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Iron overload in allogeneic hematopoietic stem cell transplant recipients.

Iron overload is associated with excess oxygen radicals and tissue peroxidation damage, which have a wellrecognized adverse effect on patients undergoing hematopoietic stem cell transplant (HSCT). (1) While the treatment of iron overload has improved over time, new methods of assessing iron overload lag behind. An elevated serum ferritin level, the most widely used surrogate marker of iron stores, has been associated with an adverse outcome for HSCT patients. (2-4) However, serum ferritin is an acute-phase reactant; hence, its reliability for assessing iron overload decreases after patients are exposed to conditioning regimens and HSCT. (5,6) Liver biopsy can be used to evaluate the body's tissue iron burden. A handful of retrospective studies (7,8) have examined the use of liver biopsies to investigate the cause of liver dysfunction in HSCT recipients. However, few have analyzed the utility of liver biopsy in determining the degree of iron overload. (9) For this reason, we conducted a retrospective study on a group of post allogeneic HSCT patients who underwent liver biopsy primarily to investigate the cause of persistent abnormal liver function test (LFT) results, mostly under a clinical suspicion of graft versus-host disease (GVHD). Our objectives were to validate the utility of the histologic semi quantitative scoring system in assessing hepatic iron and to study the effect on clinical outcomes of hepatic iron overload (HIO) in these high-risk transplant recipients.

PATIENTS AND METHODS

Study Design

Between January 1998 and March 2009, a total of 154 patients and a total of 286 patients underwent allogeneic and autologous HSCT, respectively, in our institution. After obtaining institutional review board approval, we searched the bone marrow transplant database for patients who had undergone liver biopsy. We included patients who were diagnosed, treated, and followed up at our institution for at least 1 year after transplant. We excluded autologous HSCT patients who had undergone liver biopsy (4 cases). Of 154 patients who had undergone allogeneic HSCT, 22 had transient abnormalities in their LFTs that were attributed to drug toxicity, venoocclusive disease of the liver, or another primary hepatic disorder. Sixty-four patients had persistent abnormal LFT results and were evaluated by liver biopsy. Eleven patients did not have liver biopsies due to severe coagulopathy and were given empiric treatment for GVHD. Two patients were excluded after their liver biopsies showed amyloidosis, hindering our analysis of iron burden, and 2 other patients had liver biopsies before HSCT, without posttransplant follow-up biopsy. We excluded these 2 patients from the analysis but included them in the histologic review for completion. A total of 49 patients were enrolled in the study (Figure 1). Demographic and clinical characteristics were collected (Table 1). Two patients received donor cell infusion after failure of nonmyeloablative allogeneic HSCT. Myeloablation therapy and transplantation itself have been previously published elsewhere (10) and go beyond the scope of our article. Additional clinical and laboratory data were reviewed as follows.

[FIGURE 1 OMITTED]

Assessment of Liver Dysfunction.--Liver function test results for the 49 patients were measured after transplant by using commercial autoanalyzers and included alanine aminotransferase (ALT; upper normal limit [UNL], 40 IU/L), aspartate aminotransferase (AST; UNL, 35 IU/L), alkaline phosphatase (ALK; UNL, 150 IU/L), total bilirubin (UNL, 1.2 mg/dL), [gamma]-glutamyl transpeptidase (GGT; UNL, 45 IU/L), lactate dehydrogenase (LDH; reference range, 100-190 U/L), and serum albumin (reference range, 1.5-3.5 g/dL). The presence of liver injury was defined as an unexplained abnormal elevation of any of the LFTs, twice as high as the UNL, or serum bilirubin levels above 2 mg/dL. (11) All donors and recipients were prescreened for hepatitis B and C viruses before transplant. Seven patients were actively immunized.

Liver Histopathology.--Liver biopsies were performed on the basis of abnormalities in LFTs, at the discretion of the treating physician. According to our institution's standard practice, a liver biopsy is performed when LFT results are persistently elevated for a 2-week period. A total of 56 liver specimens were reviewed from 51 patients. For the 2 patients who had multiple liver biopsies, we based the analysis on the most severe histologic abnormalities. Timing of the liver biopsies ranged from 23 to 844 days after HSCT, with a median of 188 days. Liver samples were fixed and processed routinely. Sections were stained with hematoxylin-eosin, Masson trichrome for fibrotic stages, and Prussian blue for hemosiderin-stainable granules. Moreover, immunohistochemical reactions for hepatitis B surface antigen, herpes simplex virus, and cytomegalovirus were performed occasionally when needed. Histologic sections were reviewed by 2 histopathologists (S.A. and V.S.) without access to the clinical data. Histologic grades or scores were assigned for hepatic GVHD (grade, 1-3), (12) fibrosis (Ishak grade, 1-6), (13) and iron (score, 0-4). Many iron-grading systems are now available and have been reviewed in detail. (14,15) We settled on a grading method that relies both on the degree and the pattern of iron deposits in hepatic parenchyma. Briefly, any quantitative amount of iron granule deposition within scattered hepatocytes in acinar zone 1 was given a grade 1. Grade 2 was assigned for granules seen at X100 and present in greater than 50% of hepatocytes; grade 3, to discrete granules seen at X20 in zone 1 or panacinar, with zonal gradient across the acini; and grade 4, to blue granules seen by the naked eye and microscopically present within hepatocytes, with little or no gradient present. Scattered Kupffer cells; sinusoidal, portal tract connective tissue; and bile duct epithelial staining, unless involving hepatocytes, were considered nonspecific and scored as either 0 or 1.

Assessment of Iron Load.--Serum ferritin and iron levels were reviewed for all 49 patients from the electronic medical record database. To ensure consistency in our evaluation, we included only posttransplant results within 2 months from the time of liver biopsy. Instead of an iron profile, we relied on the semiquantitative analysis of stainable liver iron granules (scores 0 to 4) as a scoring system for the assessment of the overall tissue iron load. This method has been exhaustively studied and has shown a strong concordance with the degree of hepatic iron concentration (HIC). (16-19) In these studies, an absence of stainable iron, grade 0 or 1, almost invariably corresponded to HIC below the mean value for the control group; grade 2 represented mild but significantly increased iron stores with HIC values of 1.8 mg/g or greater (normal, <1.4 mg/g dry liver weight); grade 3 represented moderately increased iron load and occurred in patients with HIC values between 3 and 7 mg/g; and grade 4 represented severe HIO with an HIC value between 12 and 35 mg/g, a concentration often associated with a high risk of cardiac disease. We chose a score of grade 2 or greater as an indication of abnormally increased iron stores with potential HIO. We then recorded the transfusion-associated iron load by documenting the total number of packed red blood cell units administrated at anytime before the time of diagnosis, during the course of treatment, and after stem cell transplant until the time of the liver biopsy.

Acute Versus Chronic GVHD.--Charts were reviewed for the 49 patients. We initially reviewed the documented overall clinical GVHD for each patient (skin, gastrointestinal, and liver) at the time of liver biopsy. Then we included the highest overall grade of both acute (scale, 0-4) and chronic (limited or extensive) GVHD, according to the previous diagnostic criteria consensus reported elsewhere. (20,21) Follow-up information was available until the last recorded visit at the time of this report (August 2009) or at time of death.

Infections.--Data of blood stream infections (BSIs) were reviewed. Significant bacteremia was defined as the recovery of a recognized pathogen from 1 or more blood cultures or the recovery of a single skin commensal from 2 or more blood cultures. (22,23) Positive blood cultures were considered nonsignificant when contamination by skin flora could not be excluded by record review. We included only the significant group in the analysis.

Statistical Analysis.--All variables were analyzed with SAS/ STAT software, version 9.2 for Windows (SAS Institute Inc, Cary, North Carolina). For analysis of the relationship between iron grade, the histologic grading of GVHD, the number of transfusions, serum ferritin levels, LFT results, and BSIs, we used the Spearman rank correlation coefficient. The results were considered statistically significant when the P value was less than .05. The Wilcoxon rank sum test was used to examine the differences between the presence and absence of HIO (scores 0 and 1 versus 2 through 4). Kaplan-Meier analysis was used to examine the effect of hepatic iron scores and different grades of acute GVHD on overall transplant survival. Differences in survival between groups were tested for statistical significance by using the log rank test.

RESULTS

Liver Histopathology

Although GVHD was the initial clinical impression in all 49 patients, hepatic GVHD was histologically identified in only 73.5% (n = 36) of patients. The presence of stainable acinar iron granules was actually the most common finding, identified in 87.8% (n = 43) of patients; HIO (ie, score [greater than or equal to] 2) was encountered in 57% (n = 28) of patients. Forty-five percent of patients (n = 22) had combined HIO and hepatic GVHD. Hepatic iron overload was the only histologic explanation of liver dysfunction in 12% (n = 6) of patients after excluding drug toxicity and sepsis. Five of these patients had extrahepatic GVHD. Cholestasis was the fourth most common histologic finding, identified in 7 patients. One patient had evidence of posttransplant lymphoproliferative disorder of the liver, which ultimately resulted in the patient's death. In addition, bile duct obstruction, histologic suspicion of viral hepatitis after a negative pretransplant viral serology result, and focal extramedullary hematopoiesis were identified in 3 different patients.

Hepatic fibrosis was present in 35% (n = 17) of the patients with grade 1 fibrosis, the most commonly identified grade (n = 10). None of the patients had significant fibrosis (score [greater than or equal to] 3) or cirrhosis, including 3 patients with viral hepatitis. One of the 2 patients who underwent liver biopsy before transplant had HIO (score 3) after a total of 58 units of packed red blood cells, but had no signs of posttransplant liver dysfunction, and was alive at the time of this report. The other patient was a 27-yearold man with a pathologic diagnosis of autoimmune hepatitis and was treated with a combination of corticosteroids and azathioprine. Six months later the patient developed aplastic anemia, perhaps related to azathioprine treatment. (24)

Effect of Primary Disease on the Degree of Iron Overload

Pullarkat et al (1) hypothesized that iron overload is more prevalent in patients with acute leukemia, myeloid malignancies, and aplastic anemia than patients with lymphoproliferative disorders and multiple myeloma. Our findings support this hypothesis, as 94% (15 of 16) of the patients with acute leukemia had HIO after a mean of 41 transfusions (range, 9-117), followed by 70% (7 of 10) of patients with myelodysplastic or myeloproliferative syndrome after a mean of 45 transfusions (range, 10-131), and finally, 17% of patients (1 of 6) with multiple myeloma after a mean of 23 transfusions (range, 7-39). The prevalence of HIO in these groups appears to correlate to some degree with the number of transfusions. Additionally, female patients had HIO more often than males (74% or 17 of 23 compared to 42% or 11 of 26, respectively).

Correlation Between HIO and Clinical Parameters and Histologic Review

Spearman rank correlations were analyzed between HIO and various laboratory parameters (Table 2). There were strong correlations between HIO and the number of transfusions (r = 0.69319, P < .001), serum ferritin (r = 0.55, P = .004), and serum LDH (r = 0.30, P = .03), while the association between HIO and histologic diagnosis of hepatic GVHD was nearly significant (r = 0.27, P = .06).

Impact of HIO on Mortality

A total of 37 patients (76%) died after the transplant, after a mean survival of 677.8 days (range, 52-3651 days) and a median overall survival of 11.2 months (Table 2). Nonrelapse-related mortality was a more common cause of death (59%, n = 22) than disease relapse (40.5%, n = 15). Fifty percent (11 of 22) of those who died from nonrelapse-related mortality had histologic HIO. Although severe HIO was observed in those patients, there was no significant statistical correlation when compared to patients who did not have HIO (P = .81 with a calculated hazard ratio of 0.68). Kaplan-Meier survival analysis (Figure 2, A) showed a disproportionate effect of HIO on treatment-related mortality. Treatment-related mortality was higher in patients with increased levels of serum bilirubin ([greater than or equal to]10 mg/dL; P < .001), older age (>50 years; P = .04), lower serum albumin levels ([less than or equal to]3 g/dL; P = .001), and those with a clinical diagnosis of acute GVHD (P = .004). Multivariate survival analysis of individual grades of acute GVHD had shown a negative effect on treatment related mortality (P = .001) (Figure 2, B). Of the 13 patients who developed chronic GVHD (7 extensive, 6 limited), only 1 died of chronic GVHD, while 3 patients died of lethal infections.

Impact of HIO on BSIs

Thirty one of 49 patients had at least 1 episode of clinically significant BSI after HSCT. There were 60 BSIs including 31 episodes (52%) of gram-negative bacteremia in 19 patients, 25 episodes (42%) of gram-positive bacteremia in 19 patients, 3 episodes (5%) of fungemia in 3 patients, and 1 episode of mycobacterium bacteremia. One bacteremic patient also had concurrent documented cytomegalovirus viremia. The most frequently isolated gramnegative organisms were Klebsiella pneumoniae (9 isolates from 7 patients) and Pseudomonas aeruginosa (8 isolates from 7 patients). The most frequent gram-positive infections were Staphylococcus aureus (6 isolates) and Enterococcus faecium (6 isolates). Seven patients had both gram-negative and gram-positive infections, while 2 patients had gram-negative, gram-positive, and fungal infections. Statistical analysis showed a modest association between HIO and the development of BSIs (r = 0.33, P = .02).

[FIGURE 2 OMITTED]

Infection-Related Mortality

Seventy percent (26 of 37) of patients who died had at least 1 documented episode of BSI and 27% (10 of 37) of patients had documented BSIs at the time of death; thus, these episodes were considered to be infection-related mortality. Although mortality was observed in the HIO group, there was no statistical association identified with infection-related mortality (P = .72). Furthermore, severe HIO (scores 3 and 4) did not seem to increase the risk of infection-related mortality (HR = 1.16, P = .49, 95% confidence interval, 0.76-1.77).

COMMENT

There is a gap between the time that patients are identified as needing stem cell transplant and the time that the actual transplant takes place. During this period, most patients are transfusion dependant and although iron overload is a clinical consideration, the need for stem cell transplant and the logistic problems behind locating the stem cell donor probably outweigh the need for prospective iron-screening protocols. This results in an ongoing lack of consensus for the definition and management of iron overload in HSCT recipients. Studies have shown an adverse association between elevated pretransplant serum ferritin levels and clinical outcomes and increased risk of disease relapse. (2,4) However, after patients are exposed to conditioning regimens and stem cell transplant, serum ferritin levels are prone to false elevation, (5) as serum ferritin is an acute-phase reactant. Thus, accurate evaluation and diagnosis of iron toxicity after transplant is a challenge. Tissue iron evaluation is the ideal method for identifying patients at risk and can be determined in the myocardium, bone marrow, or liver in the HSCT setting. Estimating iron load in the myocardium can be challenging because accumulation usually only occurs late in the disease. (25,26) Storey et al (27) recently published a study using the cumulative number of transfusions and preconditioning serum ferritin levels, combined with a semiquantitative degree of stainable iron granules, in posttransplant bone marrow biopsies (scale, 0 to 6). This unified scoring system has shown worse clinical outcome for survival after transplant in patients with high scores. However, this scoring system uses pretransplant serum ferritin levels, which may not be available in all cases. Thus, the liver remains the largest and the most accessible parenchymal organ that can be used to estimate tissue iron load after transplant. Estimating hepatic iron concentration is considered the gold standard method of hepatic iron load assessment. (16,28,29) Three methods can be used to estimate HIC in HSCT recipients: biochemical analysis of liver biopsy, magnetic resonance imaging (MRI)30 and superconducting quantum interference device susceptometer. (31,32)

[FIGURE 3 OMITTED]

Biochemical estimation can be calculated by using chemical, colorimetric, or atomic absorption analysis, (33,34) although in addition to expense, many transplant centers, ours included, do not offer this test. Noninvasive imaging analysis, such as T2 MRI, has shown promise for determining hepatic iron load but is still undergoing extensive studies in transplant patients. (35) However, we routinely perform Perls iron staining on all liver biopsies to grade the degree of iron accumulation. Although this method is widely used in clinical practice, it has some limitations, as it requires liver biopsy, which is considered an invasive procedure and carries a risk of bleeding and infection; second, it is somewhat subjective and may suffer from interobserver reproducibility. However, one advantage in our opinion is that it provides information on iron distribution within the hepatic lobule. Hepatic iron is not uncommonly seen in various other primary liver diseases such as alcoholic liver disease, chronic viral hepatitis, nonalcoholic steatohepatitis, liver cirrhosis, and more importantly, hereditary hemochromatosis. In such situations, histologic evaluations of liver specimens are essential in the core management of these patients.

Our study evaluated the use of liver biopsies in assessing the risk of transfusion-related iron overload in the posttransplant setting. In addition, we investigated the relationship between tissue iron load with an extended array of clinical data (liver function tests, serum iron studies, BSIs, and mortality). Our approach most likely excluded a significant proportion of cases involving patients who may have had iron overload without having liver dysfunction, patients who were not offered liver biopsy owing to coexisting medical conditions, and finally, autologous HSCT patients. These limitations reduced the sample size and statistical power of our study.

Previous studies have evaluated iron overload by using posttransplant serum ferritin levels. Altes et al (3) showed decreased overall survival after transplant in the patients with very high levels of serum ferritin ([greater than or equal to] 3000 ug/L) and transferrin saturation of 100% or greater in the early (first week) posttransplant period. Majhail et al (36) studied hepatic iron concentration by using MRI in patients with serum ferritin levels greater than 1000 ug/mL and demonstrated an overall HIO prevalence of 32%, using a cutoff value of greater than 1.8 mg/g, which is a value that correlates with histologic iron scores of 2 or greater. In our study, all 19 patients with serum ferritin levels greater than 1000 ng/mL demonstrated some degree of histologic HIO, while 17 (90%) had moderate or severe forms (scores 3 and 4). Eleven patients had very high serum ferritin levels ([greater than or equal to]3000 ug/mL) and 73% (8 of 11) died of disseminated bacterial infections within the first year after transplant (range, 86-393 days). On the other hand, 1 patient had a serum ferritin level close to 9000 ng/mL but did not show evidence of HIO on liver biopsy. This patient also did not develop significant BSI and was alive at the time of this report. These data highlight the fact that high levels of serum ferritin do serve as a warning sign and should prompt further evaluation with a more definitive method to rule out false-positive results.

While increased hepatic iron content can significantly accelerate hepatic fibrosis, the reported incidence of significant hepatic fibrosis in HSCT recipients varies substantially, from 5% to 80%, (6,37,38) perhaps owing to the variable incidence of viral hepatitis and other coexisting liver diseases present in different patient populations. In our study, we observed a low incidence of hepatic fibrosis (30%), which was mostly grade 1 and 2, suggesting that the effect of transfusional iron overload is not a compelling cause of liver cirrhosis, a process that may take many years to develop.

Our study evaluated the association between HIO and development of systemic infections. While we have shown that there is a direct correlation between HIO and BSI, there was no corresponding increased risk of BSI with increasing severity of HIO. In addition, mortality was not influenced by the degree of HIO. However, we observed that patients with HIO tended to experience more frequent and prolonged episodes of BSI that were lethal. Nevertheless, the data extrapolated from this finding are too few, since we only documented 10 patients with bacteremia at the time of death.

It is believed that iron overload in HSCT patients should be monitored after transfusion of 20 units of packed red blood cells, (39) and some degree of tissue iron overload may generally ensue after 50 to 60 units. We demonstrated a tendency of iron accumulation in our patient population after receiving as few as 20 to 30 units (Figure 3). Hence, more factors are likely to be involved in the etiology of iron overload in the HSCT population than simply the number of units transfused. Factors such as conditioning regimens, ineffective erythropoiesis, and impaired iron transport may also have a role in the pathophysiology of iron overload. (40)

In conclusion, our study confirmed that iron overload is a common complication of HSCT and can be diagnosed by liver biopsy. Early detection of iron overload is essential to minimizing the adverse effect associated with its presence. Hepatic iron overload is increasingly found to be associated with blood stream infections, some of which can be lethal. While the etiology is often multifactorial, a high number of transfusions should increase the index of suspicion, implying a need for close monitoring and follow-up. Lastly, while serum ferritin can be falsely elevated as an acute-phase reactant, greatly elevated serum ferritin levels should serve as an indicator of potential HIO and should therefore prompt a thorough investigation.

Our research in the field of hepatic iron overload after hematopoietic stem cell transplant has been funded by the Department of Hematology and Oncology, Henry Ford Hospital, Detroit, Michigan. The authors would like to thank the Department of Pathology, the Department of Transfusion Medicine, data coordinators, and social workers at Henry Ford for their dedicated help.

References

(1.) Pullarkat V, Blanchard S, Tegtmeier B, et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2008; 42(12):799-805.

(2.) Mahindra A, Bolwell B, Sobecks R, et al. Elevated ferritin is associated with relapse after autologous hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant. 2008; 14(11):1239-1244.

(3.) Altes A, Remacha AF, Sureda A, et al. Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant. 2002; 29(12):987-989.

(4.) Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007; 109(10):4586-4588.

(5.) McKay PJ, Murphy JA, Cameron S, et al. Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant. 1996; 17(1):63-66.

(6.) Tomas JF, Pinilla I, Garcia-Buey ML, et al. Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant. 2000; 26(6):649-655.

(7.) Ho GT, Parker A, MacKenzie JF, Morris AJ, Stanley AJ. Abnormal liver function tests following bone marrow transplantation: aetiology and role of liver biopsy. Eur J Gastroenterol Hepatol. 2004; 16(2):157-162.

(8.) Altes A, Remacha AF, Sarda P, et al. Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis. Bone Marrow Transplant. 2004; 34(6):505-509.

(9.) Sucak GT, Yegin ZA, Ozkurt ZN, Aki SZ, Karakan T, Akyol G. The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated? Bone Marrow Transplant. 2008; 42(7):461-467.

(10.) Tomas F, Gomez-Garcia de Soria V, Lopez-Lorenzo JL, et al. Autologous or allogeneic bone marrow transplantation for acute myeloblastic leukemia in second complete remission: importance of duration of first complete remission in final outcome. Bone Marrow Transplant. 1996; 17(6):979-984.

(11.) Forbes GM, Davies JM, Herrmann RP, Collins BJ. Liver disease complicating bone marrow transplantation: a clinical audit. J Gastroenterol Hepatol. 1995; 10(1):1-7.

(12.) Shulman HM, Sharma P, Amos D, Fenster LF, McDonald GB. A coded histologic study of hepatic graft versus host disease after human bone marrow transplantation. Hepatology. 1988; 8(3):463-470.

(13.) Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995; 22(6):696-699.

(14.) Crawford JM. The liver and biliary tract. In: Cotran RS, Kumar V CTRpbod, Collins, T, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, PA: WB Saunders. 1999:845-901.

(15.) Searle J, KerrJFR, HallidayJW, et al. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, eds. Pathology of the Liver. London, United Kingdom: Churchill Livingstone. 1994:219-241.

(16.) Barry M. Liver iron concentration, stainable iron, and total body storage iron. Gut. 1974; 15(5):411-415.

(17.) Deugnier YM, Turlin B, Powell LW, et al. Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases. Hepatology. 1993; 17(1):3034.

(18.) Imbert-Bismut F, Charlotte F, Turlin B, et al. Low hepatic iron concentration: evaluation of two complementary methods, colorimetric assay and iron histological scoring. J Clin Pathol. 1999; 52(6):430-434.

(19.) Sajjad S, Garcia M, Malik A, Van Thiel DH. Hepatic iron quantitation and its relationship with disease measures and histologically assessed iron content. DigDis Sci. 2008; 53(5):1390-1394.

(20.) Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980; 69(2):204-217.

(21.) Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease, I: diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12):945-956.

(22.) Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988; 16(3):128-140.

(23.) O'Grady NP. Review: paired quantitative blood cultures most accurately detect intravascular device-related bloodstream infection. ACP J Club. 2005; 143(3):77.

(24.) Spivak JL. The blood in systemic disorders. Lancet. 2000;355(9216):1707 1712.

(25.) Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001; 22(23):2171-2179.

(26.) Kondur AK, Li T, Vaitkevicius P, Afonso L. Quantification of myocardial iron overload by cardiovascular magnetic resonance imaging T2* and review of the literature. Clin Cardiol. 2009; 32(6):E55-E59.

(27.) Storey JA, Connor RF, Lewis ZT, et al. The transplant iron score as a predictor of stem cell transplant survival. J Hematol Oncol. 2009; 2:44.

(28.) Deugnier YM, Loreal O, Turlin B, et al. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology. 1992; 102(6):2050-2059.

(29.) Brissot P, Bourel M, Herry D, et al. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Gastroenterology. 1981; 80(3):557-565.

(30.) Rose C, Ernst O, Hecquet B, et al. Quantification by magnetic resonance imaging and liver consequences of post-transfusional iron overload alone in long-term survivors after allogeneic hematopoietic stem cell transplantation. Haematologica. 2007; 92(6):850.

(31.) Busca A, Falda M, Manzini P, et al. Iron overload in patients receiving allogeneichematopoietic stem cell transplantation: quantification of iron burden by a superconducting quantum interference device (SQUID) and therapeutic effectiveness of phlebotomy. Biol Blood Marrow Transplant. 2010; 16(1):115-122.

(32.) Majhail NS, Lazarus HM, Burns LJ. A prospective study of iron overload management in allogeneic hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant. 2010; 16(6):832-837.

(33.) Emond MJ, Bronner MP, Carlson TH, Lin M, Labbe RF, Kowdley KV. Quantitative study of the variability of hepatic iron concentrations. Clin Chem. 1999; 45(3):340.

(34.) Villeneuve JP, Bilodeau M, Lepage R, Cote J, Lefebvre M. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol. 1996; 25(2):172-177.

(35.) Kornreich L, Horev G, Yaniv I, Stein J, Grunebaum M, Zaizov R. Iron overload following bone marrow transplantation in children: MR findings. Pediatr Radiol. 1997; 27(11):869-872.

(36.) Majhail NS, DeFor T, Lazarus HM, Burns LJ. High prevalence of iron overload in adult allogeneic hematopoietic cell transplant survivors. Biol Blood Marrow Transplant. 2008; 14(7):790-794.

(37.) Strasser SI, Kowdley KV, Sale GE, McDonald GB. Iron overload in bone marrow transplant recipients. Bone Marrow Transplant. 1998; 22(2):167173.

(38.) El-Sayed MH, El-Haddad A, Fahmy OA, Salama II, Mahmoud HK. Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation. EurJGastroenterol Hepatol. 2004; 16(12):1347-1354.

(39.) Mahesh S, Ginzburg Y, Verma A. Iron overload in myelodysplastic syndromes. Leuk Lymphoma. 2008; 49(3):427-438.

(40.) Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005; 23(30):7594-7603.

Sharif Ali, MD; Jason D. Pimentel, MD; Javier Munoz, MD; Veena Shah, MD; Rick McKinnon, MT (ASCP); George Divine, PhD; Nalini Janakiraman, MD

Accepted for publication July 26, 2011.

From the Departments of Pathology and Laboratory Medicine (Drs Ali, Pimentel, and Shah), Hematology and Oncology, Division of Bone Marrow Transplantation (Drs Munoz and Janakiraman and Mr McKinnon), Biostatistics and Research Epidemiology (Dr Divine), Henry Ford Hospital, Detroit, Michigan. Dr Ali is now with the Department of Transplant Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Sharif A. Ali, MD, Department of Transplant Pathology, UPMC-Montefiore, Room E732, 3459 5th Ave, Pittsburgh, PA 15213 (e-mail: alisa@upmc.edu).
Table 1. Characteristics for the 51 Patients Included
in the Histologic Review

Characteristics No. of Patients

Sex, male:female 28:23
Age at time of HSCT, median (range), y 46 (22-70)
Primary disease
 Acute myeloid leukemia 14
 Myelodysplastic syndrome 9
 Myeloma 6
 Chronic lymphocytic leukemia 5
 Non-Hodgkin lymphoma 5
 Myeloproliferative syndrome 4
 Hodgkin lymphoma 3
 Acute lymphoblastic leukemia 2
 Aplastic anemia 2
 Metastatic carcinoma 1

Donor source of allogeneic blood stem cells

 Bone marrow (related:unrelated) 3:1
 Peripheral blood (related:unrelated:cord
 blood unrelated) 31:13:3

Match status
 HLA mismatched (fully matched:1 antigen
 mismatch) 45:6

Conditioning regimen
 BU-CY 19
 FLU/melphalan 12
 FLU-CY 6
 CBV 3
 CY-TBI 3
 FLU-BU 2
 ARA-C 1
 BEAM 1
 CY-VP16 1
 None 2

Myeloablative versus nonmyeloablative
 therapy 46 versus 5

Donor/recipient CMV status
 Positive/negative:positive/positive 2:20
 Negative/positive:negative/negative 16:13

Hepatitis serology
 Negative:HBV +:HCV+ 49:1:1

Abbreviations: ARA-C, cytarabine; BEAM, includes BCNU, VP-16,
cytarabine, and melphalan for treating Hodgkin lymphoma; BU, busulfan;
CBV, cyclophosphamide, BCNU, and VP-16 for treatment of nonHodgkin
lymphoma; CMV, cytomegalovirus; CY, cyclophosphamide;
FLU, fludarabine; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA,
human leukocyte antigen; HSCT, hematopoietic stem cell transplant; TBI,
total body irradiation; VP-16, etoposide.

Table 2. Spearman Correlation by Grade of Iron Overload (a)

 Iron Grade 0 Iron Grade 1
Variable Response (N = 6) (N = 15)

Histologic 0 3 (50) 4 (27)
 H-GVHD, 1 1 (17) 5 (33)
 No. (%) 2 1 (17) 4 (27)
 3 1 (17) 2 (13)
H-fibrosis 0 4 (67) 7 (47)
 1 2 (33) 6 (40)
 2 0 (0) 2 (13)
Survival

 Mean (SD) 1069 (1424) 472
 (665.0)
 Range, d 64-3821 28-2423
Transfusions,
 mean (range) 14.8 (8-32) 17.5
 (6-37)
Albumin, mean
 (range), g/dL 3.3 (3-4) 2.7
 (1-5)
GGT, mean
 (range), IU/L 1353 (90-5172) 541
 (58-1525)
LDH, mean
 (range), IU/L 334 (183-544) 557
 (172-2086)
AST, mean
 (range), IU/L 133 (25-816) 109
 (36-653)
ALT, mean
 (range), IU/L 338 (25-816) 165
 (36-653)
Bilirubin, total,
 mean (range),
 mg/dL 3.3 (0-8) 4.5
 (0-14)
ALP, mean
 (range), IU/L 249 (122-375) 600
 (82-1116)
Ferritin, mean
 (range), ng/mL 4501 (91-8909) 389
 (216-472)
Serum iron, mean
 (range), mg/dL 254 (N/A) 40.7
 (32-55)

 Iron Grade 2 Iron Grade 3 Iron Grade 4
Variable (N = 8) (N = 13) (N = 7)

Histologic 4 (50) 2 (15) 0 (0)
 H-GVHD, 1 (13) 4 (31) 2 (29)
 No. (%) 2 (25) 4 (31) 3 (43)
 1 (13) 3 (23) 2 (29)
H-fibrosis 6 (75) 12 (92) 3 (43)
 1 (13) 0 (0) 3 (43)
 1 (13) 1 (8) 1 (14)
Survival
 Mean (SD) 1045 742 244
 (1176) (756.6) (154.2)
 Range, d 223-3651 86-2521 68-415
Transfusions,
 mean (range) 47.3 45.5 70.3
 (10-128) (10-97) (31-131)
Albumin, mean
 (range), g/dL 3.0 3.2 3.0
 (2-4) (2-4) (1-4)
GGT, mean
 (range), IU/L 279 1076 784
 (51-608) (201-3627) (113-1406)
LDH, mean
 (range), IU/L 425 398 236
 (205-1275) (137-1500) (134-370)
AST, mean
 (range), IU/L 89.4 164 128
 (48-203) (43-989) (78-224)
ALT, mean
 (range), IU/L 86.0 278 143
 (7-203) (43-989) (78-224)
Bilirubin, total,
 mean (range),
 mg/dL 5.2 2.8 5.5
 (1-22) (1-7) (1-20)
ALP, mean
 (range), IU/L 195 745 1199
 (71-318) (107-1383) (96-1103)
Ferritin, mean
 (range), ng/mL 2244 7215 9395
 (125-3593) (1537-13472) (2245-23541)
Serum iron, mean
 (range), mg/dL 77.0 (N/A) 134 140
 (65-195) (96-167)

 P (b)
Variable Value

Histologic .26
 H-GVHD,
 No. (%)

H-fibrosis .27

Survival
 Mean (SD) .80

 Range, d
Transfusions,
 mean (range) <.001

Albumin, mean
 (range), g/dL .42

GGT, mean
 (range), IU/L .99

LDH, mean
 (range), IU/L .03

AST, mean
 (range), IU/L .63

ALT, mean
 (range), IU/L .67

Bilirubin, total,
 mean (range),
 mg/dL .99

ALP, mean
 (range), IU/L .49

Ferritin, mean
 (range), ng/mL .004

Serum iron, mean
 (range), mg/dL .33

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transferase;
AST, aspartate transferase; GGT, g-glutamyltransferase; GVHD,
graft-versus-host disease; H, hepatic; LDH, lactate dehydrogenase;
N/A, not available; SD, standard deviation.

(a) Summary of Spearman correlation statistics by iron overload grades.

(b) Significant P values in bold.
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Author:Ali, Sharif; Pimentel, Jason D.; Munoz, Javier; Shah, Veena; McKinnon, Rick; Divine, George; Janakir
Publication:Archives of Pathology & Laboratory Medicine
Date:May 1, 2012
Words:5739
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