**7. Liver iron content and modern non invasive imaging of iron stores**

The liver is the main iron storage site in humans, and the liver iron concentration (LIC) correlates closely with total body iron stores in patients with secondary hemosideroses such as thalassemia major, sickle cell disease and genetic hemochromatosis [36, 37]. In order to avoid liver biopsy, a number of non invasive techniques have been developed to estimate liver iron stores, including the superconducting quantum interference device (SQUID), liver quantita‐ tive computer tomography (qCT), and magnetic resonance imaging (MRI) [38-39]. MRI has became the dominant technique, because of its sensitivity, reproducibility, availability and ability to image multiple organs in a single session [39]. Hepatic MRI is now considered the gold standard method for estimating and monitoring iron stores in secondary hemosideroses and genetic hemochromatoses ("iterative radiological biopsy"), and has been a major contrib‐ utor to knowledge and care in this field during the last decade [37, 40].

As one specific feature of hemodialysis patients receiving intravenous iron in the pre-ESA era was that their bone marrow iron content was paradoxically low in up to one-third of cases despite severe hepatosplenic siderosis; thus LIC seems to be the best indicator of iron overload in hemodialysis patients, given that bone marrow analysis may be misleading even in the ESA era [5].

SQUID (also called magnetic susceptometry) is based on the determination of the magnetic volume susceptibility of paramagnetic ferritin/haemosiderin iron in the liver and has been validated by comparison with percutaneous biopsy; it does not distinguish ferritin from haemosiderin iron [38-39]. The limitations of this method relate to its scarcity (only 5 devices worldwide), its very high cost (about 1000 euros/exam) and the lack of calibration homogeneity (risk of underestimating LIC) [38-39].

Liver quantitative computer tomography (qCT) was superseded by MRI at the beginning of the 21st century [38-39]. Quantitative MRI for LIC estimation is based on the paramagnetic properties of iron, leading to a reduction in the magnetic resonance signal as the liver iron concentration increases; it does not distinguish ferritin from haemosiderin iron [39]. It is a lowcost (about 300 euros/exam), non irradiating technique that does not require gadolinium (therefore safe in CKD patients) and is available everywhere [39].

11

There are three valuable hepatic MRI methods for determining LIC: the signal-intensitity ratio, R2 relaxometry, and R2\* relaxometry [39]. The signal-intensity ratio is the reference method. It was established at Rennes University in France on a 1.5 Tesla apparatus in 2004, and is predominantly used in Europe [41]. It was validated in a cohort of 191 patients with secondary hemosiderosis, genetic hemochromatosis and hepatic diseases who underwent liver biopsy for biochemical iron assay [41]; the results were successfully replicated in 3 prospective cohorts studied by independent teams in France, the Netherlands and Spain [42-44]. Two of these studies were performed by comparison with liver biopsy [42-44]. This approach is based on a comparison between liver and muscle intensity on various sequences (T1, PD, T2, T2+, T2++) and requires a specific algorithm to analyse the results (free software available on the website of Rennes University) (figure 1)[41]. It has a sensitivity of 89% and a specificity of 80% for the diagnosis of iron overload disease, and values are linear up to 350 µmol/g of dry liver [41]; a complementary algorithm established by a Spanish team is required for higher values [39].

*Rostoker G et al. Book Hemodialysis. New Chapter: Iatrogenic iron overload in dialysis patients* 

for transfusions [33]. Tissue iron depletion with the chelator desferrioxamine was advocated

At the beginning of the 1990s, the advent of recombinant human erythropoïetin allowed simultaneous treatment of anemia and iron overload by allowing massive mobilization of iron stores and effective phlebotomy (by partial letting of the extracorporeal circuit) at the end of dialysis sessions in patients rendered non anemic [34], together with the first successful use of non invasive radiological tools (liver quantitative computer tomography) to diagnose hemo‐

**7. Liver iron content and modern non invasive imaging of iron stores**

The liver is the main iron storage site in humans, and the liver iron concentration (LIC) correlates closely with total body iron stores in patients with secondary hemosideroses such as thalassemia major, sickle cell disease and genetic hemochromatosis [36, 37]. In order to avoid liver biopsy, a number of non invasive techniques have been developed to estimate liver iron stores, including the superconducting quantum interference device (SQUID), liver quantita‐ tive computer tomography (qCT), and magnetic resonance imaging (MRI) [38-39]. MRI has became the dominant technique, because of its sensitivity, reproducibility, availability and ability to image multiple organs in a single session [39]. Hepatic MRI is now considered the gold standard method for estimating and monitoring iron stores in secondary hemosideroses and genetic hemochromatoses ("iterative radiological biopsy"), and has been a major contrib‐

As one specific feature of hemodialysis patients receiving intravenous iron in the pre-ESA era was that their bone marrow iron content was paradoxically low in up to one-third of cases despite severe hepatosplenic siderosis; thus LIC seems to be the best indicator of iron overload in hemodialysis patients, given that bone marrow analysis may be misleading even in the ESA

SQUID (also called magnetic susceptometry) is based on the determination of the magnetic volume susceptibility of paramagnetic ferritin/haemosiderin iron in the liver and has been validated by comparison with percutaneous biopsy; it does not distinguish ferritin from haemosiderin iron [38-39]. The limitations of this method relate to its scarcity (only 5 devices worldwide), its very high cost (about 1000 euros/exam) and the lack of calibration homogeneity

Liver quantitative computer tomography (qCT) was superseded by MRI at the beginning of the 21st century [38-39]. Quantitative MRI for LIC estimation is based on the paramagnetic properties of iron, leading to a reduction in the magnetic resonance signal as the liver iron concentration increases; it does not distinguish ferritin from haemosiderin iron [39]. It is a lowcost (about 300 euros/exam), non irradiating technique that does not require gadolinium

to prevent hemosiderosis or to cure organ dysfunction due to iron overload [33].

dialysis-associated hemosiderosis and to monitor iron stores [35].

utor to knowledge and care in this field during the last decade [37, 40].

(therefore safe in CKD patients) and is available everywhere [39].

era [5].

62 Updates in Hemodialysis

(risk of underestimating LIC) [38-39].

**Figure 1.** Magnetic resonance imaging quantification of hepatic iron stores according to the method of Rennes University

The second MRI technique for iron store quantification was established in Australia in 2005 on a 1.5 Tesla apparatus and is based on R2 relaxometry; it was validated in a cohort of 105 patients with thalassemia, genetic hemochromatosis and hepatic diseases who underwent liver biopsy for biochemical iron assay, and was also compared to SQUID in 23 patients [45]. It is based on R2/T2 sequences. It has a sensitivity of 86% and a specificity of 88% for the diagnosis of iron overload disease, and is linear up to 700 µmol/g of dry liver; however, it requires

The second MRI technique for iron store quantification was established in Australia in 2005 on

a 1.5 Tesla apparatus and is based on R2 relaxometry; it was validated in a cohort of 105

patients with thalassemia, genetic hemochromatosis and hepatic diseases who underwent

liver biopsy for biochemical iron assay, and was also compared to SQUID in 23 patients [45].

It is based on R2/T2 sequences. It has a sensitivity of 86% and a specificity of 88% for the

calibration of the apparatus with phantoms and also a specific configuration of the machine [45]. It is mainly used (and called Ferriscan) in Australia, New Zealand and North America.

The third MRI technique for iron store quantification is based on R2\* relaxometry: it is the most promising tool and can be used on a 1.5 Tesla apparatus with specific software; it not only quantifies iron in liver but also detects (in the same session lasting about 20 minutes) iron overload in heart, spleen and pancreas [46]. Its main limitation for LIC determination is its validation on only a small number of liver biopsies [38-39, 46].

Normal hepatic iron stores on MRI have been established on the basis of liver biopsy findings, together with categories of gradually increasing iron overload reflecting the risk of complica‐ tions; moreover, as the upper 95% of LIC in healthy adults is 32 µmol/g of dry liver and hepatic MRI accurately detects liver iron overload exceeding 50 µmol/g of dry liver, the upper limit of normal was set at 50 µmol/g in many studies [6][41][45]. According to Rennes University, LIC values between 51 and 100 µmol/g represent mild iron overload, values between 101 and 200 µmol/g moderate iron overload, and values ≥ 201 µmol/g severe iron overload [41]. Management modalities for different clinically relevant thresholds of MRI-determined LIC have been forwarded by hepatologists and haematologists (e.g chelation in hemosiderosis, phlebotomy in genetic hemochromatosis, and specific follow-up of target organs)(Table 1) [37-41][45].


**Table 1.** Clinicaly relevant LIC thresholds in secondary hemosiderosis and genetic hemochromatosis

It is very likely that radiologists will be heavily solicited in the near future by nephrology teams requesting quantitative hepatic MRI for dialysis patients, both for research purposes and for diagnosis and follow-up of iron overload. Radiologists and nephrologists should also be aware of the marked differences in the pharmacological properties of available intravenous iron products, and their potential interference with MRI (summarized in table 2) [47].


calibration of the apparatus with phantoms and also a specific configuration of the machine [45]. It is mainly used (and called Ferriscan) in Australia, New Zealand and North America.

The third MRI technique for iron store quantification is based on R2\* relaxometry: it is the most promising tool and can be used on a 1.5 Tesla apparatus with specific software; it not only quantifies iron in liver but also detects (in the same session lasting about 20 minutes) iron overload in heart, spleen and pancreas [46]. Its main limitation for LIC determination is its

Normal hepatic iron stores on MRI have been established on the basis of liver biopsy findings, together with categories of gradually increasing iron overload reflecting the risk of complica‐ tions; moreover, as the upper 95% of LIC in healthy adults is 32 µmol/g of dry liver and hepatic MRI accurately detects liver iron overload exceeding 50 µmol/g of dry liver, the upper limit of normal was set at 50 µmol/g in many studies [6][41][45]. According to Rennes University, LIC values between 51 and 100 µmol/g represent mild iron overload, values between 101 and 200 µmol/g moderate iron overload, and values ≥ 201 µmol/g severe iron overload [41]. Management modalities for different clinically relevant thresholds of MRI-determined LIC have been forwarded by hepatologists and haematologists (e.g chelation in hemosiderosis, phlebotomy in genetic hemochromatosis, and specific follow-up of target organs)(Table 1)

**<sup>125</sup> mol/g (7 mg/g) threshold for increased risk of iron induced complications and level of decision for**

**143 mol/g (8 mg/g) threshold of saturation of reticulo‐endothelial system in sickle‐cell disease**

**269 mol/g (15 mg/g) threshold of risk of hepatic fibrosis and cardiac disease in thalassemia major**

**331 mol/g (18 mg/g) threshold of risk of hepatic fibrosis or cirrhosis in patients with genetic hemochromatosis**

It is very likely that radiologists will be heavily solicited in the near future by nephrology teams requesting quantitative hepatic MRI for dialysis patients, both for research purposes and for diagnosis and follow-up of iron overload. Radiologists and nephrologists should also be aware of the marked differences in the pharmacological properties of available intravenous iron

**160 mol/g (9 mg/g) threshold of hepatic fibrosis in sickle cell disease**

**Table 1.** Clinicaly relevant LIC thresholds in secondary hemosiderosis and genetic hemochromatosis

products, and their potential interference with MRI (summarized in table 2) [47].

**Clinical thresholds of LIC in secondary hemosiderosis and genetic hemochromatosis**

**chelation therapy or phlebotomy**

validation on only a small number of liver biopsies [38-39, 46].

[37-41][45].

64 Updates in Hemodialysis

**Liver Iron content (mol/g)**

(according to Rostoker G and Cohen Y. *Magnetic resonance imaging repercussions of intravenous iron products used for irondeficiency anemia and dialysis associated anemia*. J Comp Assist Tomogr 2014: Sept 16)

**Table 2.** IV iron preparations: Physicochemical and pharmacokinetic parameters and influence on MRI
