Post-Transplant Events

The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated?

Abstract

Abnormalities in liver function tests are common in hematopoietic SCT (HSCT) recipients. We retrospectively investigated the role of liver biopsy in determining the cause of elevated liver enzymes and its impact on the management of patients in the post-HSCT setting. A total of 24 consecutive liver biopsies were obtained from 20 patients from September 2003 to December 2007. A definite histopathologic diagnosis was obtained in 91.7% of the biopsies. Iron overload (IO) was found in 75% and GVHD in 54.2% of the patients. The initial clinical diagnosis of GVHD was confirmed in 56.5% and refuted in 43.5% of the allogeneic HSCT recipients. The median number of post transplant transfusions, percent transferrin saturation and ferritin levels were found to be higher in patients who had histologically proven hepatic IO (p1=0.007, p2=0.003 and p3=0.009, respectively). Regression analysis showed a significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes. Our data suggest that hepatic IO is a frequent finding in the post-HSCT setting, which contributes to hepatic dysfunction and it should be considered in the differential diagnosis, particularly in patients with high serum ferritin levels.

Introduction

Liver dysfunction is a frequent complication of hematopoietic SCT (HSCT), occurring in 50–72% of patients with mortality rates ranging between 4 and 15%.1, 2, 3, 4, 5, 6 A substantial number of HSCT survivors suffer from chronic liver disease (CLD).4, 6 Etiology of liver dysfunction depends on factors such as type of HSCT, conditioning regimen, viral hepatitis status and the time interval post transplant that dysfunction is seen. The major causes of liver dysfunction in the early post transplant period are chemotherapy, radiotherapy, sinusoidal obstruction syndrome/venoocclusive disease (SOS/VOD), infections (hepatitis lenta) and drugs, whereas GVHD, iron overload (IO) and reactivation of viral infections such as CMV) and hepatitis B and C account for most of the cases of liver dysfunction in the intermediate and late periods.3, 4, 5, 6, 7, 8 Diagnosis usually depends on the clinical and laboratory features and exclusion of possible etiologic factors. Reactivation of virus infections and acute viral hepatitis are diagnosed with molecular viral tests, and SOS/VOD and GVHD are usually diagnosed clinically. However, the cause of elevated liver enzymes needs to be ascertained by liver biopsy occasionally in order to administer disease-specific therapy and avoid unnecessary immunosuppression. Although a very valuable diagnostic tool particularly in cases with uncertain and overlapping clinical features, liver biopsy is an invasive procedure with a significant complication rate.8 There is an increased rate of hemorrhagic complications due to thrombocytopenia during the early post transplant period, during which time transjugular biopsy is the method of choice.8, 9 We retrospectively reviewed the medical records of 20 patients in whom liver biopsy was required to clarify the cause of elevated liver enzymes post transplantation. The impact of liver biopsy in the management of liver dysfunction in these 20 HSCT recipients was also evaluated.

Patients and methods

Patients

The charts of the 207 patients (123 allogeneic and 84 autologous) who underwent HSCT at Gazi University Hospital, between September 2003 and December 2007 were retrospectively reviewed. Of the 207 patients, 193 had at least one of the liver enzymes above normal levels at some point after HSCT (118 allogeneic and 75 autologous). The majority of the liver enzyme abnormalities were transient and in the early post transplant period, and were either due to conditioning or to other hepatotoxic drugs or complications such as SOS/VOD. Patients with hepatic GVHD usually had elevated bilirubin levels±elevated liver enzymes. A total of 20 patients with persistent elevation of liver enzymes, including 13 men and 7 women with an age range of 17–52 years required 24 liver biopsies. These were at a median 211 (11–955) days after HSCT. Clinical, laboratory and histopathologic data of these 20 patients and 24 liver biopsies were reviewed. Impact of the histopathological diagnosis on subsequent patient management was also obtained from the clinical records. Details regarding patient characteristics, primary disease, conditioning regimens and treatment modifications made after histopathologic diagnosis are shown in Table 1. GVHD prophylaxis consisted of CsA and MTX. Liver function tests and hepatobiliary ultrasound were performed in every HSCT patient and were within the normal reference ranges prior to conditioning. Hepatitis B and hepatitis C viruses in the donors were negative for all 20 patients undergoing liver biopsy. Hepatitis B Ag and hepatitis C Ab positivity were seen in 2 (1 each) patients among the 20 requiring biopsy (5% each). The frequency of Hepatitis B was 3.2% for hepatitis B and 0.5% for hepatitis C in the population of 187 patients who did not require liver biopsy post-HSCT.

Table 1 Patient characteristics, liver function tests and management of the patients who had undergone liver biopsy

Liver biopsy

Liver biopsies were performed on the decision of the attending physician. However, according to institutional standard practice, a liver biopsy is performed when one or more of the liver enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyle transferase (GGT) and alkaline phosphatase (ALP) are persistently or progressively elevated in 2 weeks of follow-up. At least one of the liver enzymes was persistently high in the 20 patients described. The mean ALT level was 237.5±216.1 U/l, AST 130.5±143.4 IU/l, GGT 206.5±211.1 IU/l and ALP 255.1±306.4 IU/l. We refrained from performing a liver biopsy in patients with transient enzyme abnormalities and when the cause of the elevated liver enzymes was apparent and due to drug toxicity, SOS/VOD, viral hepatitis or reactivation of a previous hepatitis or overt GVHD. Hepatobiliary ultrasound, molecular viral markers including hepatitis B, C, CMV, herpes simplex virus (HSV), adenovirus and parvovirus were performed on detection of liver abnormalities. The biopsy procedure was conducted percutaneously under ultrasound guidance with a platelet count over 50 × 109 per liter and normal hemostatic parameters.

All biopsy specimens were fixed in 10% formalin and stained with hemotoxylin-eosin. Serial sections from each biopsy were examined, and Masson's trichrome for fibrotic stage and Prussian blue for hemosiderin deposition were used. Furthermore, immunohistochemical methods for hepatitis B surface/core Ags and CMV inclusions were performed when needed. A diagnosis of GVHD was given using the following criteria: mixed portal inflammation including eosinophils and activated lymphocytes, endothelitis and bile duct injury with lymphocytic permeation of duct epithelia, cytoplasmic vacuolization, nuclear loss, centrizonal hepatocyte necrosis, apoptosis and cholestasis. Hemosiderin deposition, both in hepatocytes and parenchymal/portal macrophages, was evaluated and graded as mild, moderate or severe according to following criteria: hemosiderin deposition visible at × 40 magnification and in 25% of hepatocytes, at × 20 magnification and in 50% of hepatocytes, at × 10 magnification and more than 50% of hepatocytes, respectively. Specimens showing marked portal lymphocytic inflammation, interface hepatitis in addition to paranchymal necrosis were investigated immunohistochemically for possible viral hepatitis. Biopsies with none to mild portal inlammation with scattered hepatocyte necrosis and sinusoidal inflammation were categorized as nonspecific.

Treatment of elevated liver enzymes was carried out either according to the clinical or histopathologic diagnosis with corticosteroids±intensifying current immunosupressive agents for GVHD, defibrotide for SOS/VOD, withdrawing the drugs suspected of interfering with hepatic functions and iron chelation in patients with IO. Informed consent was obtained from all patients and this retrospective study was approved by the institutional board of Gazi University Medical School.

Statistical analysis

Differences between groups were analyzed by the Student's t-test or Mann–Whitney U-test for continuous variables, and the χ2-test for categorical variables. Relations between variables were evaluated with Pearson's or Spearman's correlation tests. A value of P<0.05 was considered to represent a statistically significant difference. Survival analysis was carried out by using Kaplan–Meier and logrank tests. Analysis of the data was performed using SPSS for Windows V. 11.5 (SPSS Inc., Chicago, IL, USA).

Results

Elevated liver enzymes at some point post-HSCT were seen in 95.6% of patients receiving allogeneic and 89.3% of patients receiving autologous HSCT. A total of 24 liver biopsies were required in 20 patients. The time interval from allogeneic SCT to liver biopsy ranged from 11 to 955 days (median 211), and the median platelet count on the day of biopsy was 145 500 per μl (52 200–253 000). One patient had a hemorrhage after liver biopsy, which was treated conservatively with blood transfusions. There was no biopsy-related mortality.

Three patients had more than one liver biopsy. Repeating biopsies were included in the analysis as the second and third biopsies performed during different episodes of elevated liver enzymes with usually a different histopathologic diagnosis and at least 6 months apart (Table 1).

A definite histopathologic diagnosis was obtained from 22 of the 24 biopsies (91.7%). The liver biopsy was nondiagnostic in two cases (8.3%). The most common histologic diagnosis was IO, which was documented in 18 of the 24 biopsy specimens (75%). IO was the sole histopathologic abnormality in 8 of the 24 (33.3%) biopsy specimens and 13 of the 24 biopsies were diagnosed with GVHD (54.2%). Concomitant IO and GVHD were present in eight biopsies (33.3%), whereas only one biopsy (4.2%) showed IO and chronic hepatitis B infection, and one biopsy showed concomitant chronic hepatitis C, IO and GVHD. None of the biopsies revealed evidence of fibrosis or cirrhosis. Histopathology of the liver biopsies is shown in Table 2.

Table 2 Histopathologic results of liver biopsies

Liver biopsies of the five allogeneic HSCT recipients who had abnormal liver function tests and clinical signs of extrahepatic (limited, skin and/or oral) GVHD and who did not require systemic GVHD treatment in the abscence of hepatic GVHD showed no evidence of hepatic GVHD on histologic examination. Of 14 patients who had a ferritin level higher than 1000 ng/ml, 13 had histologically proven IO.

GVHD was the initial clinical diagnosis in all the allogeneic HSCT recipients with elevated liver enzymes. However, 43.5% (10/23) of these biopsies from allogeneic HSCTs showed no signs of GVHD on histologic examination, whereas 56.5% of the biopsies showed GVHD. In 33.3% of the patients IO was the only histopathologic finding. IO was mild in seven biopsies (38.9%), moderate in six biopsies (33.3%) and severe in five biopsies (27.8%).

Mean ferritin levels, percent transferrin saturation (TS), number of transfusions and inflammation markers of the patients with, and without hepatic IO are shown in Table 3. The median number of post transplantation packed red cell transfusions in patients who had histologically proven hepatic IO was 13 units (0–68), whereas it was 2 (1–9) units in patients without hepatic IO (P=0.007). The median number of platelet transfusions in patients who had histologically proven hepatic IO was 12 units (1–29), whereas it was 4.5 (1–9) units in patients without hepatic IO (P=0.007). The TS was found to be higher in patients with histologically proven IO (mean 59.9±31.7%) when compared to patients without IO (mean 26.3±15.5%; P=0.003). Serum ferritin levels were significantly higher in patients with hepatic IO (2235.9±2505.5 ng/ml) compared to patients without hepatic IO (388.5±630.0 ng/ml; P=0.009). C-reactive protein, albumin and fibrinogen levels, as markers of inflammation were not different in patients with, or without IO. Degree of hepatic iron was positively correlated with ferritin (P<0.001, r=0.673), percent TS (P=0.003, r=0.579), and number of packed red cells transfused (P=<0.027, r=0.452), and negatively correlated with serum albumin level (P=0.05, r=−0.396) on a simple correlation analysis (Figures 1, 2, 3). Only the positive correlation between degree of hepatic iron content and serum ferritin levels remained significant by regression analysis (P=0.043, R2: 0.45).

Table 3 The biochemical parameters and transfusion data of patients with and without iron overload
Figure 1
figure1

Degree of iron overload (IO) in the liver biopsy was positively correlated with ferritin levels.

Figure 2
figure2

Degree of iron overload (IO) in the liver biopsy was positively correlated with transferrin saturation.

Figure 3
figure3

Degree of iron overload (IO) in the liver biopsy was positively correlated with total number of packed red cell transfusions.

Ferritin values above 500 ng/ml were seen in 26.2% of the autologous and 66.7% of the allogeneic HSCT patients. Ferritin values were above 500 ng/ml in 62.5% of the 20 patients at the time of liver biopsy. Positive and negative predictive values of ferritin levels in reflecting hepatic IO were calculated as 93.3 and 44% for levels of ferritin >500 ng/ml.

The probability of survival was 61.3% in patients who required liver biopsy and 38.8% in patients who did not, without statistical significance. The median follow-up period was 462 days (106–1520) and 217 days (1–1565), respectively.

Discussion

Liver dysfunction is a very common complication of allogeneic HSCT and is reported in 50–84.2% of patients.3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Hepatic toxicity due to chemotherapy and radiotherapy, SOS/VOD, total parenteral nutrition, GVHD, sepsis, reactivation of viral hepatitis, CMV and IO are the most common causes of the abnormalities in liver function tests (LFTs).6, 7, 12, 13, 14, 15 Although the cause of the hepatic dysfunction is usually diagnosed by clinical and laboratory features, liver biopsy is required in patients with uncertain and/or overlapping etiology. We performed 24 percutaneous liver biopsies, median 211 days after HSCT in 20 patients. All except one of our patients who required liver biopsy had undergone allogeneic HSCT, in accordance with previous reports in the literature.3, 16 Percutaneous liver biopsy is an invasive but relatively safe diagnostic procedure in patients with normal hemostasis tests and platelet counts above 50 × 109 per liter.8 The percutaneous route was preferred in our patient cohort, as majority of the biopsies were obtained in the late post transplantation period when platelet counts were normal. A complication rate below 5% with a histopathologic diagnostic yield of 91.7% in our patient cohort indicates that percutaneous liver biopsy is a relatively safe and effective diagnostic procedure in the late stages of HSCT. In 43.5% of our patients histopathologic diagnosis brought about a change in the management of patients, mainly by withholding steroids and immunosuppresive agents. Similarly, in a recent report by Chahal et al.,17 liver biopsy was performed in 61 consecutive patients out of 1700 HSCT and histopathologic diagnosis led to a change in management in 37% of their patients.

The majority of the liver biopsies showed GVHD and/or IO in the present study which is in accordance with the literature.3, 6, 18, 19, 20, 21 The median post transplant day of liver biopsy was day+211 which accounts for the late post transplant period and explains why IO and GVHD are the most common histopathologic diagnosis rather than SOS/VOD, drug toxicity or hepatitis lenta which is seen in the earlier periods of HSCT. Whereas 75% of the biopsies showed histopathologic evidence of IO, 54.2% of the patients showed GVHD. Chronic GVHD was excluded on histopathologic diagnosis in 43.5% of the patients and avoided unnecessary corticosteroid treatment which could have increased morbidity and mortality. In 56.5% of the allogeneic patients either corticosteroids were commenced or immunosuppressive treatment was intensified with the histopathologic confirmation of GVHD. Ho et al.,3 reported liver histology consistent with IO in 84% of a selected group of their HSCT patients and the degree of hepatic IO correlated with elevated levels of ferritin and TS. The role of IO as the the actual cause of elevated liver enzymes could be questioned. Moreover, IO may be equally prevelant in patients with normal aminotransferase activity, as the fibrogenic process induced by iron is associated with little cell damage and inflammation often with borderline or even normal transaminase levels.22 However, in a recent report ‘IO-related disease’ has been defined as documented IO and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels (AST: >45 IU/l, ALT: >40 IU/l), physician diagnosed symptomatic hemochromatosis and arthropathy of the second and third metacarpophalengeal joints.23 Thus, elevated transaminases appear to be related IO in the HSCT patients described.

Serum ferritin levels were above normal in 128 (64%) and above 1000 ng/ml in 69 (35%) of our 207 patients. High serum ferritin levels were more frequent among allogeneic HSCT patients at 79.8%, compared to autologous patients with a rate of 47.1%. McKay et al.,24 found elevated serum ferritin levels in 88% of their patients at least 1 year post-HSCT. Ferritin levels and TS values were significantly higher in our patients with histopathologic evidence of hepatic IO, compared to those without IO (Table 3). Serum ferritin levels were positively correlated with hepatic IO on regression analysis, and the positive predictive value of ferritin levels >500 ng/ml in reflecting hepatic IO was calculated as 93.3% and the negative predictive value was 44%. Serum ferritin levels appeared to be important in predicting cases with hepatic IO and degree of hepatic iron content. Elevated serum ferritin levels have also recently been suggested as a test in predicting hepatic cirrhosis in patients with hemochromatosis. Waalen et al.,25 found 59 patients with ferritin levels above 1000 ng/ml among 29 699 white subjects that they screened. A total of 40% of these 59 patients were found to have hereditary hemochromatosis, whereas only 5% of these patients had elevated liver enzymes, which suggests that ferritin might be a better marker than elevated transaminases in predicting hepatic IO.

Our data suggest that the number of transfusions is a contributing factor causing IO. However, the amount of iron transfused by blood products per se does not explain the IO of the patients. Patients with IO might already be a high-risk population that requires a higher number of transfusions. It should also be noted that transfusions are by no means the only cause of IO in patients with hematologic malignancies treated with, or without HSCT. Decreased utilization of iron due to ineffective erythropoiesis, release of iron from the injured tissues, increased intestinal absorption of iron secondary to mucositis and GVHD,26 HFE mutations, abnormalities in hepcidin regulation are the other possible causes of IO in patients with hematologic malignancies and HSCT.4, 7, 26, 27

IO has important short- and long-term consequences. Free iron in the plasma is very toxic to tissues as it acts as a catalyst in the formation of hydroxyl radicals and peroxidation of lipid membranes.18, 21, 24, 28, 29, 30 Previous reports have documented an association between mucositis, opportunistic infections including aspergillus and mucor mucosis, febrile days, GVHD, SOS/VOD, hepatitis C and finally survival.1, 19, 26, 31, 32, 33, 34, 35 Patients with hemachromatosis have an increased incidence of cirrhosis, hepatocellular carcinoma and some other malignancies.35, 36, 37, 38, 39, 40 Similarly, CLD is one of the major long-term complications in HSCT survivors. Whereas Strasser et al.,4 reported a cumulative incidence of CLD in 3.8% by 20 years after transplantation in a series of 3721 patients, Tomas et al.,6 reported CLD in 57.5% of their cohort of 106 patients in 2 years follow-up, which strongly correlated with siderosis. They showed a dramatic improvement in LFTs with phlebotomy in patients with IO and hepatitis C. Azar et al.,14 reported that the only parameter which predicted liver injury in their 25 HSCT recipients was IO, whereas Angelucci et al.,35 found that the risk for progression of liver disease after HSCT strongly correlated with siderosis. Iqbal et al.,2 found varying degrees of IO in 81.25% of the HSCT patients undergoing laparoscopic liver biopsy in earlier phases of HSCT. Hepatic IO, besides fibrotic and cirrhotic potential, changes the natural course of viral hepatitis and its response to treatment and might also precipitate or mimic GVHD.4, 26, 27, 35 In this respect, we suggest that strategies which modify pre- or post transplantation IO in HSCT recipients might improve complication rates and survival.

In conclusion, liver biopsy has changed the management of a substantial number of our patients, indicating the essential role of liver biopsy in HSCT recipients with elevated liver enzymes. Our data suggest that hepatic IO is a frequent histopathologic finding among HSCT recipients with elevated liver enzymes, whereas GVHD seems to be overestimated in the same population. The significant correlation with hepatic IO, and serum ferritin levels warrants validation of the role of ferritin as a surrogate marker of hepatic IO in HSCT recipients. Treatment of IO with phlebotomy and/or iron chelators in the post transplant setting should also be investigated in prospective studies.

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Correspondence to G T Sucak.

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Sucak, G., Yegin, Z., Özkurt, Z. et al. The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated?. Bone Marrow Transplant 42, 461–467 (2008). https://doi.org/10.1038/bmt.2008.193

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Keywords

  • elevated liver enzymes
  • hematopoietic SCT
  • iron overload
  • GVHD
  • liver biopsy

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