Abdomen / Update in radiology Rev. Argent. Radiol. 2013;77(2):139-146 23 Introduction Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodyspla- sia, thalassemia, etc. (secondary hemochromatosis). Clinical diagnosis is often difficult to establish because pa- tients do not usually develop clinical symptoms until the advanced stages of the disease. Magnetic resonance imag- ing (MRI) is a noninvasive method that detects iron overload and allows to monitor treatment after diagnosis, avoiding repeated biopsies. Our purpose is to analyze the metabolism and pathophysiolo- gy of iron deposition, to describe the usefulness of MRI in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron over- load in the abdomen, also describing its appearance at MRI. Iron metabolism and hemochromatosis The average adult body contains approximately 4-5 g of iron; 4 g are functional and are present in the hemoglobin of the blood cells, in the myoglobin of muscle and in a variety of enzymes (e.g., cytochromes)1. The rest is stored in hepato- cytes and reticuloendothelial system cells (including the liver, spleen and bone marrow Kupffer cells) 1 . Medullary erythropoiesis requires around 20 mg of iron daily. Abstract Our purpose is to analyze the metabolism and pathophysiology of iron deposition, to describe the usefulness of mag- netic resonance imaging (MRI) in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron overload in the abdominal organs and its characteristic features at MRI. Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodysplasia, thalassemia, etc. (secondary hemochromatosis). MRI is a noninvasive method that detects iron overload and allows treatment monitoring after diagnosis, avoiding re- peated biopsies. This is due to the paramagnetic properties of iron accumulation in the tissues causing local distortion in the magnetic field. This phenomenon is seen as a reduction of the MRI signal in the affected organs, being directly proportional to the amount of iron deposited.- The conventional in-phase and out-of-phase MRI sequences can show iron deposition in the liver, spleen and pancreas, although milder forms may go undetected if more sensitive sequences, like gradient echo sequence, are not used, ac- cording to the technique proposed by Gandon et al., which can quantitatively estimate the severity of iron deposition. Iron deposition can show a reticuloendothelial type pattern (secondary to multiple transfusions with iron deposits in the liver, spleen and bone marrow without tissue damage), a parenchymal pattern (involving the liver and pancreas) and a mixed pattern. MRI has a fundamental role in the diagnosis of hemochromatosis, especially in the subclinical phase. It helps to stratify the severity of hepatic iron overload and assess response to treatment, avoiding invasive procedures. © 2013 Sociedad Argentina de Radiología. Published by Elsevier España, S.L. All rights reserved Keywords: Iron; Hemochromatosis; Magnetic resonance imaging; Gradient echo Noninvasive assessment of hepatic iron overload in patients with hemochromatosis J.C. Spina, M.A. Alvarez del Rivero*, C. Kidd, M. Pietrani, L. Savluky and R.D. García Mónaco Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina Received: october 2012; accepted: march 2013 ©SAR
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
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Rev. Argent. Radiol. 2013;77(2):139-146 23
Introduction Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodyspla- sia, thalassemia, etc. (secondary hemochromatosis). Clinical diagnosis is often difficult to establish because pa- tients do not usually develop clinical symptoms until the advanced stages of the disease. Magnetic resonance imag- ing (MRI) is a noninvasive method that detects iron overload and allows to monitor treatment after diagnosis, avoiding repeated biopsies. Our purpose is to analyze the metabolism and pathophysiolo- gy of iron deposition, to describe the usefulness of MRI in the estimation of hepatic iron overload using specific sequences,
and to review the different pathologies leading to iron over- load in the abdomen, also describing its appearance at MRI.
Iron metabolism and hemochromatosis
The average adult body contains approximately 4-5 g of iron; 4 g are functional and are present in the hemoglobin of the blood cells, in the myoglobin of muscle and in a variety of enzymes (e.g., cytochromes)1. The rest is stored in hepato- cytes and reticuloendothelial system cells (including the liver, spleen and bone marrow Kupffer cells)1. Medullary erythropoiesis requires around 20 mg of iron daily.
Abstract Our purpose is to analyze the metabolism and pathophysiology of iron deposition, to describe the usefulness of mag- netic resonance imaging (MRI) in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron overload in the abdominal organs and its characteristic features at MRI. Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodysplasia, thalassemia, etc. (secondary hemochromatosis). MRI is a noninvasive method that detects iron overload and allows treatment monitoring after diagnosis, avoiding re- peated biopsies. This is due to the paramagnetic properties of iron accumulation in the tissues causing local distortion in the magnetic field. This phenomenon is seen as a reduction of the MRI signal in the affected organs, being directly proportional to the amount of iron deposited.- The conventional in-phase and out-of-phase MRI sequences can show iron deposition in the liver, spleen and pancreas, although milder forms may go undetected if more sensitive sequences, like gradient echo sequence, are not used, ac- cording to the technique proposed by Gandon et al., which can quantitatively estimate the severity of iron deposition. Iron deposition can show a reticuloendothelial type pattern (secondary to multiple transfusions with iron deposits in the liver, spleen and bone marrow without tissue damage), a parenchymal pattern (involving the liver and pancreas) and a mixed pattern. MRI has a fundamental role in the diagnosis of hemochromatosis, especially in the subclinical phase. It helps to stratify the severity of hepatic iron overload and assess response to treatment, avoiding invasive procedures. © 2013 Sociedad Argentina de Radiología. Published by Elsevier España, S.L. All rights reserved Keywords: Iron; Hemochromatosis; Magnetic resonance imaging; Gradient echo
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
J.C. Spina, M.A. Alvarez del Rivero*, C. Kidd, M. Pietrani, L. Savluky and R.D. García Mónaco
Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina Received: october 2012; accepted: march 2013 ©SAR
Rev. Argent. Radiol. 2014;78(1):23-30
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
24 Rev. Argent. Radiol. 2014;78(1):23-30
Juan Carlos Spina et al.
However, only 1–2 mg of dietary iron is absorbed (i.e. 10% of the total amount ingested)1,2. But an equivalent amount is lost each day because of epithelial desquamation, menstrua- tion, and other forms of blood loss 2. The rest of the daily iron requirement is obtained through an adequate recycling mechanism that includes the reuse of iron found in senescent erythrocytes. Thus, the absorption is physiologically well controlled while excretion has no effec- tive mechanism 3. The iron absorbed by the small intestine (duodenum and proximal jejunum) binds to transferrin–a transport protein in blood 1,3,4. Once iron is bound to transferrin, it is selectively deposited in hepatocytes, red blood cells (blood tissue-form- ing precursors and erythron) or, to a lesser extent, in other iron containing tissues, like muscle 3. Instead, the reticuloendothelial system cells store iron derived from the phagocytosis of senescent erythrocytes (a process known as extravascular hemolysis) 1,2. This processed iron may be stored intracellularly as ferritin or released into the circulation bound to transferring 1. Excess iron may result from increased intestinal absorption or parenteral administration (blood transfusion) (table 1) 1-3. Thus, iron storage diseases can be classified into 2 groups: primary, including genetic hemochromatosis, and secondary, which comprises chronic diseases or diseases related to mul- tiple transfusions (secondary hemochromatosis) (table 2). Primary hemochromatosis is a recessive autosomal disorder that alters a protein involved in the regulation of iron absorp- tion3,5. Most of these patients are homozygous or hetero- zygous for this mutation and have iron absorption two or three times higher than that of the unaffected population. Primary hemochromatosis is considered the most common genetic disease in the white population, with a rate of dis- ease of 0.2%–0.5% for homozygous and as much as 10% for heterozygous 2. Absorbed iron is transported to the liver, where it accumu-
lates initially in the periportal hepatocytes. Reticuloendothe- lial system cells absorb normal amounts of iron from eryth- rocytes, but rapidly release intracellular ferritin, being unable to store excess iron (the same as intestinal mucosal cells) 1. Making a clinical diagnosis is often difficult for two reasons: firstly, patients usually remain asymptomatic during the first decade of their disease; but in addition, the first signs and symptoms of liver dysfunction, diabetes mellitus, cardiomy-
Table 1: Features of primary and secondary hemochromatosis 2*.
Primary hemochromatosis Secondary hemochromatosis
Hereditary autosomal recessive disease Parenteral administration of iron (repeated blood transfusions) Increased intestinal absorption with normal dietary intake of iron Dietary iron overload Iron excess deposits in liver, pancreas, heart, pituitary gland, Iron is predominantly deposited in the thyroid and synovium cells reticuloendothelial system Leads to cellular damage, organ dysfunction, Less toxic and development of malignant tumors. * Modified from 2
Table 2: Classification or iron overloads. Hemochromatosis 5*.
Secondary hemochromatosis
Ineffective erythropoiesis with increased erythroid activity ß thalassemia Sideroblastic anemia Pyruvate kinase deficiency Increased oral iron intake African iron overload (Bantu siderosis) Chronic liver diseases Chronic alcoholic liver disease Porphyria cutanea tarda
*Modified from 5
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
Rev. Argent. Radiol. 2014;78(1):23-30
25
Figure 1. Conventional non-contrast enhanced magnetic resonance imaging in a healthy patient: (a) T2-weighted sequence, (b) in-phase sequence, (c) fat-suppressed T1-weighted sequence and (d) out-of-phase sequence.
a b
c d
Figure 2. Conventional magnetic resonance imaging in a young patient with hemochromatosis secondary to thalassemia and multiple transfusions who was splenectomized: (a) T2-weighted sequence, (b) in-phase sequence, (c) fat-suppressed T1- weighted sequence and (d) out-of-phase sequence. MR image shows a decrease in the signal intensity of the liver, which is even more evident on the in-phase image (b). Also note the decrease in signal intensity of the pancreatic parenchyma in this sequence (star) in relation to the out-of-phase sequence (d). There is also a decrease in the signal intensity of the bone marrow vertebrae in all sequences, flagged with a circle in (a).
a b
c d
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
26 Rev. Argent. Radiol. 2014;78(1):23-30
Juan Carlos Spina et al.
opathy and/or arthropathy are nonspecific. In fact, they are often attributed to other causes 1,2,4. Laboratory values used in the diagnosis of hemochromatosis include the ferritin level and the transferrin saturation index, which are generally increased in these cases6. However, these tests have low sensitivity and specificity, with false-positive re- sults found in alcohol abusers and with false-negative results found in young patients with hemochromatosis 2. Even if liver hepatic biopsy is considered the reference stan- dard method for diagnosis, it is an invasive procedure with potential risks, susceptible to sampling error because of the tiny amount of tissue obtained. MR imaging is a noninvasive method that is useful for detect- ing the presence of iron overload and for monitoring therapy once diagnosis has been established, thus avoiding repeated biopsies. This is due to the paramagnetic properties of iron ions, whose accumulation in the tissues causes local distor- tion in the magnetic fields, with a consequent loss of signal intensity in the affected organs that is proportional to the amount of iron deposition.
Hepatic iron overload: detection and characterization by specific gradient-echo sequences
Conventional MRI study of the liver includes a T2-weighted se- quence, a fat-suppressed T1-weighted sequence, an in-phase and out-of-phase sequence and eventually a T1-weighted se- quence with fat suppression after the administration of intra- venous contrast (fig. 1). As previously mentioned, because of the paramagnetic properties of the iron ions accumulated in tissues, a local distortion occurs in the magnetic fields with a consequent loss of signal intensity in the affected organs that is proportional to the iron deposition 2 (fig. 2). In-phase and out-of-phase sequences can demonstrate the presence of hepatic iron overload in tissues 7,8 (fig. 3). The
in-phase sequence shows a decrease in the signal intensity of tissues, as compared to the out-of-phase sequence. This effect, which is the opposite of the effect observed in patients with steatosis (fig. 4), occurs because the echo time of the in-phase sequence is usually higher than that of the out-of-phase se- quence; therefore, the in-phase pulse sequence is more sensi- tive to iron deposits because of the increased T2* effect. Even if with conventional in-phase and out-phase imaging we can infer the presence of iron deposition in the liver, spleen and pancreas, slight iron overloads might go unnoticed if we do not use more sensitive sequences, such as the gradient- echo sequences (fig. 5). The latter, according to the tech- nique proposed by Gandon et al., can quantitatively estimate the severity of iron deposition (fig. 6) 9. When GRE sequences are obtained with increasingly longer echo times, iron de- position becomes evident, even in slight overloads, and the approximate value can be estimated from a worksheet 9.11. Hepatic iron overload estimation may be performed using scanners of 0.5T, 1.5T, 3T and 5T 9,12, by choosing the ap- propriate protocol depending on the equipment. In addition to being classified as primary or secondary, iron storage diseases may be divided into 3 types according to the iron deposition pattern (table 3) 2,13: parenchymal, reticulo- endothelial or mixed (fig. 7).
Parenchymal deposition pattern
This pattern occurs as a result of increased iron absorption. The pattern is observed mainly in patients with primary he- mochromatosis or in cases of chronic anemia with ineffective erythropoiesis (thalassemia syndromes, congenital dyseryth- ropoietic anemias, and sideroblastic anemias). Initially, the iron in excess accumulates in the periportal hepatocytes and then spreads to the rest of the liver, the pancreas, and the thyroid, causing tissue damage. In this pattern, signal intensity decreases in the liver and the pancreas, while in the spleen and the bone marrow, signal
Table 3: Patterns of iron deposition in the body 2*.
Deposition pattern Liver Spleen Pancreas Bone marrow
Parenchymal Yes No Yes No Reticuloendothelial Yes Yes No Yes Mixed Yes Possibly Possibly Possibly * Modified from 2
Rev. Argent. Radiol. 2014;78(1):23-30
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
Rev. Argent. Radiol. 2014;78(1):23-30
27
Figure 3. Comparative in-phase and out-of-phase sequences in 2 patients: one healthy (a and b) and the other with secondary he- mochromatosis (c and d). Note the diffuse hypointensity of the hepatic parenchyma (star) and, to a lesser extent, of the spleen (c).
a b
c d
Figure 4. MRI in two different patients with in-phase and out-of-phase sequences. (a and b) Secondary hemochromatosis with accentuated diffuse hypointensity of the hepatic parenchyma in the in-phase sequence (a). (c and d). Hepatic steatosis: MRI shows a decrease in the signal intensity of the hepatic parenchyma in the out-of-phase sequence (d).
a b
c d
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
28 Rev. Argent. Radiol. 2014;78(1):23-30
Juan Carlos Spina et al.
Figure 5. Specific gradient-echo sequences in a patient with hepatic iron overload: (a) T1-weighted GRE 120/4/90; (b) DP- weighted GRE 120/4/20; (c) T2-weighted GRE 120/9/20; (d) T2+-weighted GRE 120/14/20; (e) T2++-weighted GRE 120/21/20. Note the decrease in the signal intensity as compared with the paraspinal muscles. The in-phase sequence (f) does not show alterations in the signal intensity of the liver.
a b
c d
e f
Figure 6. Signal intensity measurements done by means of regions of interest (ROIs) of approximately 1 cm2. Three ROIs must be placed on the right part of the liver to avoid artifacts and 2 ROIs must be placed on the paraspinal muscles (right and left). These ROIs must be placed on the same image in all sequences in order to avoid global signal intensity variations. At the time of placing the ROI on the image, try to avoid liver vessels, heterogeneous areas, artifacts and particularly the decrease in signal intensity of the (paraspinal muscle, adjacent to the lung bases.
Rev. Argent. Radiol. 2014;78(1):23-30
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
Rev. Argent. Radiol. 2014;78(1):23-30
29
intensity is preserved. Nevertheless, in young patients with slight iron overload, the signal intensity in the pancreas may be preserved.
Reticuloendothelial deposition pattern
In iron overload secondary to multiple transfusions, iron de- position generally occurs in the reticuloendothelial system cell
of the liver, spleen, and bone marrow. Unlike the parenchy- mal deposition pattern, this type of accumulation is not as- sociated with tissue damage. The signal intensity of the spleen and bone marrow can be used to evaluate the type of deposition pattern because in the parenchymal form, no effect is normally observed on these structures. In addition, the signal intensity of the pan- creas is generally preserved, except when the amount of iron administered (by multiple transfusions) exceeds the storage capacity of the reticuloendothelial system.
Figure 7. Classification of iron overload diseases according to the iron deposition pattern. MRI in 3 different patients with in-phase and out-of-phase sequences: (a and b) parenchymal pattern; note the decrease in signal intensity in the in-phase sequence, both in the liver and in the pancreas (stars), indicating the presence of iron deposition; (c and d) reticuloendothelial pattern, iron deposition in the liver, spleen and bone marrow (stars); (e and f) mixed pattern: patient with iron deposition in the liver, spleen and pancreas, as well as in the bone marrow (stars).
a b
c d
e f
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
30
Mixed deposition pattern
Patients with chronic anemias caused by ineffective erythro- poiesis (such as thalassemia) often require multiple transfu- sions, which can result in atypical distribution patterns (pa- renchymal and reticuloendothelial deposition).
Conclusion
Hemochromatosis is a disease with little clinical impact, which sometimes makes diagnosis difficult in the early stages of the disease. However, knowledge of the imaging findings, the patterns of iron distribution and associated diseases can facilitate diagnosis. MR imaging has a fundamental role, es- pecially in the subclinical stage, because it can contribute to stratify the severity of hepatic iron overload and assess the response to treatment, avoiding invasive procedures.
References 1. Siegelman ES, Mitchell DG, Semelka RC. Abdominal iron deposition: metabo-
lism, MR fi ndings, and clinical importance. Radiology. 1996;199:13-22. 2. Queiroz-Andrade M, Blasbalg R, Ortega CD, Rodstein MA, Baroni RH,
Rocha MS, et al. MR imaging findings of iron overload. Radiographics. 2009;29:1575-89.
3. Murray RK, Mayer PA, Granner DK, Rodwell VW, eds. Harper Bioquímica ilustrada. México: El Manual Moderno; 2004.
4. Cingolani HE, Houssay AB et al. Fisiología humana de Houssay. Buenos Aires: El ateneo; 2005.
5. Cotran RS, Kumar V, Collins T, Robbins SL. Patología estructural y funcio- nal. Madrid: McGraw-Hill Interamericana; 1999.
6. Rubinstein A, Terrasa S. Medicina familiar y práctica ambulatoria. Buenos Aires: Panamericana; 2006.
7. Merkle EM, Nelson RC. Dual gradient-echo in-phase and opposed-phase hepatic MR imaging: a useful tool for evaluating more than fatty infi ltra- tion or fatty sparing. Radiographics. 2006;26:1409-18.
8. Boll DT, Merkle EM. Diffuse liver disease: strategies for hepatic CT and MR imaging. Radiographics. 2009;29:1591-614.
9. Gandon Y. Iron, liver and MRI [consultado Ene 2009]. Disponible en: http://www.radio.univ-rennes1.fr /Sources/EN/Hemo.html
10. Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Rijcken TH, Stark DD. He- patic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. 1999;212:227-34.
11. Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special ap- plications. Radiographics. 2009;29:1433-49.
12. Anwar M, Wood J, Manwani D, Taragin B, Oyeku SO, Peng Q. Hepatic iron quantifi cation on 3 Tesla (3 T) magnetic resonance (MR): technical challenges and solutions. Radiol Res Pract. 2013;2013:628150.
13. Siegelman ES, Mitchell DG, Rubin R, Hann WL, Kaplan KR, Steiner RM, et al. Parenchymal versus reticuloendothelial iron overload in the liver: dis- tinction with MR imaging. Radiology. 1991;179:361-6.
Introduction Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodyspla- sia, thalassemia, etc. (secondary hemochromatosis). Clinical diagnosis is often difficult to establish because pa- tients do not usually develop clinical symptoms until the advanced stages of the disease. Magnetic resonance imag- ing (MRI) is a noninvasive method that detects iron overload and allows to monitor treatment after diagnosis, avoiding repeated biopsies. Our purpose is to analyze the metabolism and pathophysiolo- gy of iron deposition, to describe the usefulness of MRI in the estimation of hepatic iron overload using specific sequences,
and to review the different pathologies leading to iron over- load in the abdomen, also describing its appearance at MRI.
Iron metabolism and hemochromatosis
The average adult body contains approximately 4-5 g of iron; 4 g are functional and are present in the hemoglobin of the blood cells, in the myoglobin of muscle and in a variety of enzymes (e.g., cytochromes)1. The rest is stored in hepato- cytes and reticuloendothelial system cells (including the liver, spleen and bone marrow Kupffer cells)1. Medullary erythropoiesis requires around 20 mg of iron daily.
Abstract Our purpose is to analyze the metabolism and pathophysiology of iron deposition, to describe the usefulness of mag- netic resonance imaging (MRI) in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron overload in the abdominal organs and its characteristic features at MRI. Iron overload in the liver may be due to a genetic disorder (primary hemochromatosis), or to multiple blood transfusions and chronic diseases like increased absorption, myelodysplasia, thalassemia, etc. (secondary hemochromatosis). MRI is a noninvasive method that detects iron overload and allows treatment monitoring after diagnosis, avoiding re- peated biopsies. This is due to the paramagnetic properties of iron accumulation in the tissues causing local distortion in the magnetic field. This phenomenon is seen as a reduction of the MRI signal in the affected organs, being directly proportional to the amount of iron deposited.- The conventional in-phase and out-of-phase MRI sequences can show iron deposition in the liver, spleen and pancreas, although milder forms may go undetected if more sensitive sequences, like gradient echo sequence, are not used, ac- cording to the technique proposed by Gandon et al., which can quantitatively estimate the severity of iron deposition. Iron deposition can show a reticuloendothelial type pattern (secondary to multiple transfusions with iron deposits in the liver, spleen and bone marrow without tissue damage), a parenchymal pattern (involving the liver and pancreas) and a mixed pattern. MRI has a fundamental role in the diagnosis of hemochromatosis, especially in the subclinical phase. It helps to stratify the severity of hepatic iron overload and assess response to treatment, avoiding invasive procedures. © 2013 Sociedad Argentina de Radiología. Published by Elsevier España, S.L. All rights reserved Keywords: Iron; Hemochromatosis; Magnetic resonance imaging; Gradient echo
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
J.C. Spina, M.A. Alvarez del Rivero*, C. Kidd, M. Pietrani, L. Savluky and R.D. García Mónaco
Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina Received: october 2012; accepted: march 2013 ©SAR
Rev. Argent. Radiol. 2014;78(1):23-30
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
24 Rev. Argent. Radiol. 2014;78(1):23-30
Juan Carlos Spina et al.
However, only 1–2 mg of dietary iron is absorbed (i.e. 10% of the total amount ingested)1,2. But an equivalent amount is lost each day because of epithelial desquamation, menstrua- tion, and other forms of blood loss 2. The rest of the daily iron requirement is obtained through an adequate recycling mechanism that includes the reuse of iron found in senescent erythrocytes. Thus, the absorption is physiologically well controlled while excretion has no effec- tive mechanism 3. The iron absorbed by the small intestine (duodenum and proximal jejunum) binds to transferrin–a transport protein in blood 1,3,4. Once iron is bound to transferrin, it is selectively deposited in hepatocytes, red blood cells (blood tissue-form- ing precursors and erythron) or, to a lesser extent, in other iron containing tissues, like muscle 3. Instead, the reticuloendothelial system cells store iron derived from the phagocytosis of senescent erythrocytes (a process known as extravascular hemolysis) 1,2. This processed iron may be stored intracellularly as ferritin or released into the circulation bound to transferring 1. Excess iron may result from increased intestinal absorption or parenteral administration (blood transfusion) (table 1) 1-3. Thus, iron storage diseases can be classified into 2 groups: primary, including genetic hemochromatosis, and secondary, which comprises chronic diseases or diseases related to mul- tiple transfusions (secondary hemochromatosis) (table 2). Primary hemochromatosis is a recessive autosomal disorder that alters a protein involved in the regulation of iron absorp- tion3,5. Most of these patients are homozygous or hetero- zygous for this mutation and have iron absorption two or three times higher than that of the unaffected population. Primary hemochromatosis is considered the most common genetic disease in the white population, with a rate of dis- ease of 0.2%–0.5% for homozygous and as much as 10% for heterozygous 2. Absorbed iron is transported to the liver, where it accumu-
lates initially in the periportal hepatocytes. Reticuloendothe- lial system cells absorb normal amounts of iron from eryth- rocytes, but rapidly release intracellular ferritin, being unable to store excess iron (the same as intestinal mucosal cells) 1. Making a clinical diagnosis is often difficult for two reasons: firstly, patients usually remain asymptomatic during the first decade of their disease; but in addition, the first signs and symptoms of liver dysfunction, diabetes mellitus, cardiomy-
Table 1: Features of primary and secondary hemochromatosis 2*.
Primary hemochromatosis Secondary hemochromatosis
Hereditary autosomal recessive disease Parenteral administration of iron (repeated blood transfusions) Increased intestinal absorption with normal dietary intake of iron Dietary iron overload Iron excess deposits in liver, pancreas, heart, pituitary gland, Iron is predominantly deposited in the thyroid and synovium cells reticuloendothelial system Leads to cellular damage, organ dysfunction, Less toxic and development of malignant tumors. * Modified from 2
Table 2: Classification or iron overloads. Hemochromatosis 5*.
Secondary hemochromatosis
Ineffective erythropoiesis with increased erythroid activity ß thalassemia Sideroblastic anemia Pyruvate kinase deficiency Increased oral iron intake African iron overload (Bantu siderosis) Chronic liver diseases Chronic alcoholic liver disease Porphyria cutanea tarda
*Modified from 5
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
Rev. Argent. Radiol. 2014;78(1):23-30
25
Figure 1. Conventional non-contrast enhanced magnetic resonance imaging in a healthy patient: (a) T2-weighted sequence, (b) in-phase sequence, (c) fat-suppressed T1-weighted sequence and (d) out-of-phase sequence.
a b
c d
Figure 2. Conventional magnetic resonance imaging in a young patient with hemochromatosis secondary to thalassemia and multiple transfusions who was splenectomized: (a) T2-weighted sequence, (b) in-phase sequence, (c) fat-suppressed T1- weighted sequence and (d) out-of-phase sequence. MR image shows a decrease in the signal intensity of the liver, which is even more evident on the in-phase image (b). Also note the decrease in signal intensity of the pancreatic parenchyma in this sequence (star) in relation to the out-of-phase sequence (d). There is also a decrease in the signal intensity of the bone marrow vertebrae in all sequences, flagged with a circle in (a).
a b
c d
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
26 Rev. Argent. Radiol. 2014;78(1):23-30
Juan Carlos Spina et al.
opathy and/or arthropathy are nonspecific. In fact, they are often attributed to other causes 1,2,4. Laboratory values used in the diagnosis of hemochromatosis include the ferritin level and the transferrin saturation index, which are generally increased in these cases6. However, these tests have low sensitivity and specificity, with false-positive re- sults found in alcohol abusers and with false-negative results found in young patients with hemochromatosis 2. Even if liver hepatic biopsy is considered the reference stan- dard method for diagnosis, it is an invasive procedure with potential risks, susceptible to sampling error because of the tiny amount of tissue obtained. MR imaging is a noninvasive method that is useful for detect- ing the presence of iron overload and for monitoring therapy once diagnosis has been established, thus avoiding repeated biopsies. This is due to the paramagnetic properties of iron ions, whose accumulation in the tissues causes local distor- tion in the magnetic fields, with a consequent loss of signal intensity in the affected organs that is proportional to the amount of iron deposition.
Hepatic iron overload: detection and characterization by specific gradient-echo sequences
Conventional MRI study of the liver includes a T2-weighted se- quence, a fat-suppressed T1-weighted sequence, an in-phase and out-of-phase sequence and eventually a T1-weighted se- quence with fat suppression after the administration of intra- venous contrast (fig. 1). As previously mentioned, because of the paramagnetic properties of the iron ions accumulated in tissues, a local distortion occurs in the magnetic fields with a consequent loss of signal intensity in the affected organs that is proportional to the iron deposition 2 (fig. 2). In-phase and out-of-phase sequences can demonstrate the presence of hepatic iron overload in tissues 7,8 (fig. 3). The
in-phase sequence shows a decrease in the signal intensity of tissues, as compared to the out-of-phase sequence. This effect, which is the opposite of the effect observed in patients with steatosis (fig. 4), occurs because the echo time of the in-phase sequence is usually higher than that of the out-of-phase se- quence; therefore, the in-phase pulse sequence is more sensi- tive to iron deposits because of the increased T2* effect. Even if with conventional in-phase and out-phase imaging we can infer the presence of iron deposition in the liver, spleen and pancreas, slight iron overloads might go unnoticed if we do not use more sensitive sequences, such as the gradient- echo sequences (fig. 5). The latter, according to the tech- nique proposed by Gandon et al., can quantitatively estimate the severity of iron deposition (fig. 6) 9. When GRE sequences are obtained with increasingly longer echo times, iron de- position becomes evident, even in slight overloads, and the approximate value can be estimated from a worksheet 9.11. Hepatic iron overload estimation may be performed using scanners of 0.5T, 1.5T, 3T and 5T 9,12, by choosing the ap- propriate protocol depending on the equipment. In addition to being classified as primary or secondary, iron storage diseases may be divided into 3 types according to the iron deposition pattern (table 3) 2,13: parenchymal, reticulo- endothelial or mixed (fig. 7).
Parenchymal deposition pattern
This pattern occurs as a result of increased iron absorption. The pattern is observed mainly in patients with primary he- mochromatosis or in cases of chronic anemia with ineffective erythropoiesis (thalassemia syndromes, congenital dyseryth- ropoietic anemias, and sideroblastic anemias). Initially, the iron in excess accumulates in the periportal hepatocytes and then spreads to the rest of the liver, the pancreas, and the thyroid, causing tissue damage. In this pattern, signal intensity decreases in the liver and the pancreas, while in the spleen and the bone marrow, signal
Table 3: Patterns of iron deposition in the body 2*.
Deposition pattern Liver Spleen Pancreas Bone marrow
Parenchymal Yes No Yes No Reticuloendothelial Yes Yes No Yes Mixed Yes Possibly Possibly Possibly * Modified from 2
Rev. Argent. Radiol. 2014;78(1):23-30
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
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Figure 3. Comparative in-phase and out-of-phase sequences in 2 patients: one healthy (a and b) and the other with secondary he- mochromatosis (c and d). Note the diffuse hypointensity of the hepatic parenchyma (star) and, to a lesser extent, of the spleen (c).
a b
c d
Figure 4. MRI in two different patients with in-phase and out-of-phase sequences. (a and b) Secondary hemochromatosis with accentuated diffuse hypointensity of the hepatic parenchyma in the in-phase sequence (a). (c and d). Hepatic steatosis: MRI shows a decrease in the signal intensity of the hepatic parenchyma in the out-of-phase sequence (d).
a b
c d
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
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Juan Carlos Spina et al.
Figure 5. Specific gradient-echo sequences in a patient with hepatic iron overload: (a) T1-weighted GRE 120/4/90; (b) DP- weighted GRE 120/4/20; (c) T2-weighted GRE 120/9/20; (d) T2+-weighted GRE 120/14/20; (e) T2++-weighted GRE 120/21/20. Note the decrease in the signal intensity as compared with the paraspinal muscles. The in-phase sequence (f) does not show alterations in the signal intensity of the liver.
a b
c d
e f
Figure 6. Signal intensity measurements done by means of regions of interest (ROIs) of approximately 1 cm2. Three ROIs must be placed on the right part of the liver to avoid artifacts and 2 ROIs must be placed on the paraspinal muscles (right and left). These ROIs must be placed on the same image in all sequences in order to avoid global signal intensity variations. At the time of placing the ROI on the image, try to avoid liver vessels, heterogeneous areas, artifacts and particularly the decrease in signal intensity of the (paraspinal muscle, adjacent to the lung bases.
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intensity is preserved. Nevertheless, in young patients with slight iron overload, the signal intensity in the pancreas may be preserved.
Reticuloendothelial deposition pattern
In iron overload secondary to multiple transfusions, iron de- position generally occurs in the reticuloendothelial system cell
of the liver, spleen, and bone marrow. Unlike the parenchy- mal deposition pattern, this type of accumulation is not as- sociated with tissue damage. The signal intensity of the spleen and bone marrow can be used to evaluate the type of deposition pattern because in the parenchymal form, no effect is normally observed on these structures. In addition, the signal intensity of the pan- creas is generally preserved, except when the amount of iron administered (by multiple transfusions) exceeds the storage capacity of the reticuloendothelial system.
Figure 7. Classification of iron overload diseases according to the iron deposition pattern. MRI in 3 different patients with in-phase and out-of-phase sequences: (a and b) parenchymal pattern; note the decrease in signal intensity in the in-phase sequence, both in the liver and in the pancreas (stars), indicating the presence of iron deposition; (c and d) reticuloendothelial pattern, iron deposition in the liver, spleen and bone marrow (stars); (e and f) mixed pattern: patient with iron deposition in the liver, spleen and pancreas, as well as in the bone marrow (stars).
a b
c d
e f
Noninvasive assessment of hepatic iron overload in patients with hemochromatosis
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Mixed deposition pattern
Patients with chronic anemias caused by ineffective erythro- poiesis (such as thalassemia) often require multiple transfu- sions, which can result in atypical distribution patterns (pa- renchymal and reticuloendothelial deposition).
Conclusion
Hemochromatosis is a disease with little clinical impact, which sometimes makes diagnosis difficult in the early stages of the disease. However, knowledge of the imaging findings, the patterns of iron distribution and associated diseases can facilitate diagnosis. MR imaging has a fundamental role, es- pecially in the subclinical stage, because it can contribute to stratify the severity of hepatic iron overload and assess the response to treatment, avoiding invasive procedures.
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