Liver Iron Concentration (LIC)

Iron and the liver

The liver is a major repository for iron, and therefore liver iron concentration (LIC) provides an accurate measure of whole-body iron levels.1 The LIC is inversely linked to prognosis and is therefore widely used to determine the necessary dose and efficacy of a chelation regimen.2

Threshold LIC levels primarily based on relationship with outcomes in patients with transfusion-dependent thalassemia.3

Iron level LIC (mg Fe/g dry weight)
Normal <1.2
Iron Overload

- Mild

- Moderate

- Severe

3-7

7

15

In patients with transfusion-dependent thalassemia (TDT), LIC values >7 have been associated with liver disease while values >15 mg Fe/g dry liver weight are associated with progressive liver fibrosis and increased morbidity and mortality.2,4,5 In non-transfusion-dependent thalassemia (NTDT), LIC values ≥5 mg Fe/g dry liver weight have been associated with increased risk of several morbidities including vascular, endocrine, and bone disease.6

Studies with sickle cell disease (SCD) patients and mean LIC values >7 mg Fe/g dry liver weight show high proportion of hepatic fibrosis while patients with mean values >15 mg/g mg Fe/g dry liver weight show evidence of endocrine disease.7

Moreover, LIC determined on MRI is an independent factor for post-transplant outcome in patients with AML and MDS undergoing allogeneic stem cell transplantation.8

Annual measurement is recommended by most guidelines, although some guidelines recommend more or less frequent monitoring for high-risk or low-risk patients, respectively.9-11

Measurement

Biopsy

A liver biopsy can be undertaken as an outpatient procedure under local anesthetic. A small incision is made between the rips and under ultrasound guidance a needle takes a sample of tissue.12,13 At least 0.5g (at dry weight) should be obtained. The samples are eventually paraffin-embedded and the liver iron is measured following the application of acid to ‘digest’ the soft tissue.14 Spectrophotometric approaches can then be used to quantify the remaining iron.14

The measure of LIC in this way is the reference standard, but it remains an invasive procedure and is subject to inter-operator variability.15 There can also be sampling variability brought about by iron-free foci or iron-overloaded nodules leading to higher variation.14-16 Consequently, biopsies drawn from fibrotic or cirrhotic livers should be interpreted with caution.14

Advantages and disadvantages of liver biopsy in ascertaining liver iron concentration [Cappellini 2014].

 Pros  Cons
 
  • Validated reference standard
  • Direct measurement that generally provides reliable information
  • Allows concurrent histological/pathological assessment
  • Quantitative, specific and sensitive
  • Allows for measurement of non-hematological storage iron
  • Positive correlation with morbidity and mortality
 
  • Invasive: associated risk of bleeding, infection and pain
  • Requires skilled physician and standardized laboratory techniques
  • Risk of sampling error, particularly in patients with cirrhosis
  • Cannot be repeated frequently

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is commonly used across many disease areas: by applying a magnetic field to the human body, one is able to create images of the body’s soft tissues. Yet the process of magnetic resonance can provide quantitative information about specific tissues, and it is this function that is applied when attempting to establish the consequences of iron on the heart or liver tissue.

There are currently two MRI techniques commonly used for the assessment of iron overload in different organs. The R2 (1/T2) and T2* (1/R2*) techniques. For assessment of liver iron, both the R2 and T2* techniques are used as they have been validated against liver biopsy measurements of iron.17

Both T2 and R2* are also equally effective in evaluating chronic response to iron chelation.18

Although the T2* technique has shown international reproducibility,19 R2 MRI remains the only technique that has been calibrated and validated across multiple scanners in patients of different ages, with different stages of liver fibrosis and grades of liver inflammation, and in the presence of chelation therapy.20

The R2 MRI technique FerriScan® is approved by the FDA.

A range of commercial and free-to-use applications / software are available to process the information acquired from liver MRI.

Superconducting Quantum Interference Device (SQUID)

The Superconducting Quantum Interference Device (SQUID) takes the form of a super-cooled magnet that harnesses the paramagnetic susceptibility of iron in the body. As iron stored in ferritin and hemosiderin are the only relevant paramagnetic materials in the human body, the overall paramagnetic response of the body is proportional to the quantity of iron (in these states) that the body contain.21

By lowering a patient into a known, constant magnetic field, the change in magnetic flux can be quantified and compared to a reference medium of water. Therefore the iron in the liver can be quantified by placing the subject in such a position that the liver lays immediately over the sensor.21 The value ascertained is termed the Biomagnetic Liver Susceptometry (BLS).

Next: Cardiac Iron

Thalassemia

Iron Chelation Therapy in Thalassemia Find out more…

Sickle Cell Disease

Iron Chelation Therapy in Sickle Cell Find out more…

Myelodysplastic Syndromes

Iron Chelation Therapy in MDS Find out more...

References

  1. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343(5):327-331.
  2. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89(3):739-761.
  3. Leitch HA. Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments. Drugs. 2011;71(2):155-177.
  4. Angelucci E, Muretto P, Nicolucci A, et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood. 2002;100(1):17-21.
  5. Telfer PT, Prestcott E, Holden S, et al. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol. 2000;110(4):971-977.
  6. Musallam KM, Cappellini MD, Taher AT. Evaluation of the 5mg/g liver iron concentration threshold and its association with morbidity in patients with beta-thalassemia intermedia. Blood Cells Mol Dis. 2013;51(1):35-38.
  7. Olivieri NF. Progression of iron overload in sickle cell disease. Semin Hematol. 2001;38(1 Suppl 1):57-62.
  8. Wermke M, Schmidt A, Middeke JM, et al. MRI-based liver iron content predicts for nonrelapse mortality in MDS and AML patients undergoing allogeneic stem cell transplantation. Clin Cancer Res. 2012;18(23):6460-6468.
  9. Musallam KM, Angastiniotis M, Eleftheriou A, et al. Cross-talk between available guidelines for the management of patients with beta-thalassemia major. Acta Haematol. 2013;130(2):64-73.
  10. Cappellini MD, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassemia (TDT). 3rd Ed. Nicosia, Cyprus: Thalassemia International Federation; 2014.
  11. Taher A, Vichinsky E, Cappellini MD, et al. Guidelines for the management of non-transfusion dependent thalassemia (NTDT). Nicosia, Cyprus: Thalassemia International Federation; 2013.
  12. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2009;49(3):1017-1044.
  13. National Institute of Diabetes and Digestive and Kidney Diseases. Liver Biopsy (http://www.niddk.nih.gov/health- information/health-topics/diagnostic-tests/liver- biopsy/Pages/diagnostic-test.aspx, accessed 10 September 2015).
  14. Crisponi G, Ambu R, Cristiani F, et al. Does iron concentration in a liver needle biopsy accurately reflect hepatic iron burden in beta-thalassemia? Clin Chem. 2000;46(8 Pt 1):1185-1188.
  15. Barry M, Sherlock S. Measurement of liver-iron concentration in needle-biopsy specimens. Lancet. 1971;1(7690):100-103.
  16. Butensky E, Fischer R, Hudes M, et al. Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis. Am J Clin Pathol. 2005;123(1):146-152.
  17. St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005;105(2):855-861.
  18. Wood JC, Zhang P, Rienhoff H, et al. R2 and R2* are equally effective in evaluating chronic response to iron chelation. Am J Hematol. 2014;89(5):505-508.
  19. Kirk P, He T, Anderson LJ, et al. International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers. J Magn Reson Imaging. 2010;32(2):315-319.
  20. St Pierre TG, El-Beshlawy A, Elalfy M, et al. Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration. Magn Reson Med. 2014;71(6):2215-2223.
  21. Sheth S. SQUID biosusceptometry in the measurement of hepatic iron. Pediatr Radiol. 2003;33(6):373-377.