Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy
Ashraf Soliman1, Mohamed Yassin2, Fawzia Al Yafei3, Lolwa Al-Naimi3, Noora Almarri3, Aml Sabt3 and Vincenzo De Sanctis4
Department of Pediatrics, Alexandria University Children’s Hospital ,
2 Departments of Pediatrics, Hamad Medical Center (HMC), Doha – Qatar
3 Departments of Hematology, Hamad Medical Center (HMC), Doha – Qatar
4 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, 44121 Ferrara , Italy.
Received: September 5, 2013
Accepted: March 19, 2014
Meditter J Hematol Infect Dis 2014, 6(1): e2014025, DOI 10.4084/MJHID.2014.025
This article is available on PDF format at:
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox (DFX), an oral single dose therapy, has improved the compliance to chelation.
Aims: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level.
Methods: Only BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM.
Results: DFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations (r = 0.45 and 0.33 respectively , p < 0.05) . IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.
The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.
Conclusions: Some impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.
β and α thalassaemias are the most common inherited single-gene
disorders in the world. Iron overload is a consequence of chronic
transfusion therapy that adversely affects the function of the heart,
liver and endocrine glands. Even with the administration of effective
subcutaneous (s.c.) iron chelation therapy with desferrioxamine (DFO),
over 50% of patients die before the age of 35 years, mainly because of
poor compliance with s.c. chelation regimens.
A high prevalence of hepatic hemosiderosis (grades 3-4) has been recorded in many studies.[2-4] Hepatic fibrosis is also still not uncommon in patients with β thalassemia major (BTM) despite the use of chelation therapy. This could reflect the rather unsatisfactory compliance rate with DFO treatment observed in many of BTM patients. Thus, early and accurate diagnosis of liver disease followed by prompt intervention may prevent liver disease progression.[2-4]
The liver is the primary site of iron storage and the only site for synthesis of transferrin and ferritin. Free ferrous iron is highly toxic and normally is protein-bound within the liver. Unbound, iron catalyzes the production of free radicals, which have been implicated in lipid peroxidation and hepatotoxicity. Lipid peroxidation may be the primary event causing hepatocellular injury secondary to iron overload.[5-8]
Significant correlation between ferritin iron concentration and individual liver iron concentration, measured non-invasively by superconducting quantum interference device biomagnetometry (SQUID) has been reported in patients with BTM and hemochromatosis. However, the relation between serum ferritin concentration and liver iron improves when serum ferritin is lower than 2500 µg/ and in the absence of hepatitis.[5-8] In a large cohort of patients on chronic transfusion, a strong statistical correlation has been found between liver histology, serum ferritin and liver iron content (LIC).
In addition, patients with thalassemia have a high prevalence of hepatitis B and C infections.[10-12] HCV infected patients had significantly higher enzymes than non- infected. Chronic hepatitis C virus infection has been associated with liver iron loading. The cause of elevated serum iron indices in some HCV-infected individuals is not clear. The concomitant increase of in serum alanine aminotransferase (ALT) levels suggests that iron and ferritin be released from damaged hepatocytes as a result of hepatic necro-inflammation. In addition, increased iron has been shown to enhance HCV replication in vitro. Furthermore, hyperferritinemia and increased iron stores have been associated with the severity of liver damage in non-alcoholic fatty liver diseases (NAFLD), and iron depletion reduced insulin resistance and liver enzymes. Serum ferritin concentration is an important determinant of liver enzyme levels, and increased serum ferritin level is an independent predictor of liver damage in these patients, so it is useful to identify patients at risk of steatohepatitis and advanced fibrosis.[16-21] Histological evidence of hepatic iron accumulation has also been associated with an increased risk of fibrosis in large multicenter studies, in patients with NAFLD both from Europe and the United States. The β globin mutations, the best predictor of parenchymal iron overload in the Mediterranean area, are associated with almost double risk of severe fibrosis.[20-24]
These data suggest that incorporation of serum ferritin level can improve the performance of noninvasive scoring of liver damage in patients with chronic liver disease and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients. Experimental evidence suggests that iron depletion induced by chelators induce glucose uptake and utilization in hepatocytes in vitro and in vivo liver, increasing insulin receptor binding activity and signaling.[26,27]
Randomized and controlled trials have established that the oral deferasirox (DFX) efficacy is comparable to the standard iron chelator, DFO administered as a parenteral infusion, in reducing liver iron concentration and serum ferritin levels. However, DFX may be more effective than DFO in actual clinical practice owing to the improvement in quality of life and, hence, increased compliance associated with the oral route of administration.[28-30]
We investigated and reviewed the liver function in 40 BMT patients attending the Hematology Clinic of Hamad Medical Center, Doha (Qatar) during follow-up of 10 years, in order to ascertain the relationship, between serum ferritin concentrations and different liver functions, before and after DFX therapy.
Patients and Methods
The study was designed on the basis of observational study. Subjects
were randomly recruited from the hematology and endocrinology clinics
of HMC Doha (Qatar) and analyzed in the Biochemistry Laboratory of HMC.
A detailed history including the age at diagnosis of BMT and clinical
presentation and transfusion and chelation data was taken from the
patient, mother or the attendant. The ethical committee of Hamad
Medical Center has approved the study protocol as a part of protocol
for studying the endocrine and biochemical functions in thalassemic
patients. Waiver of informed consent was taken for accessing data of
patients before inclusion in the study. The diagnosis of BMT was
confirmed by Hb-electrophoresis in all the patients.
The patients who fulfilled the inclusion criteria were incorporated in the study. All the planned information were obtained and recorded in the data collecting sheet properly. A total of 45 subjects were included in the study. All but five patients did not complete the study (three left the city and two had splenectomy).
Inclusion and Exclusion Criteria
Patients with a confirmed diagnosis of BTM above the age of 5 years
were randomly selected. All the subjects were on regular blood
transfusions and iron chelation using subcutaneous pump infusion of DFO
five days per week. Exclusion criteria included: (1) Thalassemia trait
or intermedia type, (2) History of jaundice due to viral hepatitis (3)
History of splenectomy, (4) Positive screening test for hepatitis C or
Only patients with hepatitis negative screening (checked every year), and on treatment with DFO for at least five years or on treatment with DFX for four years or more were enrolled.
Liver function tests including serum bilirubin, ALT, aspartate transferase (AST), albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every six months in all these patients.
Variables including age, serum ferritin, bilirubin, ALT, AST, ALP, and
IGF-I concentrations are expressed as mean +/- standard deviation.
Comparison of variables before versus after DFX treatment was performed
using Student’s t test or analysis of variance as appropriate.
The possible associations between serum ferritin and different liver functions are tested using linear regression equation. The level of significance was set at 0.05 in the analyses, and all the statistical testing was two sides.
Forty patients with BTM were evaluated longitudinally every six months
from age of eight to 18 years. Their mean age at the beginning of the
study was 6.8 +/- 1.2 years and at the end of the study was 18.4 +/-
They started iron chelation therapy with DFO at the age of 3.8 +/- 0.9 years. They were shifted to oral DFX (20 mg/kg/day) at the age of 13.8 +/- 1.5 years.
|Table 1. Long-term changes in liver functions in thalassemic patients.|
Liver functions followed longitudinally are presented in Table 1. After initiation of oral DFX, the serum ferritin level significantly decreased in all BTM patients (p < 0.001). This was associated with mild, but significant, decrease in serum ALT, AST and ALP concentrations and increase in IGF-I concentrations (p<0.01) (Figure 1-6). Albumin concentrations did not change after treatment. There was a mild significant increase in serum bilirubin concentrations.
|Figure 1. Serum ferritin concentrations (µg/L) before and after DFO therapy.|
|Figure 2. Serum ALT concentrations (U/L) before and after DFO therapy.|
|Figure 3. Serum AST concentrations (U/L) before and after DFO therapy.|
Figure 4. Serum ALP concentrations (U/L) before and after
DFO therapy. |
|Figure 5. Serum bilirubin concentrations (µmol/L) before and after DFO therapy.|
|Figure 6. Serum IGF-I concentrations (ng/dl) before and after DFO therapy.|
ALT and AST levels were correlated significantly with serum ferritin concentrations (r = 0.45 and 0.33 respectively, p < 0.05) (Figure 7). IGF-I concentrations were correlated significantly with serum ALT (r = - 0.26, p = 0.05) and serum ferritin (r = -0.29, p = 0.02) concentrations. IGF-I concentrations were not correlated with AST, ALP, bilirubin or albumin levels (p > 0.05). (Table 2)
|Figure 7. Correlation between ALT to serum ferritin concentrations in thalassemia patients.|
|Table 2. Correlation between liver functions and ferritin concentrations in thalassemic patients.|
In our BMT patients
with negative hepatitis screening, DFO treatment
given at a younger age was not associated with significant hepatic
dysfunction. However, the DFX treatment significantly induced a
decrease of ALT, AST and ALP concentrations.
The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron overload, even in the absence of hepatitis.
In thalassemia, abnormal liver function appears to be related to the
high ferritin levels and the age when transfusions was initiated.[5-9]
Iron-induced liver disease is often aggravated by viral infection. Hepatic siderosis, portal fibrosis and even cirrhosis may develop despite iron chelation therapy.[13-15] Elevated serum ALT levels should alert the clinician about the possibility of hepatitis due to multiple blood transfusions.[31,32]
In this longitudinal study liver, function tests and serum ferritin levels were observed for more than 10 years in patients with BTM with negative screening for hepatitis C and B in order to exclude the possible effects of hepatitis in the production determination of liver dysfunction. They started iron chelation therapy with DFO at the age of 3.8 +/- 0.9 years then were shifted to oral DFX (20 mg/kg/day) at the age of 13.8 +/- 1.5 years.
Liver functions, followed longitudinally, showed that the DFX treatment decreased serum ferritin level significantly in all patients with BTM. This effect was maintained during the five years of treatment (p < 0.001). These findings support the concept that DFX may be even more effective than DFO in improving liver function because of better compliance to treatment.[28,30]
Reduction of serum ferritin concentration was associated with a significant decrease in serum ALT, AST and ALP concentrations and increase in IGF-I levels. The significant correlations between serum ferritin concentrations and ALT and AST levels (p < 0.01) suggest that the reduction of hepatic iron load and LIC reduce the hepatic cellular derangement and cell damage and improve liver functions. In support to this view, histological changes of liver biopsy specimens have been shown to correlate significantly with ALT and serum ferritin level.[33-34]
Measurement of fibrosis not only helps to stage the severity of disease, it allows serial determination of disease progression. Unfortunately, neither measuring liver enzymes nor IGF-1 can determinate the extent of hepatic fibrosis progression in BMT patients and different outcomes of liver disease may be expected in these patients. A non-invasive method for fibrosis determination (e.g. transient elastography) could add some information about liver damage at the end of follow-up, allowing a useful comparison with the evolution of laboratory data and the efficacy of treatment.
In a study on 40 thalassemic children, using the Knodell histological activity index (HAI), 28 children (70%) had 3-4 grade hemosiderosis, 24 (60%) had HAI score between 13/22 to 18/22 and 18 patients (45%) developed cirrhotic changes. The study done by Li et al. revealed that 30% cases showed HAI stage three and 44% patients showed grade 3-4 hemosiderosis in transfusion dependent BMT children. Another study by Jean et al. including histological evaluation of liver biopsy in 86 children with thalassemia indicated that some patients developed cirrhosis as early as 7-8 years of age.
IGF-I concentrations were significantly decreased in our BMT patients compared to age and sex published standards. IGF-I concentrations were correlated significantly with serum ALT (r = - 0.26; p = 0.05) suggesting that impaired liver function (increased ALT) may be an important cause of decreased synthesis of hepatic IGF-I in these patients. Negative associations between aspartate aminotransferase (AST) and γ- GT and IGF-1 levels, as well as between AST activity and IGF-1 levels have been detected in patients with chronic liver diseases.
Physiologically, GH stimulates liver IGF-I synthesis and secretion. Therefore, individuals with GH sufficiency should have normal serum IGF-1 level. In thalassemia major, the prevalence of low serum IGF-1 was much higher than that of the GH deficiency.[38,39] The IGF-I response and the linear growth after exogenous administration of GH were less than that seen in GH deficient children treated with GH.[39,40] These data suggest that thalassemic patients had some degree of GH insensitivity. Many factors, other than GH, could control hepatic IGF-I synthesis and circulating IGF-1 level. Patients with chronic liver disease could have low serum IGF-1 despite sufficient GH secretion.[39-41]
Hepatic stellate cells are stimulated by insulin-like growth factor 1 (IGF-I) and high IGF-1 levels attenuate fibrogenesis and accelerate liver regeneration. This effect is mainly mediated by up-regulation of hepatic growth factor and down-regulation of transforming growth factor β 1. Therefore, decreased IGF-1 levels in BMT patients may impair the regeneration and increase the risk for deterioration of function and chronicity. In our study, a significant increase in IGF-I levels as a consequence of decreased ferritin levels after the use of DFX therapy points out to a possible better prognosis of hepatic regeneration and/or improvement of synthetic hepatic functions in these patients.
In hepatitis-seronegative BMT patients, DFO treatment given at a
younger age was associated with mild significant hepatic dysfunction.
However, DFX treatment significantly decreased serum ALT, AST and ALP
and increased IGF-I concentrations. The positive correlation between
serum ferritin and ALT concentrations and the negative correlation
between IGF-I concentrations and ferritin and ALT suggest that hepatic
iron overload impairs in these patients the hepatic functions and
decreases IGF-I synthesis, even in the absence of hepatitis. 
- Genes and human disease. WHO.
- Telfer PT, Garson JA, Whitby K, Grant PR, Yardumian A, Hoffbrand AV, Wonke B. Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemia patients. Br J Haematol 1997;98:850-5. http://dx.doi.org/10.1046/j.1365-2141.1997.2953112.x
- Jean G, Terzoli S, Mauri R, Borgatti L, Di Palma A, Piga A, Magliano M, Melevendi M, Cattaneo M.. Cirrhosis associated with multiple transfusions in thalassaemia. Arch Dis Child 1984;59:67-70. http://dx.doi.org/10.1136/adc.59.1.67
- Aldouri MA, Wonke B, Hoffbrand AV. Iron state and hepatic disease in patients with thalassaemia major, treated with long term subcutaneous desferrioxamine. J Clin Pathol 1987;40:1353-9. http://dx.doi.org/10.1136/jcp.40.11.1353
- Larson AM, Taylor SL, Bauermeister D, Rosoff L Jr, Kowdley KV. Pilot Study of the Relationship Between Histologic Progression and Hepatic Iron Concentration in Chronic Hepatitis C. J Clin Gastroenterol. 2003; 37:406-11 http://dx.doi.org/10.1097/00004836-200311000-00012
- Kaddah A,El-Shabrawi M, Saleh A, Al Gaithy A, Basalama A. Liver iron content and histological findings versus serum ferritin in detection of different grades of hemosiderosis in hepatic diseases in thalassemia major. J A C 2005; 6: 475-84
- de Virgiliis S, Sanna G, Cornacchia G, Argiolu F, Murgia V, Porcu M, Cao A.Serum ferritin, liver iron stores, and liver histology in children with thalassaemia. Arch Dis Child. 1980 ;55:43-5. http://dx.doi.org/10.1136/adc.55.1.43
- Li CK, Chik KW, Lam CW, To KF, Yu SC, Lee V, Shing MM, Cheung AY, Yuen PM. Liver disease in transfusion dependent thalassaemia major. Arch Dis Child 2002;86:344-7 http://dx.doi.org/10.1136/adc.86.5.344
- Vogel E, Lebensburger JD, Bai S, Fineberg
N,Hilliard L, Vadlamud N, Dimmit R, Kelly D, Thomas H, Howard TH. Liver
histology, liver iron concentration (LIC), and serum ferritin in a
large cohort of chronically transfused children with sickle cell
anemia: Limitations of LIC as a marker for hepatic injury and ferritin
as an indicator for chelation initiation. 53rd ASH annual meeting 2011
- Okada S, Taketa K, Ishikawa T, Koji T, Swe T, Win N, Win KM, Mra R, Myint TT. High prevalence of hepatitis C in patients with thalassemia and patients with liver diseases in Myanmar (Burma). Acta Med Okayama. 2000;54:137-8.
- Mohamed R. EL-Shanshorya, Ibrahim A. Kabbashb, Hanan H. Soliman, Hala M. Nagyd and Said H. Abdoud. Prevalence of hepatitis C infection among children with ß-thalassaemia major in Mid Delta, Egypt: a single centre study. Trans R Soc Trop Med Hyg 2013; 107: 224-8. http://dx.doi.org/10.1093/trstmh/trs024
- Irshad M, Peter S. Spectrum of viral hepatitis in thalassemic children receiving multiple blood transfusion. Indian J Gastroentrol 2002;21:183-4.
- Ragab L, Helal S, Zaghloul N, El-Raziky M, Afifi R, Musallam KM, Taher AT. Clinical virologic analysis of hepatitis C infection in transfusion dependent ß thalassemia major children. Int J Lab Hem 2010;32:184-90. http://dx.doi.org/10.1111/j.1751-553X.2009.01155.x
- Nelson JE, Kowdley KV. Iron and Hepatitis C. Curr Hepat Rep 2004;3:140-7. http://dx.doi.org/10.1007/s11901-004-0024-7
- Kakizaki S, Takagi H, Horiguchi N, Toyoda M, Takayama H, Nagamine T, Mori M, Kato N. Iron enhances hepatitis C virus replication in cultured human hepatocytes. Liver 2000; 20:125-8. http://dx.doi.org/10.1034/j.1600-0676.2000.020002125.x
- Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, Sanyal AJ, Nelson JE. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:77-85. http://dx.doi.org/10.1002/hep.24706
- Valenti L, Dongiovanni P, Fargion S. Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease. World J Gastroenterol 2012 ; 18: 3782-86 http://dx.doi.org/10.3748/wjg.v18.i29.3782
- Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011;43:89-95. http://dx.doi.org/10.1016/j.dld.2010.07.006
- Nielsen P, Günther U, Dürken M, Fischer R, Düllmann J. Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance. J Lab Clin Med. 2000;135:413-8. http://dx.doi.org/10.1067/mlc.2000.106456
- Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011; 43:89-95. http://dx.doi.org/10.1016/j.dld.2010.07.006
- Tsimihodimos V, Gazi I, Kalaitzidis R, Elisaf M, Siamopoulos KC. Increased serum ferritin concentrations and liver enzyme activities in patients with metabolic syndrome. Metab Syndr Relat Disord. 2006;4:196-203. http://dx.doi.org/10.1089/met.2006.4.196
- Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, Canavesi E, Lattuada E, Roviaro G, Marchesini G. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010;138:905-12 http://dx.doi.org/10.1053/j.gastro.2009.11.013
- Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol. 2011;55:920-32. http://dx.doi.org/10.1016/j.jhep.2011.05.008
- Valenti L, Canavesi E, Galmozzi E, Dongiovanni P, Rametta R, Maggioni P, Maggioni M, Fracanzani AL, Fargion S. Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2010;53:927-33 http://dx.doi.org/10.1016/j.jhep.2010.05.023
- Dongiovanni P, Valenti L, Ludovica Fracanzani A, Gatti S, Cairo G, Fargion S. Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol. 2008;172:738-47. http://dx.doi.org/10.2353/ajpath.2008.070097
- Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011;43:89-95. http://dx.doi.org/10.1016/j.dld.2010.07.006
- Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol. 2011;55:920-32 http://dx.doi.org/10.1016/j.jhep.2011.05.008
- Cappellini MD, Taher A. Deferasirox (Exjade) for the treatment of iron overload. Acta Haematol. 2009;122:165-73 http://dx.doi.org/10.1159/000243801
- Meerpohl JJ, Antes G, Rücker G, Fleeman N, Motschall E, Niemeyer CM, Bassler D. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2012 Feb 15;2:CD007476.
- Imran F, Phatak P. Pharmacoeconomic benefits of deferasirox in the management of iron overload syndromes. Expert Rev Pharmacoecon Outcomes Res. 2009;9:297-304. http://dx.doi.org/10.1586/erp.09.26
- Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga A, Melevendi C, Di Gregorio F, Burattini MG, Terzoli S. Survival and causes of death in thalassemia major. Lancet 1989; 2:27-30. http://dx.doi.org/10.1016/S0140-6736(89)90264-X
- Thakerngpol K, Fucharoen S, Boonyaphipat P, Srisook K, Sahaphong S, Vathanophas V, Stitnimankarn T. Liver injury due to iron overload in Thalassaemia: histopathologic and ultrastructural studies. Biometals 1996; 9:177-83. http://dx.doi.org/10.1007/BF00144623
- Win LL, Ni H, Sin S, Naing Z. Extremely high serum ferritin levels associated with abnormal liver function In multi-transfused patients with beta thalassemia major in Myanmar. Internet J Hematol. 2013 Vol 9, Number 1. (Letter) http://ispub.com/IJHE/9/1/163
- Afzal S, Ahmad M, Roshan E, Mubarik A, Qureshi AH, Saleem N, Khan SA. Morphological study of liver biopsy in Thalassaemia major. J Pak Med Assoc. 2004;54:415-8.
- Don C. Rockey and Scott L. Friedman. Section I: Pathophysiology of the Liver: Hepatic fibrosis and cirrhosis. Elsevier health publications. https://www.us.elsevierhealth.com/media/us/samplechapters/9781416032588/9781416032588.pdf P 78:108
- Mushtaq S, Muzaffar M, Khadim MT, Tariq WZ, Mamoon N. A morphological study of Histological Activity Index (HAI) and scoring system in Hepatitis C. J Pak Med Assoc 1997; 47:162-5.
- Himoto T, Tani J, Miyoshi H, Yoneyama H, Mori H, Inukai M, Masugata H, Goda F, Senda S, Haba R, Masaki T. The ratio of insulin-like growth factor-I/insulin-like growth factor-binding protein-3 in sera of patients with hepatitis C virus-related chronic liver disease as a predictive marker of insulin resistance. Nutr Res. 2013 ;33:27-33. http://dx.doi.org/10.1016/j.nutres.2012.11.007
- Karamifar H, Karimi M, Amirhakimi G, Shabatialaei M, De Sanctis V. Reduced insulin-like growth factor I concentrations in iron-overloaded beta thalassaemic patients with normal growth hormone secretion and liver function. Pediatr Endocrinol Rev 2004;2 (Suppl 2):256-8.
- Soliman AT, El Banna N, Ansari BM. GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia. Eur J Endocrinol. 1998 ;138:394-400. http://dx.doi.org/10.1530/eje.0.1380394
- Low LCK, Postel-Vinay MC, Kwan EYW, Cheung PT. Serum growth hormone (GH)binding protein, IGF-1 and IGFBP-3 in patients with ß-thalassemia major and the effect of GH treatment. Clin Endocrinol 1998;48:641-6. http://dx.doi.org/10.1046/j.1365-2265.1998.00470.x
- Soliman AT, Abushahin A, Abohezeima K, Khalafallah H, Adel A, Elawwa A, Elmulla N. Age related IGF-I changes and IGF-I generation in thalassemia major. Pediatr Endocrinol Rev. 2011;8 (Suppl 2):278-83.
- Wallek G, Friedrich N, Ittermann T, Mayerle J, Völzke H, Nauck H, Spielhagen C. IGF-1 and IGFBP-3 in patients with liver disease/IGF-1 und IGFBP-3 bei Patienten mit Lebererkrankungen. Laboratoriumsmedizin. Volume 37, Issue 1, Pages 13-20, ISSN (Online) 1439-0477, ISSN (Print) 0342-3026, March 2013. http://dx.doi.org/10.1515/labmed-2012-0032