic iron overload. C, Axial T2-weighted FSE image (TR 3550, TE 88 milliseconds) obtained at a slightly different level through the liver shows abnormal low signal intensity of the liver (L) and pancreas (P) and normal signal intensity of the spleen (S). This is the typical distribution of abdominal iron in advanced GH.
Figure 4. MR demonstration of iron overload of the myocardium in a 51-year-old man with genetic hemochromatosis, cirrhosis, and liver failure who was being considered for liver transplantation. A, Heavily T2*-weighted GRE image (TR 100 millisecond, flip angle 90, TE 20 millisecond) through the level of the interatrial septum shows very low signal intensity myocardium (***) indicative of iron deposition within the myocardium. Lower images (not shown) revealed iron overload of the liver. Because of the presence of myocardial iron, the patient was no longer considered a candidate for a liver transplant without also a heart transplant. The patient died shortly after MR imaging. B, Gross photograph of the heart at autopsy shows marked iron overload within the right ventricle (arrow) stained with Prussian blue. The left ventricle (curved arrow) shows bronzed discoloration. The myocardium is both dilated and hypertrophied. C, Histologic section of the myocardium obtained at autopsy shows marked iron deposition (curved arrow) in the myocytes (Prussian blue original stain, magnification 40). Myocyte hypertrophy is present as evidenced by enlarged nuclei (long arrow), which normally should be only twice the size as an erythrocyte (short arrow).
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Figure 4. See legend on opposite page
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direct multiplanar capabilities of MR imaging allows demonstration of the entire myocardium.l8, 21, 49
Treatment of GH Once a diagnosis of GH has been made, treatment consists of a vigorous schedule of phlebotomy. Depletion of excess iron usually requires 50 to 150 phlebotomies over a 9to 24-month period. After this initial iron is removed, 4 to 10 additional phlebotomies per year are required to prevent excess iron reaccumulation. 6 30 If treatment is initiated in the early stages of the disease, patients can progress to a normal life expectancy. If left untreated, parenchymal deposition results in significant organ dysfunction and damage. Even patients with only mild to moderate organ damage benefit from phlebotomy, with decreased complications of portal hypertension and preservation of cardiac function. Impotence and arthropathy, however, tend to have a poor response to therapy. 26 30 Neonatal Hemochromatosis Neonatal hemochromatosis is a severe and usually fatal disease characterized by massive hepatic iron deposition with fulminant liver failure presenting in the perinatal period. Liver transplantation is the only effective treatment but often is unsuccessful. 3 Neonatal hemochromatosis reveals the same iron distribution as GH, with progressive parenchymal involvement of the liver, pancreas, and myocardium, and sparing of the spleen. MR imaging evaluation of extrahepatic iron overload may be of specific value because marked siderosis of the liver can be physiologic in the perinate. Therefore, liver biopsy alone may result in an erroneous diagnosis.l8
sions. Iron from transfused erythrocytes is accumulated within the RE cells of the liver, spleen, and bone marrow (Fig. 5). If the number of transfusions is low, this type of iron deposition is clinically insignificant. The iron storage capacity of the RE system is 10 g, which is the amount of iron contained in 40 U of blood. Patients who receive much more than 40 U of blood can exceed the iron storage capacity of the RE system and develop iron overload of parenchymal cells. 4 0 , 51 These patients with transfusion-dependent severe anemias are treated with iron chelation therapy to prevent the sequelae of parenchymal iron deposition, such as cirrhosis and diabetes. One group of investigators found that quantitative imaging was accurate in estimating liver iron in transfusion-dependent patients who were being treated with chelation therapy, provided there was no underlying cirrhosis. 5 Cirrhosis with Diffuse Liver Siderosis Diffuse iron deposition also occurs in the liver of patients who have non-GH-induced cirrhosis. The degree of deposition is usually mild and does not require treatment. The cause of the excess iron deposition is not well understood but may be related to anemia, pancreatic insufficiency, or decreased transferrin synthesis. Differentiation between patients with GH and those with diffuse iron deposition caused by cirrhosis alone can be difficult because they may have similar signs, symptoms, and laboratory values. Although liver biopsy or genetic testing can differentiate between the two in most cases, this can also be accomplished with a rapid MR scan. A cirrhotic patient with pancreatic iron overload most likely has GH (see Figs. 2 and 3). In contrast, the pancreas of most cirrhotic patients who do not have GH reveals normal signal intensity. The degree of hepatic signal loss caused by iron is also lower in cirrhotics without GH.41, 42
SECONDARY HEMOCHROMATOSIS Transfusional Iron Deposition Disease The other main route of excess iron into the body is through multiple parenteral transfu-
Erythrogenic HemochromatosisThalassemia without Transfusion In diseases of ineffective erythropoiesis, such as thalassemia major, erythropoietic tissues in the bone marrow increase the demand
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Figure 5. Iron overload secondary to multiple transfusions in a 51-year-old man with leukemia. A, Axial T1-weighted opposed-phase GRE image (TR ⳱ 235, TE ⳱ 2.1, flip angle ⳱ 90⬚) shows that whereas the liver (L) is higher signal intensity than the spleen (S), both these organs are of much lower signal intensity than pancreas (P) and paraspinal muscle (M). B, In-phase image (similar imaging parameters except TE ⳱ 4.2) obtained at the same level as Figure 5A shows moderate to marked loss of signal intensity of the liver (L) and spleen (S) indicating iron overload. C, Heavily T2*weighted GRE image (TR ⳱ 117, TE ⳱ 20, flip angle ⳱ 20⬚) shows liver and spleen signal intensity to be equal to background noise. The pancreas (p) is of minimally lower signal intensity than paraspinal muscle (m) and may reflect early saturation of the reticuloendothelial system by iron.
for iron, resulting in excess absorption. This hyperplastic response is referred to as erythropoietic or erythrogenic hemochromatosis and can also be present in sideroblastic and megaloblastic anemias.51 Interestingly, the MR images of appearance of patients with erythropoietic hemochromatosis who have not undergone transfusion can be the same as that of patients with GH (see Fig. 1). Excess iron is preferentially deposited in parenchymal cells of the liver, as in GH, but it is not deposited in RE cells because the latter are able to mobilize their iron to meet the patient’s erythropoietic needs. Thus, in patients with either GH or erythrogenic hemo-
chromatosis, there is marked signal hypointensity on MR images within hepatic or pancreatic parenchyma and normal signal intensity in the spleen and bone marrow.43 The subgroup of transfusion-dependent thalassemic patients like other patients with transfusional iron overload, also has decreased splenic signal intensity caused by excess RE iron.51 FOCAL ACCUMULATIONS OF IRON Siderotic Liver Nodules Patients with hepatic cirrhosis caused by GH have been shown to be at increased risk
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for developing hepatocellular carcinoma (HCC).3, 30, 32 In addition, hepatic iron deposition may be a possible risk factor for the development of HCC, even in the absence of GH.10, 20 Patients with cirrhosis can accumulate hepatic iron in two ways. One pattern is mild deposition diffusely throughout the hepatic parenchyma (Fig. 6). The other pat-
tern is focally within regenerative nodules (Fig. 7).28 The liver is believed to be especially vulnerable to the potentially toxic and mutagenic effects of excessive tissue iron.10 Some investigators have attempted to use MR imaging to help establish a causal relationship. Ito and colleagues20 reported that the frequency of
Figure 6. Segmental hepatic iron overload and mild diffuse increase in liver iron in a 42-year-old man with a history of cirrhosis from hepatitis C and prior splenectomy. A, Axial T1-weighted opposedphase GRE (TR ⳱ 180, TE ⳱ 2.1, flip angle ⳱ 90⬚) shows normal signal intensity liver (L) and an absent spleen. There is a very subtle wedge-shaped region of lower signal intensity in a subcapsular portion of the right lobe of the liver (arrows). Based on this image alone, distinguishing between segmental iron overload and focal hepatic steatosis is not possible. B, In-phase image (similar imaging parameters except TE ⳱ 4.2) obtained at the same level shows even lower segmental signal intensity (arrows). Had the low signal intensity on the opposed-phase image been secondary to steatosis, it may be expected that this region is isointense or hyperintense to the surrounding liver on this in-phase image. C, Heavily T2*-weighted GRE image (TR ⳱ 100, TE ⳱ 20, flip angle ⳱ 20⬚) shows moderate to marked segmental signal loss (arrows) indicating focal iron overload. The remainder of the liver is mildly hypointense relative to skeletal muscle (m) indicating mild iron deposition. Without the presence of the spleen, it is impossible to determine if the liver iron is secondary to chronic liver disease or prior transfusions based on the MR images alone. The small amounts of iron in the surrounding liver was not enough to result in demonstrable signal loss on the T1-weighted GRE images in A and B.
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Figure 7. Use of GRE images to reveal siderotic nodules in a 45-year-old man with cirrhosis secondary to hepatitis C. A, Axial FSE T2-weighted image (TR ⳱ 4500, TE ⳱ 102) shows several low signal intensity foci (arrows) within the posterior segment of the right lobe of the liver. It is difficult to distinguish a potential siderotic nodule from normal flow void within some of the central lesions. B, Corresponding heavily T2*-weighted GRE sequence (TR ⳱ 100, TE ⳱ 20, flip angle ⳱ 20⬚) shows a greater number of very low signal intensity siderotic nodules (white arrows) and high signal intensity within intrahepatic portal venous branches (curved arrow). The authors use heavily T2*-weighted sequences to qualitatively assess the degree of hepatic iron overload and to reveal siderotic nodules. It is the latter that often provides the best depiction of the nodular components of a cirrhotic liver. Siderotic nodules of the spleen (black arrows) (Gamna Gandy bodies) are better revealed on this sequence.
HCC in patients with siderotic regenerative nodules visible with MR imaging was significantly higher than that in patients without iron in such nodules. The presence of such nodules is not necessary for HCC development because some patients in their study had HCC without siderotic regenerative nodules. They suggest two possible mechanisms for the carcinogenetic effect of hepatic iron. The first is a direct one in which free cellular iron may induce mutations by generating reactive oxygen species. An indirect possibility is that excess hepatic iron may facilitate the persistence of chronic hepatitis B and C viral infections, which are major risk factors for the development of HCC.20 Chapoutot and colleagues 10 indirectly support this theory with their report that liver iron deposition was more common in hepatitis C–infected patients who developed HCC than in hepatitisC patients who did not. Krinsky and colleagues 24 showed no increase in HCC or dysplastic nodules in patients with siderotic nodules when they com-
pared these liver findings with explanted livers. By not performing explant sectioning, Ito and colleagues20 may have missed small foci of HCC in their non-HCC control group and thus overestimated the relationship between siderotic nodules and the presence of HCC. Even though it remains unclear whether iron-containing nodules are at risk for developing foci of dysplasia and hepatocellular carcinoma, MR imaging is useful for detecting and characterizing any foci of cancer that develop within iron-rich nodules. Because the cells that constitute HCCs tend to lose the ability to store excess iron, the tumors appear as bright nodules within a dark nodule on T2- or T2*-weighted images. This distinctive ‘‘nodule in a nodule’’ pattern should be considered HCC until proved otherwise.25 Longitudinal MR imaging studies of such lesions have demonstrated rapid interval growth, suggesting that aggressive treatment should be considered.39 We have found that heavily T2*-weighted images are also helpful
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Figure 8. Diffuse hepatocellular carcinoma and siderotic regenerating nodules in a 68-year-old man with alcoholic cirrhosis. A, Axial T2-weighted FSE image (TR ⳱ 4800, effective TE ⳱ 84) shows a nodular contour of the liver and ascites (A) in keeping with cirrhosis and portal hypertension. There is an infiltrating mass (M) of the left lobe of the liver with extension into the right lobe (arrow). B, Heavily T2*-weighted GRE image (TR ⳱ 100, TE ⳱ 9, flip angle ⳱ 20⬚) obtained at the same level provided better contrast between tumor (M and arrow) and surrounding cirrhotic liver. An additional nodule of hepatoma (small arrow) is better delineated in the right lobe. The cells, which comprise hepatoma, unlike hepatocytes that are not involved by tumor, tend to lose the ability to store excess iron. Thus, T2*-weighted images may show better tumor-liver contrast in patients with iron deposition of the liver.
in delineating the extent of infiltrating HCC in cirrhotic livers that contain iron. Any ironspared region of liver should be considered cancer (Fig. 8).
Segmental Iron Accumulation Reports on multiple patients have linked increased hepatic iron levels to alterations in portal flow. In cases of portal compression, thrombosis, and shunting, segmental or lobar regions of decreased signal intensity corresponded to increased hepatocyte iron at histologic examination. 22, 23, 29 Hepatocytes normally receive their iron supply from the portal flow. Therefore, it is likely that the abnormal accumulation in these cases was caused by a decreased release of iron secondary to metabolic disturbance rather than an increased accumulation. MR imaging can reveal these segmental areas of increased iron and exclude a diagnosis of an associated malignancy (see Fig. 6).
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masses with chemical shift MR imaging: How to select echo times. Radiology 195:285–286, 1995 49. Waxman S, Eustace S, Hartnell GG: Myocardial involvement in primary hemochromatosis demonstrated by magnetic resonance imaging. Am Heart J 128:1047–1049, 1994
50. Worwood M: Pathogenesis and management of haemochromatosis. Br J Haematol 105(suppl 1):16– 18, 1999 51. Yoon DY, Choi BI, Han JK, et al: MR findings of secondary hemochromatosis: Transfusional vs erythropoietic. J Comput Assist Tomogr 18:416–419, 1994 Address reprint requests to Evan S. Siegelman, MD Department of Radiology University of Pennsylvania Medical Center 3400 Spruce Street 1st Floor Silverstein Philadelphia, PA 19104–4283 e-mail: [email protected]