Patients who underwent orthotopic liver transplantation at the London
Health Sciences Centre from 1985 to 1998 and from whom genomic DNA from
peripheral blood lymphocytes was available for molecular genetic
studies were eligible for inclusion. (Since 1985, it has been routine
practice in our institution to extract pretransplantation DNA and store
it at –80°C.) Liver donors were chosen on the basis of
available pretransplantation DNA. The control population consisted of
voluntary blood donors who participated in an ongoing population
screening study for hemochromatosis. This study was approved by the
Human Ethics Committee of the University of Western Ontario. Both the
transplantation population and blood donor population were
predominantly white with Northern European ancestry.
All explanted livers were examined microscopically after fixation in
formalin and paraffin embedding. The slides were stained with
hematoxylin-eosin and Perls' stain for iron. Histological iron
assessment was performed on a scale of 0 to 4+ using criteria outlined
by Scheuer et al.16 Any liver tissue that had 2+ or greater
hepatocellular iron by histology was considered to represent
hemosiderosis in this study and had supplemental biochemical iron
quantitation from the paraffin block by atomic absorption
spectrophotometry. This method assures that the iron analysis was
performed on representative liver tissue. The hepatic iron index was
the hepatic iron concentration (µmol/g dry weight) divided by the
patient age (normal < 1.9). The pathological assessment of the
explanted livers occurred without knowledge of the HFE
genotypes. The HFE genotypes were correlated with histological
and biochemical iron quantitation. Excessive alcohol consumption was
considered to be >60 g ethanol per day.
HFE Genotyping
Frozen DNA extracted from peripheral blood lymphocytes (obtained from
patients before liver transplantation) was available for polymerase
chain reaction (PCR) study on 304 liver recipients and 141 donors. All
available cases had C282Y testing. Heterozygotes for C282Y and all
patients who had 2+ or greater iron by histology (regardless of C282Y
status) were tested for a second hemochromatosis mutation, H63D. The
presence of significant iron overload in H63D heterozygotes or
homozygotes has been a rare observation.17 Genotyping was
performed by restriction enzyme analysis as previously
described.18 All cases identified as homozygotes or
heterozygotes for the C282Y mutation on agarose gel electrophoresis
were confirmed by acrylamide electrophoresis. Homozygotes and equivocal
heterozygotes for C282Y had confirmatory direct DNA sequencing.
DNA Sequencing
An HFE exon 4 sense primer
(5´-AAGCAGCCAATGGATGCCAAGC-3´) and an HFE exon 5
antisense primer (5´-TCCAATGAACAAGATGACGAC-3´) were
designed to produce a 411-bp PCR product that included the
G845e
A mutation site. These primers were used in
50-µL PCR reactions that contained 1× PCR-buffer, 1.5 mmol/L
MgCl2,
250 µmol/L dNTP mix, 1 µmol/L of each primer,
2.5 U Taq polymerase, and 1 µg of genomic DNA. The reaction
was denatured at 94°C for 4 minutes, and then amplification was
performed at 94°C for 45 seconds, 55°C for 45 seconds, and
72°C for 1 minute for 40 cycles. DNA sequencing was performed using
the ABI Prism BigDye Terminator Cycle Sequencing Ready Reaction Kit
(Perkin Elmer Applied Biosystems, Mississauga, Ontario, Canada) by the
J. P. Robarts Research Institute Sequencing Facility (London, Ontario,
Canada). The PCR product was purified using the QIAquick PCR
purification kit (Qiagen Inc., Mississauga, Ontario, Canada), and 100
to 300 ng of DNA was used in each sequencing reaction, which involved a
PCR reaction using 8 µL of terminator ready reaction mix containing
A, C, G, and T dye terminators, dNTPs, Tris and MgCl2
,
ampliTaq DNA polymerase, and 3.2 pmol of sequencing primer. The PCR
reaction was cycled 25 times through 96°C for 30 seconds, 50°C
for 15 seconds, and 60°C for 4 minutes. After ethanol
precipitation, the DNA was dried and resuspended in loading buffer, and
the samples then underwent electrophoresis on the ABI PRISM 377 DNA
Sequencer.
Statistical Methods
Differences in hepatic iron concentration between heterozygotes and
wild-type recipients were compared using the Mann-Whitney test.
Prevalence was compared between recipients and blood donors using
2 testing and the Fisher exact test. The primary
survival outcome assessed was between C282Y heterozygous and wild-type
recipients. Patient survival was also compared between: 1) C282Y
heterozygous and wild-type donors into all recipients; 2) C282Y
heterozygotes and wild-type donors into wild-type recipients; and 3)
C282Y heterozygotes and wild-type donors into C282Y heterozygous
recipients using Kaplan-Meier survival curves and the log rank test.
Two-sided P values < .05 were considered to be statistically
significant.
Liver Recipients
The average age of adult patients in our series was 55.4 years (range,
18-71 years). There were 164 males and 140 females. There were 20
children whose average age was 4.4 years (range, 2-16 years). The mean
follow-up period was 2.13 years (range, 0.03-6.0 years). The most
common etiologies of end-stage liver disease in this series were
chronic active hepatitis, chronic hepatitis C, primary sclerosing
cholangitis, primary biliary cirrhosis, alcoholic liver disease, and
cryptogenic cirrhosis. There were 15 patients with chronic hepatitis C
and excessive alcohol consumption included in the hepatitis C group.
The most common etiologies of end-stage liver disease in children were
congenital biliary atresia, metabolic liver disease, and cryptogenic
cirrhosis. There were 27 cases of acute liver failure and 277 cases of
cirrhosis. There was 1 heterozygote in the 27 cases of fulminant
hepatic failure. The prevalence of C282Y heterozygotes by disease group
are shown in Table 1
.
Table 1. Prevalence of Heterozygotes for C282Y Mutation of the HFE Gene
by Diagnosis
| Diagnosis | n | C282Y
Heterozygotes | >2+
Iron |
| Idiopathic chronic active hepatitis* | 50 | 5 | 16 |
| Hepatitis C† | 43 | 1 | 10 |
| Primary sclerosing
cholangitis | 43 | 4 | 1 |
| Primary biliary cirrhosis | 35 | 2 | 0 |
| Alcoholic cirrhosis | 31 | 7 | 8 |
| Cryptogenic
cirrhosis* | 24 | 1 | 0 |
| Autoimmune | 15 | 1 | 3 |
| Hepatic vein thrombosis | 10 | 1 | 0 |
 1
-Antitrypsin deficiency | 9 | 0 | 4 |
| Massive hepatic necrosis | 9 | 1 | 0 |
| Hepatitis B | 7 | 0 | 2 |
| Wilson's disease | 5 | 2 | 1 |
| Acute hepatitis | 4 | 0 | 0 |
| Congenital hepatic fibrosis | 2 | 0 | 0 |
| Phenytoin toxicity | 2 | 0 | 0 |
| Polycystic liver disease | 2 | 0 | 0 |
| Sarcoidosis | 2 | 0 | 0 |
| Biliary atresia | 2 | 0 | 0 |
| Alagille syndrome | 2 | 0 | 0 |
| Methotrexate | 1 | 0 | 0 |
| Nonalcoholic steatohepatitis | 1 | 0 | 0 |
| Secondary biliary cirrhosis | 1 | 0 | 0 |
| Acetaminophen overdose | 1 | 0 | 0 |
| Glycogen storage
disease | 1 | 1 | 1 |
| Hepatocellular carcinoma | 1 | 0 | 0 |
| Total‡ | 303 | 26 | 46 |
*Some cases of idiopathic chronic active hepatitis and cryptogenic
cirrhosis were classified before the availability of hepatitis C
serology.
†This includes 15 cases with excessive alcohol consumption.
‡One C282Y homozygote is not included in this table. |
Genotyping
In the recipient population, there were 26 heterozygotes (26 of 304
[8.6%]) and 1 homozygote, respectively
(Table 2
). The prevalence of heterozygotes
in presumably healthy blood donors was 8.4% (440 of 5,211). The
difference in the prevalence of C282Y heterozygosity between the liver
transplant recipients and voluntary blood donors is not statistically
significant (P = 1.0, 2, Fisher exact test).
Previously, the heterozygote frequency in this region by pedigree
analysis has been estimated at 11%.19 The H63D mutation
prevalence was 15.8% (9 of 57) in the 57 recipient patients tested.
The H63D mutation is no more common in the subgroup of patients with
end-stage liver disease tested in this study than in general
population-based controls. There were three compound heterozygotes
(i.e., one C282Y mutation and one H63D mutation) in the
recipient population in our study. In the present series, there were 31
patients who underwent orthotopic liver transplantation for alcoholic
cirrhosis (without hepatitis C). Seven of these patients were
heterozygotes for the C282Y mutation, for a prevalence of 23% (7 of
31). All of the patients with concomitant hepatitis C and excess
alcohol consumption (n = 15) were wild type for the C282Y mutation.
This prevalence for heterozygosity in alcoholic disease was increased,
as compared with voluntary blood donors (P = .02) and the
remainder of the liver transplant recipient group (P = .03,
2). No other disease group had an increased
representation of heterozygotes.
Table 2. C282Y Heterozygotes and Homozygotes (recipient group) Diagnosis and
Iron Status
| Age | Clinical Diagnosis | C282Y | H63D | Fe | HIC* | HII* |
| 57 | Hemochromatosis | Homozygote | Wild type | 4 | 331 | 5.80 |
| 24 | Autoimmune | Heterozygote | Wild type | 0 |
| 20 | Hepatic vein thrombosis | Heterozygote | Wild type | 1 |
| 21 | CAH | Heterozygote | Wild type | 1 |
| 67 | CAH | Heterozygote | Wild type | 2 | 67 | 1.00 |
| 59 | CAH | Heterozygote | Wild type | 3 | 67.8 | 1.15 |
| 57 | CAH | Heterozygote | Wild type | 3 | 59.1 | 1.04 |
| 52 | CAH | Heterozygote | Wild type | 1 |
| 30 | CRYPTO | Heterozygote | Wild type | 1 |
| 48 | ETOH | Heterozygote | Wild type | 3 | 111.9 | 2.33 |
| 48 | ETOH | Heterozygote | Heterozygote | 1 |
| 55 | ETOH | Heterozygote | Wild type | 0 |
| 65 | ETOH | Heterozygote | Wild type | 1 | 4 | 0.06 |
| 59 | ETOH | Heterozygote | Wild type | 0 |
| 55 | ETOH and HCC | Heterozygote | Wild
type | 3 | 57.3 | 1.04 |
| 68 | ETOH and HCC | Heterozygote | Heterozygote | 3 | 118 | 1.70 |
| 40 | HEP C | Heterozygote | Wild type | 1 |
| 64 | Massive necrosis | Heterozygote | Wild type | 0 |
| 66 | PBC | Heterozygote | Wild type | 0 |
| 44 | PBC | Heterozygote | Wild type | 0 |
| 59 | PSC | Heterozygote | Wild type | 1 |
| 44 | PSC | Heterozygote | Heterozygote | 0 |
| 30 | PSC | Heterozygote | Wild type | 0 |
| 43 | PSC | Heterozygote | Wild type | 1 |
| 25 | Storage (GLY) | Heterozygote | Wild type | 1 |
| 37 | Wilson's | Heterozygote | Wild type | 1 |
| 21 | Wilson's | Heterozygote | Wild type | 1 |
Abbreviations: C282Y, C282Y genotype; H63D, H63D genotype of the
HFE gene; Fe, histological iron (0-4+); HIC, hepatic iron
concentration (µmol/g of dry liver weight, normal 0-35); HII, hepatic
iron index (tissue iron in µmol/g of dry liver weight divided by the
age of the patient; CAH, chronic active hepatitis; CRYPTO, crypotgenic
cirrhosis; ETOH, alcoholic cirrhosis; HEP C, hepatitis C; HCC,
hepatocellular carcinoma; PBC, primary biliary cirrhosis; PSC, primary
sclerosing cholangitis; Storage, glycogen storage disease.
*HIC and HII determined only if histological iron 2+ or greater. |
Hepatic Iron Analysis
The liver iron grade (0-4+) in all explanted livers is shown in
Table 3
. There were 6 of 26 (23%) C282Y
heterozygotes and 40 of 277 (14%) wild-type recipients with 
2+ iron
(P = .25, 2, Fisher exact test). In patients
with 2+ iron, the mean hepatic iron concentration in C282Y
heterozygotes (n = 6) was 80 ± 27 µmol/g (mean ±
SD) and in wild-type recipients (n = 39, hepatic iron not available in
1 case), it was 62.3 ± 34 µmol/g (P = .15)
(Fig.
1). There were 5 wild-type recipients
(2 hepatitis C, 2 idiopathic chronic active hepatitis, 1 autoimmune
hepatitis) and 1 C282Y heterozygote with a hepatic iron index greater
than 1.9. One compound heterozygote (C282Y/H63D) had 3+ histological
iron (hepatic iron index = 1.7), while the other 2 did not have any
stainable iron. In the pediatric cases, 14 cases had no stainable iron,
and 6 cases had 1+ stainable iron.
Table 3. Liver Iron Grade in Heterozygotes and Wild-Type Recipients
| Liver iron grade | 0 | 1 | 2 | 3 | 4 |
| C282Y
heterozygotes (n = 26) | 8 | 12 | 1 | 5 | 0 |
| Wild-type
(n = 277) | 142 | 95 | 27 | 13 | 0 |
Fig. 1. Hepatic iron concentration in explanted livers with 2+, 3+, or 4+
stainable iron in C282Y heterozygotes and wild-type recipients. The
dotted line represents the upper limit of the normal range - 35
µmol/g dry weight. The mean hepatic iron concentration in C282Y
heterozygotes (n = 6) was 80 ± 27 µmol/g, and in wild-type
recipients (n = 39), it was 62.3 ± 34 µmol/g (P = .15,
Mann-Whitney test).
|
|
|
Click on Image to view full size
|
Survival Data
The actuarial patient survival between C282Y heterozygote recipients
and wild-type recipients is shown in Fig.
2
(P = .33, log rank test). There were no significant differences
in patient survival between C282Y heterozygotes and wild-type donors
into normal recipients. There were no significant differences in
patient survival between C282Y heterozygotes and wild-type donors into
C282Y heterozygous recipients. There were 10 retransplants in 1
heterozygous recipient and 9 wild-type recipients.
Fig. 2. Actuarial patient survival after liver transplantation in C282Y
heterozygous and wild-type recipients (P = .33, log rank
test).
|
|
|
Click on Image to view full size
|
Donor Population
DNA was available for HFE genotyping in 141 liver donors. There
were 24 C282Y heterozygotes and no homozygotes (prevalence of
heterozygotes and homozygotes were 17.0% and 0%, respectively). The
prevalence of the C282Y mutation was found to be significantly greater
in the liver donors than recipients. This possibly could be explained
on the basis of sampling variability. The iron status of the
transplanted livers was, for the most part, not known, because liver
biopsies are not routinely taken at the time of transplantation. There
were 2 H63D heterozygotes (of the 24 tested) in the donor population,
for a prevalence of 8.3%. Both of these patients were compound
heterozygotes. Posttransplantation liver biopsies were reviewed in 9
patients who received heterozygous grafts. Only 1 recipient had a liver
with stainable iron (2+, 38 days after transplantation). This donor was
also a compound heterozygote.
Hemosiderosis is a well-recognized feature of end-stage liver disease
of various etiologies, including alcoholic cirrhosis,3,7
hepatitis C,3,7,10,11 and 1
-antitrypsin
deficiency.7,14 Usually, iron does not accumulate to levels
seen in the cirrhotic stage of hereditary hemochromatosis in these
diseases. The etiology of iron overload in such conditions remains
unclear, although it is likely multifactorial. It has been hypothesized
that some of these patients are heterozygotes or even homozygotes for
the C282Y mutation of the recently described hemochromatosis gene,
HFE.7
The prevalence of the C282Y mutation in patients with end-stage liver
disease who underwent orthotopic liver transplantation in this study
was 8.5% (26 of 304 patients) and was 8.4% in the population-based
control group (440 of 5,211). This difference is not statistically
significant. Thus, the overall prevalence of the C282Y mutation of the
HFE gene is not increased in patients with end-stage liver
disease. A potential problem with the control group is that we assumed
that the control population was healthy. However, because we did not
have liver tissue to examine, we cannot conclude that the controls did
not have fibrosis, cirrhosis, or hemosiderosis. Stainable iron 2+ was
more frequent in C282Y heterozygotes (23%) than in patients with
wild-type HFE (14%); however, mean hepatic iron concentration
was not significantly different. Eight of 26 C282Y heterozygotes (31%)
had no stainable iron. Previous pedigree studies have demonstrated
biochemical abnormalities in serum ferritin and transferrin saturation
in approximately 10% of heterozygotes,3,20,21 but many of
these cases may have been compound heterozygotes. A greater prevalence
of C282Y heterozygotes was found in patients with alcoholic liver
disease. This was the only subset of patients with a statistically
significant increased prevalence of the C282Y mutation (7 of 31,
prevalence of 23%) relative to the control group (prevalence of
8.4%). In a small study, De Knegt et al. showed that the prevalence of
C282Y mutation in patients with alcoholic cirrhosis was 27% (4 of
15).22 Grove et al.23 did not demonstrate an
increased prevalence of C282Y in a small study of HFE mutations
in patients with alcoholic liver disease. It is likely that other
factor(s) contribute to the hemosiderosis seen in alcoholic cirrhosis,
because four alcoholic patients in our study had 2+ iron but were
found to be genotypically wild type for HFE. Also, 2 alcoholic
C282Y heterozygotes did not exhibit any stainable iron. Because
alcoholism is more prevalent in hemochromatosis, an increased
prevalence of the gene is not an unexpected observation.24
Several subgroups of patients exhibited iron overload despite low
frequencies of C282Y mutations, as expected. For example, hemosiderosis
was common in hepatitis C cirrhosis, as reported by
others,10,11,25 but only 1 C282Y mutation was found in 53
patients in our study. There were 9 patients with cirrhosis secondary
to 1
-antitrypsin deficiency. Four of these cases had
2+ stainable iron, but there were no C282Y mutations detected. Thus,
these findings are similar to those of Fargion et al.26
Also, hemosiderosis was common in idiopathic chronic active hepatitis,
although no statistically significant increase in C282Y mutations
relative to controls was observed. Hemosiderosis was distinctly
uncommon in primary biliary cirrhosis and primary sclerosing
cholangitis, in keeping with the results of a previous
study.7
There were 6 patients in this series with hepatic iron indices greater
than 2 but without clinical or pedigree evidence of hemochromatosis.
Only 1 of these patients was heterozygous for C282Y, while the others
were genotypically wild type. These results cast serious doubts on the
specificity of biochemical iron quantitation for diagnosing
hemochromatosis in end-stage liver disease.27
Non-hemochromatosis end-stage liver disease may have patchy iron
distribution, and therefore, a single hepatic iron determination may
not be entirely representative of the entire organ.28-30
Importantly, there were no adverse effects of transplanting livers
heterozygous for C282Y. Specifically, we did not observe a survival
difference between patients who received livers with or without C282Y
mutations. In theory, patients should not accumulate iron if they
receive a liver with a C282Y mutation, because iron absorption likely
depends primarily on the genotype of the small intestine.31
Because approximately 10% of the general population are heterozygous
for the C282Y mutation, it is important to maintain the eligibility of
this large group as potential liver donors. Survival in C282Y
heterozygous recipients did not statistically differ from wild-type
recipients. Mortality post–liver transplantation is most commonly
related to opportunistic infections, graft rejection, and recurrent
diseases that are unlikely to be related to iron overload. The
long-term survival in heterozygous recipients was significantly better
than previous studies describing transplantation in putative
hemochromatosis homozygotes (1-year survival of 58% ).32
In summary, there was no increased prevalence of the C282Y mutation in
304 patients with end-stage liver disease. Although stainable iron is
common in C282Y heterozygotes, hepatic iron concentration did not
differ between heterozygotes and wild-type recipients with end-stage
liver disease. Therefore, both genetic prevalence and biochemical iron
measurements do not support the hypothesis that heterozygotes are more
predisposed to other forms of end-stage liver disease. Transplantation
of heterozygous livers is a safe and effective clinical practice.
Acknowledgment
The authors acknowledge the support of the Liver Transplant Team, Dr.
Bill Wall, Dr. David Grant, Dr. Cam Ghent, Dr. Paul Marotta, and the
advice and assistance of Colin Bradley and Leslie Valberg.
1. Adams PC. Population screening for hemochromatosis. Hepatology 1999;29:1324-1327.
2. Beckman LE, Saha N, Spitsyn V, Van Landeghem G, Beckman L. Ethnic differences in the HFE codon 282 (Cys/Tyr) polymorphism. Hum Hered 1997;47:263-267.
3. Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med 1996;335:1799-1805.
4. Feder JN, Gnirke A, Thomas W, Tsuchihasi Z, Ruddy D, Basava A, Dormishian F, et al. A novel MHC class I–like gene is mutated in patients with hereditary hemochromatosis. Nat Genet 1996;13:399-408.
5. Jouanolle AM, Fergelot P, Gandon G, Yaouanq J, Le Gall JY, David V. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations. Hum Genet 1996;100:544-547.
6. Jazwinska EC, Cullen LM, Busfield F, Pyper W, Webb S, Powell LW, Morris CP, et al. Haemochromatosis and HLA-H. Nat Genet 1996;14:249-251.
7. Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology 1997;112:882-888.
8. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 1997;349:321-323.
9. Santos M, Clevers HC, Marx JJ. Mutations of the hereditary hemochromatosis candidate gene HLA-H in porphyria cutanea tarda. N Engl J Med 1997;336:1327-1328.
10. Haque S, Chandra B, Gerber MA, Lok AS. Iron overload in patients with chronic hepatitis C: a clinicopathologic study. Hum Pathol 1996;27:1277-1281.
11. Smith BC, Grove J, Guzail MA, Day C, Daly A, Burt A, Bassendine M. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 1998;27:1695-1699.
12. Kazemi-Shirazi L, Datz C, Maier-Dobersberger T, Kaserer K, Hackl F, Polli C, Steindl P, et al. The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. Gastroenterology 1999;116:127-134.
13. George DK, Goldwurm S, MacDonald GA, Cowley L, Walker N, Ward P, Jazwinska E, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998;114:311-318.
14. Rabinovitz M, Gavaler JS, Kelly RH, Van Thiel DH. Association between heterozygous alpha 1-antitrypsin deficiency and genetic hemochromatosis. Hepatology 1992;16:145-148.
15. Crawford DH, Jazwinska EC, Cullen LM, Powell LW. Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation. Gastroenterology 1998;114:1003-1008.
16. Scheuer PJ, Williams R, Muir AR. Hepatic pathology in relatives of patients with hemochromatosis. J Pathol Bacteriol 1962;84:53-54.
17. Moirand R, Jouanolle AM, Brissot P, Le Gall JY, David V, Deugnier V. Phenotypic expression of HFE mutations: a French study of 110 unrelated iron-overloaded patients and relatives. Gastroenterology 1999;116:372-377.
18. Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998;114:319-323.
19. Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS. Genetic and phenotypic expression of hemochromatosis in Canadians. Clin Invest Med 1983;6:171-179.
20. Bassett ML, Halliday JW, Powell LW. HLA typing idiopathic hemochromatosis: distinction between homozygotes and heterozygotes with biochemical expression. Hepatology 1981;1:120-126.
21. Adams PC. Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis: an analysis of 255 heterozygotes. Am J Hematol 1998;45:146-149.
22. De Knegt RJ, Hepkema B, Slooff M, Jansen P. Hemochromatosis gene mutation in liver transplant patients [Abstract]. Hepatology 1997;26:499A.
23. Grove J, Daly AK, Burt AD, Guzail MA, James O, Bassendine MF, Day CP. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease. Gut 1998;43:262-266.
24. Adams PC, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings. Hepatology 1996;23:724-727.
25. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers L, Parker T, Redick J, Schiff E, et al. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1998;108:1104-1109.
26. Fargion S, Bissoli F, Fracanzani AL, Suigo E, Sergi C, Taioli E, Ceriani R, et al. No association between genetic hemochromatosis and alpha1-antitrypsin deficiency. Hepatology 1997;24:1161-1164.
27. Adams PC, Bradley C, Henderson AR. Evaluation of the hepatic iron index as a diagnostic criterion for genetic hemochromatosis. J Lab Clin Med 1997;130:509-514.
28. Cotler SJ, Bronner MP, Press R, Carlson T, Perkins J, Emond M, Kowdley K. End-stage liver disease without hemochromatosis associated with elevated hepatic iron index. J Hepatol 1998;29:257-262.
29. Deugnier Y, Turlin B, LeQuilleuc D, Moirand R, Loreal O, Messner M, Meunier B, et al. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol 1997;21:669-675.
30. Villeneuve J, Bilodeau M, Lepage R, Cote J, Lefebrve M. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol 1996;25:172-177.
31. Adams PC, Ghent CN, Grant DR, Frei JV, Wall WJ. Transplantation of a donor liver with haemochromatosis: evidence against an inherited intrahepatic defect. Gut 1991;32:1082-1083.
32. Kowdley K, Hassanein T, Kaur S, Farrell F, VanThiel D, Keeffe E, Sorrell M, et al. Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis. Liver Transpl Surg 1995;1:237-241.
- From the Departments of 1Pathology and 2
Medicine, Division of Gastroenterology, London Health
Sciences Centre, London, Ontario, Canada.
- Supported by a research grant from the Physicians' Services
Incorporated Foundation of Ontario.
- Received January 6, 1999
- Accepted June 18, 1999
- Address reprint requests to: Dr. Paul C. Adams, Department of Medicine,
London Health Sciences Centre, 339 Windermere Road, London, Ontario,
Canada N6A 5A5. E-mail: padams@julian.uwo.ca
; fax: (519)
663-3232.
Copyright © 1999 by the American Association for the Study of Liver Diseases
- 0270-9139/99/3003-0011$3.00/0
| Articles with References to this Article |
TOP |
This article is referenced by these articles:
Increased hepatic iron and cirrhosis: No evidence for an adverse effect on patient outcome following liver transplantation
Hepatology
December 2000 • Volume 32 • Number 6
Katherine A. Stuart1, Linda M. Fletcher1, Andrew D. Clouston2, Steve V. Lynch3, David M. Purdie4, Paul Kerlin1, Darrell H. G. Crawford1
Liver transplantation in patients with hepatic iron overload: Favorable or unfavorable outcome?
Hepatology
December 2000 • Volume 32 • Number 6
Emmet B. Keeffe, MD
Stanford University Medical Center, Stanford, CA
)
)
