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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism. (HEPATOLOGY 2004;39:1655–1662.)

Hereditary hemochromatosis (HH) is an autosomal recessive condition associated with an inappropriate increase in intestinal iron absorption.1 The majority of patients with HH are homozygous for a guanine-to-adenine base mutation in a novel gene (HFE) which results in a substitution of cysteine by tyrosine at position 282 of the gene product.

The liver is the principal organ in which excess iron is deposited in HH, and this may result in hepatic cirrhosis. Orthotopic liver transplantation (OLT) is a well-established therapy for end-stage liver disease with 1-year and 5-year survival rates of 88% and 74%, respectively.2, 3 Approximately 20% of patients undergoing OLT have significant hepatic hemosiderosis, which is usually independent of HFE mutations (known as “cirrhosis-associated iron overload”).4 Although it is controversial, several groups have suggested that patients with excess hepatic iron have increased mortality and morbidity following OLT.5, 6 However, in these studies it is difficult to be confident of the exact outcome of OLT for HH because genotyping was not performed on some occasions, and many patients may have had cirrhosis-associated iron overload. Because of the high prevalence of iron overload in the general population, inadvertent transplantation of an iron-loaded donor liver is not uncommon. Such an event could have important consequences. First, early graft function may be compromised because iron catalyzes the production of reactive oxygen species and may exacerbate ischemia-reperfusion injury.7 Furthermore, if iron persists in the donor graft, the risk of subsequent hepatic fibrosis may be increased, and long-term graft survival could be compromised. However, available data suggest that an iron-loaded liver from a homozygous-affected subject transplanted into an individual without HFE mutations results in early mobilization of the iron from the donor liver.8–10

The aims of this study were (1) to examine the posttransplant morbidity, mortality, and parameters of iron metabolism in a series of patients who underwent OLT for HH and (2) to review the posttransplant follow-up and histological findings of recipients of iron-loaded livers, with specific emphasis on graft function and persistence of hepatic iron stores. The latter was conducted to provide insights into the clinical implications of transplantation of an iron-loaded donor liver.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

Study and Control Population.

This multinational study included patients who underwent OLT at the Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK; the Queensland Liver Transplant Service, Princess Alexandra Hospital, Brisbane, Australia; the Victorian Liver Transplant Service, The Austin Hospital, Melbourne, Australia; the West Australian Liver Transplant Service, Sir Charles Gardiner Hospital, Perth, Australia; the Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney, Australia; and the New Zealand Liver Transplant Service, Auckland, New Zealand. Collectively, these institutions performed 3,600 primary OLTs on adult patients with cirrhosis between January 1982 and June 2001. The etiology of the cirrhosis and the indication for OLT were confirmed by review of a central database in each institution. Review of medical records of patients with a pretransplant diagnosis of hemochromatosis and/or excess iron in the explant was performed. 22 patients were identified who also met the following criteria for inclusion in the study: (1) HFE mutation analysis confirming that a subject was homozygous for the C282Y mutation; or (2) evidence of marked systemic iron loading associated with a family history of iron overload and/or an HLA A3 B7 haplotype. To be included in the study, therefore, all subjects had at some stage demonstrated phenotypic expression of the underlying genetic defect. The medical records of these 22 subjects were further reviewed to obtain relevant clinical, laboratory, and follow-up details.

We also reviewed 675 donor liver biopsies at 1 participating institution (the Liver and Hepatobiliary Unit, University Hospital, Birmingham, UK), where 12 donor livers were identified with increased siderosis (defined in this study as greater than grade 1 according to the method of Scheuer et al.11) at the time of implantation, i.e., time zero biopsy. Demographic, clinical, and laboratory details of these 12 donors were recorded (including HFE status of 5 donors and 9 recipients). The etiology of cirrhosis in the recipient and the degree of siderosis in the explanted liver were confirmed by review of pathological records. The warm-ischemia and cold-ischemia time were noted as were measurements of early graft function, including peak serum aspartate aminotransferase (AST) level, peak prothrombin time, and peak serum bilirubin concentration. Each patient had undergone at least 1 follow-up liver biopsy 0.1 to 8.5 years after OLT. The degree of siderosis in the follow-up biopsies was compared with the degree of siderosis of the time zero biopsy, as well as with additional previous biopsies.

Hepatic Iron Assessment, HFE Genotyping, and HLA Status.

Liver iron stores were graded 0 to 4 following Perls' Prussian blue stain according to the method described by Scheuer et al.11 For the measurement of hepatic iron concentration, liver tissue was excised from the paraffin block, heated on a hot plate to melt the paraffin, soaked in xylol, and washed in ethanol. The specimen was dried overnight at 60°C, weighed, digested in 150 μL nitric acid, and diluted with deionized water to 500 μL. Iron concentration was measured colorimetrically.12HFE mutation analysis was performed as described previously.13 HLA typing was performed prior to OLT using standard microlymphocytoxicity assays on DNA extracted from peripheral blood lymphocytes.

Immunosuppression Protocol.

Maintenance immunosuppressive protocol consisted of either cyclosporine or tacrolimus, often in combination with a small maintenance dose of corticosteroids or azathioprine. In general, the dose of the calcineurin antagonists was adjusted to maintain trough whole blood concentrations of cyclosporine of 100-150 ng/mL and tacrolimus of 5 to 8 ng/mL. The dose of cyclosporine and tacrolimus was adjusted according to plasma levels, renal function, and systemic complications of the calcineurin inhibitors.

Resource Utilization.

Resource utilization was defined by the duration of the transplant operation, the length of stay in the intensive care ward, and the total duration of the hospital stay in the initial posttransplantation period.

Statistical Evaluation.

Normally distributed variables were expressed as mean ± SD. Nonparametric tests (Mann-Whitney) were used to compare the medians of continuous variables that were not normally distributed between the groups. Crude survival outcomes were calculated by Kaplan-Meier survival analysis.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

Characteristics of HH Patients Who Underwent OLT.

Seventeen of the 22 HH subjects were homozygous for the C282Y mutation in HFE. The remaining 5 subjects met criteria for inclusion in the study. All patients were male (mean age 54 years). Table 1 shows the clinical characteristics of the 22 HH patients. Five patients had not commenced venesection, and 7 patients were undergoing a venesection program at the time of transplantation. Ten patients were on maintenance venesection protocols. Seven patients had significant hepatic iron loading at the time of transplantation, as evidenced by grade 4 hepatic iron stores. Eleven of the 22 patients consumed at least 60 grams of alcohol per day for more than 10 years. All HH OLT recipients were cirrhotic. Hepatocellular cancer (HCC) was present in 8 of the 22 patients. Four of these patients underwent transplantation despite the presence of large tumors (7cm, 9cm, 10cm, and 12cm) before guidelines regarding transplantation for HCC were established. Patient 3 had a 2-cm tumor resected 6 months prior to transplantation. Two patients had atrial fibrillation, and 2 patients had impaired left ventricular function on echocardiography performed shortly prior to transplantation (left ventricular ejection fraction 40%). Nine patients had impaired glucose tolerance requiring therapy.

Table 1. Clinical and Laboratory Characteristics of Patients With Hereditary Hemochromatosis
Patient No.OutcomeAge (y)Extent of VxFe Grade ExplantIndication for OLTAlcohol > 60 g/dHCCCardiac DiseaseDiabetes Mellitus
  • Abbreviations: V, venesection; Fe grade, histological iron grade; A, alive; P, partial; ESLD, end-stage liver disease; AF, atrial fibrillation; D, deceased; M, maintenance; LVEF, left ventricular ejection fraction; NIL, no venesection.

  • *

    Cause of death related to HCC.

1A51P3ESLDYesNoAFNo
2D59P2HCCNoYes < (5 cm)*NoNo
3A58M1ESLDNoYes (2 cm)NoNo
4A56P4ESLDNoNoNoNo
5A54P4ESLDYesNoNoNo
6D58M0HCCNoYes (7 cm)NoYes
7A52M1ESLDYesYes (2 cm)NoNo
8A60M2ESLDYesNoLVEF < 40No
9A57M1ESLDYesNoNoYes
10D55P4ESLDNoNoAFYes
11D53P3ESLDNoYes (4 cm)*NoYes
12A60NIL4ESLDYesNoNoYes
13D40NIL3ESLDYesNoNoYes
14D63NIL4ESLDYesNoLVEF < 40No
15D64M1HCCNoYes (9 cm)*NoNo
16A39P2ESLDYesNoNoNo
17D45NIL4ESLDYesNoNoNo
18D63M1HCCNoYes (12 cm)*NoYes
19D44NIL4ESLDNoNoNoYes
20A48M2ESLDYesNoNoNo
21A54M1ESLDNoNoNoYes
22D62M2HCCNoYes (10 cm)*NoNo

Survival and Resource Utilization Data of HH Patients Who Underwent OLT.

Eleven patients have died and 11 patients remain alive. Figure 1 shows the Kaplan-Meier survival curves for all HH patients (N = 22) and for 18 HH patients with small HCC (<5cm) or no HCC compared to the overall adult OLT survival data. The 1-year, 3-year and 5-year posttransplantation survival was 72%, 62%, and 55%, respectively, whereas the survival of the 18 patients who met Mazzafero criteria14 was 74%, 68%, and 60%, respectively.

thumbnail image

Figure 1. Kaplan-Meier estimates of post-OLT survival for all hemochromatosis patients (HH; N = 22) and hemochromatosis patients with no tumor or tumors less than 5 cm (n = 18) and data of control patients from multiple centers.

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Recurrent HCC was the cause of death in 5 patients. Four of these patients had tumors greater than 5 cm and would not be considered for OLT given present-day indications. Cardiac-related events were responsible for 4 other deaths. Only 1 of those patients had previous evidence of myocardial dysfunction. One surviving patient had a left ventricular ejection fraction of 40% pre-OLT and has developed symptomatic congestive cardiac failure since transplantation.

A comparison of resource utilization of HH patients who had marked hepatic iron loading (grade 4) and those who had lesser amounts of iron at the time of transplantation (grade 3 or less) is shown in Table 2. The more heavily iron-loaded subjects tended to have longer intensive care ward stay and inpatient stay compared to those with less iron. There was a significantly longer inpatient stay in the HH patients with diabetes mellitus (P < .03; Table 2).

Table 2. Resource Utilization of OLT Patients With Hereditary Hemochromatosis
 OTICWIPS
  1. NOTE. (a) patients with grade-4 iron loading compared to those with less than grade-4 iron loading; (b) patients with diabetes compared to those without diabetes. (Numbers represent median value of each group).

  2. Abbreviations: OT, operative time (h); ICW, days in intensive care unit; IPS, in patient stay posttransplant (d); Fe grade, histological iron grade; NS, not significant.

a   
Explant Fe grade = 4 (n = 6)7.0010.0021.00
Explant Fe grade < 4 (n = 16)7.003.0014.00
P valueN/SN/SN/S
b   
Diabetes (n = 8)7.004.2527.00
Nondiabetic (n = 14)7.004.0015.00
P valueN/SN/S.03

Reaccumulation of Iron in Donor Liver in HH Patients Following OLT.

Follow-up iron indices on surviving HH patients is shown in Table 3 (N = 11). Of 11 surviving patients, 10 had neither biochemical nor histological evidence of iron reaccumulation after a median follow-up period of 4 years (maximum follow-up 9 years). Furthermore, no patient had an elevated transferrin saturation, which is considered to be the earliest phenotypic marker of HH. One patient (patient 12), who has been followed for 3 years after transplantation, showed a progressive increase in serum ferritin concentration with grade 1–2 siderosis on liver biopsy. This patient has commenced a course of venesection with a progressive fall in serum ferritin concentration. The HFE status of the donor is not known, but the iron stores of the donor organ were not increased at the time of implantation. The HLA haplotype of the donor was A8 B24.

Table 3. Follow-up Iron Indices on Surviving Hereditary Hemochromatosis Patients
Patient No.Duration of Follow-up (y)Serum Ferritin μg/L% TSFe Grade
  1. Abbreviations: TS, transferrin saturation; Fe-grade, histological iron grade; NA, not available.

12NANANA
3115100 (4 y)
4499250 (2 y)
54233210 (4 y)
75102150 (1 y)
8410917NA
995841NA
123573461–2 (3 y)
164140NA0–1 (1 y)
2035642NA
211.52515NA

Characteristics of Recipients and Donors of Iron Loaded Grafts.

Eight of the 12 recipients of iron-loaded grafts were male, and the mean age of these 12 subjects was 54 years (range, 35–62 years; Table 4). Two recipients had increased iron stores (grade 2–3) in their explanted liver, but neither carried HFE mutations. An additional 2 recipients had grade 1 iron stores in their explant, whereas explant iron stores were normal in the remaining 8 patients. The age range of the donors was 23 to 61 years, and 7 of the donors were male. The degree of iron loading in the donor organ (i.e., time zero biopsy) varied as follows: grade 1–2 (5 patients), grade 2 (2 patients), grade 2–3 (3 patients), and grade 3 (2 patients). In all cases, iron deposition was in hepatocytes in a periportal distribution. HFE genotyping was available on 5 of the 12 donors. Two donors were homozygous for the C282Y mutation with grade 2 and grade 3 hepatic iron stores. Another 2 patients were heterozygotes, 1 with grade 1–2 and 1 with grade 2 iron stores, and 1 was normal (grade 1–2). Ten of the 12 recipients had HFE genotyping and all were normal, apart from subject 12, who was heterozygous for the C282Y mutation.

Table 4. Characteristics of Recipients of Iron-Loaded Grafts
PatientRecipient Age/SexIndication for OLTRecipient HFESiderosis in Explant (grade)Donor Age/SexDonor HLADonor HFESiderosis Grade Post-OLT*Current Clinical Status
0 y0–1 y1–2 y2–3 y>3 y
  • Abbreviations: AAT, alpha-1 antitrypsin deficiency; CC, homozygous normal; NA, not available; LFT, liver function test; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; D, deceased; CY, heterozygous hemochromatosis; HBV, chronic viral hepatitis B; CRYPT, cryptogenic cirrhosis; FHF, fulminant hepatic failure; YY, homozygous hemochromatosis; ALD, alcoholic liver disease; WD, Wilson's Disease.

  • *

    Hepatic iron concentration in parentheses (μmol/g dry weight).

a49 MAATCC2–323 MA1,B8 A1,B8NA1–20NANANAnormal LFT
b54 FPBCNA037 FA1,3 B7,14NA1–2000NAnormal LFT
c35 MPSCCC055 FA11,19 B5,22NA1–2NANA0NArecurrent PSC/D
d42 MPSCCC042 MA3,9 B7,37CY1–21–2NANANArecurrent PSC
e50 MHBVCC155 MA24,25 B1,23CC1–2000NAnormal LFT
f49 FCRYPTCC042 MA1,3 B8,27CY21NANANAnormal LFT
g35 FFHFCC045 FA1,3 B7,37YY2 (112)2–3NA2–3 (95)2–3normal LFT
h62 MALDCC024 MA2,19 B12,21NA2–32–3NANA2–3mild fibrosis; steatohepatitis
i60 MALDCC161 FA2,9 B5NA2–32–32–3NANAcirrhosis, steatohepatitis
j48 FAATCC2–338 MA3,11 B2,22NA2–32–32–3NA3normal LFT
k52 MPSCNA051 FA1,28 B16,35NA333NANAmild anaemia
l37 MWDCY041 MA1,28 B7,37YY3 (255)34 (191)3–42venesection

Early Liver Function in Patients Receiving Donor Grafts With Increased Iron Stores.

Using univariate and multivariate analyses, we found no relationship between grade of siderosis and peak AST value, peak prothrombin time, or peak serum bilirubin concentration. When other factors previously shown to influence graft function were considered, we found statistical trends suggesting relationships between the grade of steatosis and peak serum bilirubin concentration (P = .09), and between donor age and peak prothrombin time (P = .15).

Long-term Histological and Clinical Sequelae of Patients Who Received Grafts With Increased Iron Stores.

The mean duration of follow-up of the 12 patients who underwent transplant with livers with increased iron stores was 4 years (range, 1-8.5 years; Table 4). Iron stores regressed to normal in 4 patients (subjects a, b, c, and e), all of whom had mild (grade 1-2) siderosis in the donor liver. Mobilization of hepatic iron was rapid in these patients: they had no evidence of iron accumulation in the first available protocol liver biopsy which, in 3 of the 4 patients, was performed within 1 year of transplantation. HFE genotyping was available in only 1 of these 4 donor-recipient pairs, and both donor and recipient were homozygous normal.

Hepatic iron stores were slow to mobilize in some patients. Four patients (subjects g, h, i, l) had liver biopsies at least 3 years after liver transplantation. Slow mobilization of hepatic iron was seen in both male and female recipients and both occurred in the absence of the C282Y mutation in the recipient and was independent of the gender of the donor. Genotyping was available in 2 of these donor-recipient pairs, and both donors were homozygous for the C282Y mutation whereas the recipients were normal (subject g) or heterozygous (subject l) for the C282Y mutation.

Hepatic iron concentration for subjects g and l are shown in Table 4. In both patients, iron concentrations fell relatively slowly posttransplant: by 15% and 25%, 2 years and 1 year (112–95 and 255–191 μmol/g dry weight), subjects g and l, respectively.

One patient with persistent siderosis developed cirrhosis. The progression to cirrhosis was demonstrated in annual biopsies over a 4-year period and occurred in association with grade 3 siderosis, severe steatosis, and features of steatohepatitis including Mallory's hyaline and pericellular fibrosis. The recipient was obese (weight 104 kg) and denied any significant alcohol use. One other patient (weight 100 kg) had established fibrosis which also occurred in the presence of features of steatohepatitis. Liver function tests were normal in the majority of patients despite persistent iron loading, although those patients with recurrent primary sclerosing cholangitis, steatosis, and fibrosis had elevations in all liver enzymes. No patient had any evidence of hemolysis after transplantation. One patient with an increase in the degree of siderosis (Perls' stain) in the graft commenced a venesection program that resulted in a significant decrease in liver iron stores.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

This study highlights the paradox between the frequency of homozygosity for the C282Y mutation15–17 and the number of liver transplants performed for HH. The institutions participating in this study have performed in excess of 3,600 liver transplants for end-stage liver disease. However, only 22 patients had undergone liver transplant for HH. This discordance is emphasized by the observation that 11 of the 22 subjects who underwent OLT consumed excessive alcohol, and 2 other subjects had additional causes of liver disease (α1 antitrypsin deficiency, chronic viral hepatitis C). Thus, OLT was performed in only 9 patients (0.26% of all adult transplants) in whom iron was the only hepatotoxin. It is unlikely that the small number of HH patients requiring OLT is due to early diagnosis and treatment because even in high-prevalence regions, the proportion of the total HH population undergoing venesection is small.18 We cannot totally exclude the fact that we may have misclassified as controls some patients with HH. In 1 center, genotyping was performed on most patients with positive iron staining on explant. Of the 282 patients who were assessed, positive iron staining was present in 37% of subjects, and only 4 were homozygous for C282Y mutation. By extrapolation to the total control population (3,578 patients), the largest number of HH patients we should expect is 53. These data illustrate that the disease burden of HH, in terms of impact on liver transplant programs, is modest, and this emphasizes our observations of the increased risk of cirrhosis in HH patients who consume excess alcohol.19

Despite being an uncommon indication for OLT, it is likely that most liver transplant centers will have to consider transplantation in HH patients. There is conflicting evidence in the literature regarding the outcome of liver transplantation for iron overload, and interpretation of this data is confused by the observation that iron accumulates in end-stage liver disease independent of HFE mutations.4–6, 20, 21 Most patients included in the studies addressing the outcome of iron-loaded subjects probably had cirrhosis-associated iron overload rather than true HH. The present study provides important information that should be considered when HH patients are assessed for OLT. First, overall survival is poor, and these patients require careful clinical evaluation of perioperative and postoperative risk factors. Fifty percent of the HH patients transplanted at these institutions have died. The most outstanding patient variable predicting death was the presence of HCC. The risk of HCC is increased approximately 100-fold in HH patients with cirrhosis.22 Our data emphasize this association because 35% of the HH population who underwent transplantation had HCC. This study suggests that the current guidelines regarding transplantation in patients with intercurrent HCC14 should be applied to HH patients: 4 of the 5 subjects who died from recurrent HCC had tumors that were 7, 9, 10, and 12 cm in diameter. One other patient who died from HCC had venous invasion at the time of transplantation. Four patients died from cardiac-related events, and 1 other patient suffered life-threatening cardiac arrhythmias. Interestingly, only 1 of the 4 patients had abnormal left ventricular function prior to OLT, suggesting that detailed assessment of cardiac function, e.g., stress echocardiography and 24-hour Holter tape monitoring, may assist in identifying those patients at risk of post-OLT cardiac events.

It is of interest that iron does not usually reaccumulate in the donor liver in HH patients. This provides clues to the site of the primary defect in HH. Our study identified only 1 patient with evidence of a progressive increase in serum ferritin concentration and hepatic iron stores. Venesection was commenced with a reduction in body iron stores. Another patient had a slight increase in hepatic iron stores (grade 0–1) as assessed by Perls' stain. Data from our hepatic iron concentration database of liver disease patients show that no patient with a negative Perls' stain had a hepatic iron concentration greater than 20 μmol/g dry weight (in 45 cases, hepatic iron concentration = 11.38 ± 7 μmol/g dry weight [mean ± SD]). In contrast, none of the surviving patients had either biochemical or histological evidence of iron reaccumulation after a median follow-up period of 4 years (maximum follow-up, 9 years). Furthermore, no patient had elevated serum transferrin saturation, considered to be the earliest phenotypic marker of HH. In those subjects with short follow-up times, the time interval between OLT and reassessment of iron may be too brief to determine if they express the HFE phenotype, given the variable accretion of iron seen in HH. However, it is essential to recognize that, in the patient with the longest follow-up (9 years), there is still no evidence of iron reaccumulation. One of the patients with significant iron loading at the time of transplantation showed a progressive fall in serum ferritin concentration and transferrin saturation without venesection, suggesting that liver transplantation attenuated the phenotypic expression of the underlying genetic defect. This is emphasized by the recent report by Parolin et al.23 in which 41 adult subjects with a hepatic iron index of greater than 1.9 in their explant liver were studied, only 4 of whom were homozygous for the C282Y mutation. Follow-up liver biopsies 1 year post-OLT showed that 3 of these patients had lost their hepatic iron stores.

We have demonstrated that significant iron loading in a donor liver from a C282Y homozygous person could be slow to mobilize. This contrasts with other published reports. Previously, Adams et al.8 described a case whereby a marked increase in hepatic iron was demonstrated in a recipient 30 days after OLT. Presumably, inadvertent transplantation of an iron-loaded graft had occurred, and the 19-year-old female recipient showed a rapid and progressive decline in serum ferritin concentration and hepatic iron concentration which normalized 6 months after transplantation. Dabkowski et al.10 described a situation in which a liver from a patient with HH was transplanted into a recipient with normal iron metabolism, and the liver iron concentration and serum ferritin concentration returned to normal within 2 years. In contrast to these reports, we demonstrated that mobilization of hepatic iron in iron-loaded donor grafts may take many years. The duration of follow-up was up to 4 years, with multiple biopsies in some individuals. Quantitative measurements of hepatic iron were performed sequentially in 2 individuals who received C282Y homozygous livers and their hepatic iron concentration reduced by 15% and 25% at 2 years and 1 year, respectively. At this rate of spontaneous mobilization—and assuming that it remains linear—normalization of hepatic iron concentration may take in excess of 5 to 6 years in these subjects. A number of factors may influence the rate of mobilization of iron from an iron-loaded liver transplanted into a non-HH recipient, not the least of which may be the iron status of the recipient at the time of OLT. These factors may account for the variability in mobilization with liver iron levels of 4 of the 12 recipients apparently dropped to normal whilst other recipients were slow to mobilize hepatic iron stores.

The clinical implications of slowly mobilizing iron stores are not clear, but it is of concern that 1 patient with grade 3 iron and steatohepatitis developed cirrhosis. The progression to cirrhosis was demonstrated in annual biopsies over a 4-year period. One additional patient with steatohepatitis showed established, albeit minor fibrosis. There is evidence that livers of rats with steatosis are more susceptible to iron-induced lipid peroxidation and hepatic fibrogenesis than control animals. It is possible that excess iron in the donor may potentiate the risk of other hepatotoxic insults, and attending clinicians should be aware of this risk if they are caring for patients who have inadvertently received iron-loaded grafts. In contrast, increased donor iron does not adversely effect early graft function after OLT. Iron may exacerbate ischemia-reperfusion injury because iron catalyzes the production of reactive oxygen species. In this study, there was no relationship between the degree of iron loading and any measure of early graft function, such as peak AST levels, serum bilirubin concentration, or prothrombin time. Thus, the current antioxidant content of preservation solutions appears to be sufficiently protective against reactive oxygen species that may be generated by excess donor iron.

In summary, OLT for HH is uncommon despite the high prevalence of the C282Y mutation in HFE in Caucasians. However, posttransplant survival in affected patients is poor, and these patients require careful clinical evaluation of perioperative and postoperative risk factors, particularly the presence of HCC. Donor graft siderosis can be slow to mobilize and possibly potentiate other hepatotoxins. However, there was no consistent biochemical evidence of iron reaccumulation in HH patients who received a non–iron-loaded liver, suggesting that the storage iron excess in HH may not wholly depend on the role of the intestine in increased iron absorption, but also may depend on factors in the liver that modulate iron metabolism.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  • 1
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