GASTROENTEROLOGY 2002;122:281–289
Excess Alcohol Greatly Increases the Prevalence of Cirrhosis
in Hereditary Hemochromatosis
LINDA M. FLETCHER,* JEANNETTE L. DIXON,‡ DAVID M. PURDIE,‡ LAWRIE W. POWELL,‡
and DARRELL H. G. CRAWFORD*
*Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, and ‡Population Health
and Clinical Sciences Division, The Queensland Institute of Medical Research, Brisbane, Australia
See editorial on page 563.
Background & Aims: The progression of fibrosis to cirrhosis is the most significant prognostic factor in hereditary hemochromatosis. We aimed to determine the
range of hepatic iron concentration associated with cirrhosis in the absence of alcohol and other pro-fibrogenic
cofactors and to quantify the contribution of excess
alcohol consumption to the development of cirrhosis.
Methods: Liver biopsy data were evaluated on 224
C282Y homozygous hemochromatosis subjects. To determine the effect of alcohol alone on the development
of fibrosis, subjects with viral hepatitis or nonalcoholic
steatohepatitis were excluded. Subjects were divided
into those who consumed less than 60 g alcohol per day
and those who consumed 60 g per day or more. Results:
Seven percent of subjects who consumed less than 60 g
per day had severe fibrosis/cirrhosis compared with
61% of excess alcohol consumers. Conclusions: Hemochromatosis subjects who drink more than 60 g alcohol
per day are approximately 9 times more likely to develop cirrhosis than those who drink less than this
amount, and the range of hepatic iron concentration
associated with cirrhosis in the absence of cofactors
was 233– 675 ␮mol/g dry weight.
he excess iron that is characteristically deposited in
a periportal distribution in hepatocytes in hereditary
hemochromatosis (HHC) results in significant toxicity.
A number of studies have suggested that the excess iron
generates reactive oxygen species that exceed the normal
antioxidant defenses and cause peroxidation of lipid
membranes resulting in cell damage.1– 4 The subsequent
cellular response in the liver as it attempts repair of this
injury, is associated with the initiation of fibrogenic
pathways.5,6 Progression from fibrosis to cirrhosis is critical in the clinical management of HHC because cirrhosis
is associated with significant reduction in life expectancy
as the 5-year survival in untreated cirrhotic patients is
T
50%.7–9 There is also a greatly increased risk of development of primary hepatocellular carcinoma (HCC).10
Liver disease of various causes may have similar basic
mechanisms underlying fibrogenesis to iron toxicity. Reactive oxygen species have been implicated in stellate cell
activation in alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and chronic viral hepatitis.11–15 Progressive fibrosis and cirrhosis develop in up to 20%–30%
of subjects with these diseases if the offending insult is
not attenuated. A combination of 2 or more toxic insults
may potentiate more aggressive disease. For example,
alcohol consumption has been shown to have a significant
impact on both the histologic and clinical progression of
chronic hepatitis C virus infection,16 –18 and iron overload
complicated by viral hepatitis and/or alcohol may have
accelerated the development of cirrhosis.19 –23
The extent to which iron alone contributes towards
the development of fibrosis and therefore to the pathogenesis of the liver disease in HHC remains unclear. It
has been previously suggested that the critical iron
threshold at which fibrosis/cirrhosis occurs is 400 –500
␮mol/g dry weight, although patients in these studies
may have had other concomitant liver disease.24,25 Although there is general agreement that the mean hepatic
iron concentration (HIC) is higher in HHC patients with
cirrhosis compared with those without cirrhosis, it seems
unlikely that there exists a discrete threshold value for
cirrhosis. Rather, it is more likely that there is range of
the HIC above which the risk of cirrhosis is increased and
below which the risk is low. In this study, we reevaluated
the range of hepatic iron associated with cirrhosis in
HHC in subjects without any profibrogenic stimuli other
than iron. In addition, we aimed to quantify the additive
Abbreviations used in this paper: HCC, hepatocellular carcinoma;
HFE, hemochromatosis gene; HHC, hereditary hemochromatosis; HIC,
hepatic iron concentration; HII, hepatic iron index; NASH, nonalcoholic
steatohepatitis.
© 2002 by the American Gastroenterological Association
0016-5085/02/$35.00
doi:10.1053/gast.2002.30992
282
FLETCHER ET AL.
effect of excessive alcohol consumption to the development of severe fibrosis/cirrhosis in HHC.
Materials and Methods
Subjects
The 224 subjects included in this study form part of a
comprehensive and well characterized data base of hemochromatosis subjects and their families. Subjects were included in
this study if they had been genotyped for mutations in the
hemochromatosis gene (HFE), had undergone liver biopsy
with measurement of HIC, and had available serum biochemical data measured at the time of biopsy. No subject had
commenced venesection therapy or was a regular blood donor.
All subjects were homozygous for the C282Y mutation in
HFE. Subjects aged less than 20 years were excluded because
the likelihood of significant fibrosis being present in subjects
less than 20 years of age was small.26
Clinical and Laboratory Data
All subjects were interrogated and the data recorded
predominantly by 1 physician (L.W.P.) and no more than 3
different physicians. Alcohol consumption was assessed by
detailed questioning of patients (and in some cases relatives)
and reflected both current and past (⬎10 years) drinking
habits in grams of ethanol equivalent per day.
Serum concentration of alanine aminotransferase, aspartate
aminotransferase, gamma glutamyltransferase, and biochemical indices of iron proteins (serum ferritin, transferrin saturation) were measured by standard biochemical analyses. Liver
blood tests were classed as abnormal if either one or more
of alanine aminotransferase, aspartate aminotransferase, and
gamma glutamyltransferase were elevated above the laboratory
reference range. Viral serology (anti– hepatitis C virus and
hepatitis B surface antigen) was determined when liver blood
tests were abnormal. In those subjects in which laboratory
testing was not available, clinical evaluation did not suggest
chronic viral hepatitis in any patient.
HIC
HIC was measured by atomic absorption spectrophotometry on fresh biopsy specimens as previously described.24
We included iron-loaded rat liver as an internal control. The
hepatic iron index (HII) was calculated as previously described
(HII ⫽ HIC/age).24
Histologic Grading of Fibrosis and Steatosis
Liver biopsies were stained with hematoxylin and eosin, van Gieson’s and Masson’s trichrome for collagen, and
Perls’ Prussian blue for iron. Histologic assessment of iron
grade on a scale of 0 to 4 (according to the method of Scheuer)
after Perls’ staining was performed.27 The level of fibrosis was
recorded as 0, no fibrosis; 1, mild fibrosis with enlarged fibrotic
portal tracts; 2, moderate peri-portal or portal-portal septa but
intact architecture; 3, severe fibrosis with architectural distor-
GASTROENTEROLOGY Vol. 122, No. 2
tion but no cirrhosis; and 4, cirrhosis with annular fibrosis
with architectural distortion. Steatosis was recorded as mild,
moderate, or severe.
Patient Groups
To determine the impact of alcohol alone on the development of fibrosis in subjects with iron overload, subjects
who had concomitant liver disease whose pathogenesis is associated with fibrosis (viral hepatitis or NASH) were excluded
from statistical analysis. Patients were divided into those who
consumed less than 60 g alcohol per day and those who drank
equal to or more than 60 g alcohol per day.
Statistical Analysis
The variables age, serum ferritin, transferrin saturation, HIC, and HII were all assessed for normality, and appropriate transformations were performed to normalize the
measures for statistical analysis. Age was approximately normally distributed and thus required no transformation; HIC
and HII were approximately normally distributed after natural
log transformations; square root transformations of serum ferritin and transferrin saturation were applied to normalize the
distribution of these variables. Mean ⫾ standard deviation
(of the untransformed variables) was used to summarize these
variables. Student t tests and analysis of variance were conducted on the transformed variables to test for differences in
means between groups. Linear regression (on normalized measures) was used to compare means between groups while
adjusting for potential confounding by age and/or sex. Pearson’s correlation coefficient was used to measure the degree of
association between 2 approximately normally distributed
measures; however, to assess the correlation between HIC and
degree of fibrosis (graded 0 to 4), a Spearman’s non-parametric
coefficient was used.
To compare proportions between groups, Pearson’s chisquared tests were used; however, when comparisons of proportions were done on small subgroups (e.g., among cirrhotic
patients), a Fisher exact test was used instead. For comparative
purposes, subjects with mild and moderate fibrosis were
grouped together and subjects with severe fibrosis and cirrhosis
were also combined. The statistical package SPSS version 10.1
(SPSS Inc., North Sydney, Australia) was used to conduct all
analyses.
Results
Figure 1 shows the distribution of the study
population in relation to alcohol consumption and liver
blood tests. Of the 224 subjects, 18 patients were excluded because of coexistent viral hepatitis (6) or NASH
(12). One hundred seventy (82.5%) of the 206 remaining
subjects had an alcohol consumption of less than 60 g per
day, whereas 36 (17.5%) subjects drank equal to or more
than 60 g alcohol per day. One hundred seventeen
(68.8%) of those subjects who drank less than 60 g
February 2002
IRON, ALCOHOL, AND CIRRHOSIS IN HEMOCHROMATOSIS
Figure 1. Distribution of study population of hereditary hemochromatosis subjects in relation to alcohol consumption and liver blood tests.
alcohol per day had normal liver blood tests. Of these,
88 had no fibrosis, 27 had mild or moderate fibrosis,
and only 2 had cirrhosis. Fifty-three (31.1%) of the
low alcohol consumers had abnormal liver blood tests.
Twenty-three patients had no fibrosis, 20 had fibrosis,
and 10 were cirrhotic. In contrast, the majority of subjects who drank 60 g per day or more had abnormal liver
blood tests (28 of 36; 77.8%), and 21 of these 28 (75%)
patients were cirrhotic, whereas one subject with normal
liver blood tests was cirrhotic.
The laboratory characteristics of patients in relation to
alcohol consumption are detailed in Table 1. Male sub-
283
jects predominated over female subjects in both groups
(M:F 104:66, 34:2, respectively), but there was a significantly higher proportion of males among those who
drank 60 g or more of alcohol per day (94%) than in
those who drank less than 60 g per day (61%; P ⬍
0.001). The mean and median age were similar in both
groups; however, serum ferritin concentration and transferrin saturation were significantly higher among high
alcohol consumers, which remained after adjustment for
sex differences between the groups (P ⬍ 0.001). Mean
HIC and HII were similar between the 2 groups. HIC
did not correlate with age in either of the 2 groups of
patients (alcohol ⬍60 g/day, r ⫽ 0.235; alcohol ⬎60
g/day, r ⫽ 0.227). The overall distribution of subjects in
relation to histologic iron grade was significantly different in low alcohol consumers when compared with heavy
alcohol consumers, indicating that the majority of heavy
alcohol consumers were more likely to have higher iron
grades (P ⬍ 0.033; Table 1).
Relationship Between HIC, Alcohol,
and Fibrosis
HIC was positively correlated with degree of fibrosis (graded 0 to 4) in those subjects who drank less
than 60 g per day (r ⫽ 0.379; P ⬍ 0.001) and in those
subjects who consumed excess alcohol (Spearman’s r ⫽
0.367; P ⫽ 0.027). The relationship between the HIC
and degree of fibrosis is shown in Figure 2. The HIC
(mean ⫾ SD) in those subjects with an alcohol consump-
Table 1. Characteristics of C282Y Homozygous HHC Patients Grouped Into Those Who Consume Less Than 60 g Alcohol per
Day and Those Who Consume Equal to or More Than 60 g Alcohol Per Day
Total
population
n ⫽ 206
Alcohol ⬍ 60 g/day (n ⫽ 170)
male:female 104:66
Alcohol ⱖ 60 g/day (n ⫽ 36)
male:female 34:2
Variable
Mean ⫾ SD
Median
Age ( yr)
Serum ferritin
(␮g/L)
% Transferrin
saturation
HIC (␮mol/g
dry weight)
HII
Elevated ALT
and/or
AST, GGT
Fe grade (n)
1
2
3
4
42.3 ⫾ 14.6
41
946 ⫾ 836
678
77 ⫾ 18
81
27–100
89 ⫾ 12
182 ⫾ 120
4.5 ⫾ 3.0
148
3.7
23–675
0.5–18.8
31.2%
N/A
N/A
4 (2%)
23 (13%)
79 (47%)
64 (38%)
Range
20–74
33–4500
Mean ⫾ SD
Median
43 ⫾ 10
42
Range
Sex-adjusted
P value
0.652
0.402
405–4400
⬍0.001
⬍0.001
93
48–100
⬍0.001
⬍0.001
239 ⫾ 175
5.6 ⫾ 4.2
167
4.9
22–847
0.6 ⫾ 20.1
0.109
0.163
0.338
0.569
77.8%
N/A
N/A
2083 ⫾ 1159
1936
1 (3%)
3 (8%)
9 (25%)
23 (64%)
26–66
Crude
P value
⬍0.001
0.033a
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, ␥-glutamyltransferase; N/A, nonapplicable.
aSignificance of overall distribution of subjects in relation to iron grade in subjects who consume less than 60 g per day compared with those
who consume equal to or more than 60 g per day.
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FLETCHER ET AL.
Figure 2. Relationship between HIC (mean ⫾ SD) and fibrosis in
those subjects who consume less than 60 g alcohol per day (䊐)
compared with those who drink greater than or equal to 60 g per
day (1). Numbers in parentheses represent numbers of subjects
in each group. *P value between groups with no fibrosis vs. severe/cirrhosis; mild/mod fibrosis vs. severe/cirrhosis in subjects
with alcohol consumption ⬍60 g/day (䊐). **P value comparing
patients with severe fibrosis/cirrhosis who consume ⬍60 g/day
and those with severe fibrosis/cirrhosis who consume ⱖ60 g/day.
tion of less than 60 g per day was 151 ⫾ 96 ␮mol/g dry
weight (n ⫽ 111), no fibrosis; 197 ⫾ 109 ␮mol/g dry
weight (n ⫽ 47), mild/moderate fibrosis; and 406 ⫾ 125
␮mol/g dry weight (n ⫽ 12), severe fibrosis/cirrhosis
(normal range 5– 40 ␮mol/g dry weight). The mean HIC
of those subjects who consumed 60 g alcohol per day or
more and who had cirrhosis (271 ⫾ 186 ␮mol/g dry
weight, n ⫽ 22) was significantly higher than those with
no fibrosis (141 ⫾ 98 ␮mol/g dry weight, n ⫽ 6), or
mild/moderate fibrosis (228 ⫾ 179 ␮mol/g dry weight,
n ⫽ 8) (P ⬍ 0.001). There was no significant difference
between the mean HIC in subjects with no fibrosis (P ⫽
0.854) or subjects with mild/moderate fibrosis (P ⫽
GASTROENTEROLOGY Vol. 122, No. 2
0.913) who consumed less than 60 g alcohol per day
compared with those who drank more than this amount.
However, the mean HIC at which cirrhosis developed
was lower in the alcoholic group compared with those
subjects who consumed less than 60 g/day (P ⫽ 0.003).
After adjusting for age and sex, this difference between
drinking groups remained significant (P ⫽ 0.045), indicating that those subjects who had disease complicated
by alcohol consumption developed cirrhosis at significantly lower HICs than those whose disease was not
complicated by alcohol.
The distribution of HIC in relation to the degree of
fibrosis in both groups is shown in Figure 3. In the
subjects who drank less than 60 g alcohol per day,
cirrhosis was present in 12 (7%) subjects. Cirrhosis was,
however, present in 22 of 36 (61.1%) of those subjects
who consumed 60 g per day or more (Figure 3), indicating that cirrhosis was 8.7 (95% confidence interval ⫽
4.7–15.8) times more frequent in HHC subjects who
consumed alcohol in excess compared with those who did
not. No subject who consumed less than 60 g alcohol per
day and who had an HIC less than 233 developed cirrhosis; however, 50% of subjects who drank more than
60 g per day and had an HIC less than 233 had cirrhosis.
When subjects who consumed less than 60 g alcohol per
day were considered in relation to liver blood tests (Figure 4), only 2 subjects (1.7%) with normal liver blood
tests had cirrhosis. These 2 subjects with normal liver
blood tests were elderly men (aged 63 years and 67 years)
who had markedly elevated serum ferritin (2231 and
3100 ␮g/L, respectively). In subjects with abnormal liver
blood tests, 18.9% (10 of 53) of subjects who consumed
less than 60 g per day had cirrhosis compared with 75%
(21 of 28) of subjects who consumed 60 g or more per
Figure 3. Relationship between HIC and fibrosis in (A ) all subjects who consume less than 60 g alcohol/day (n ⫽ 170) and (B) those subjects
who drink equal to or more than 60 g per day (n ⫽ 36). Numbers in parentheses represent numbers of subjects in each group. Horizontal bars
represent mean HIC.
February 2002
IRON, ALCOHOL, AND CIRRHOSIS IN HEMOCHROMATOSIS
285
Figure 4. Relationship between HIC and fibrosis in (A ) subjects who drink less than 60 g per day and who have normal liver blood tests (LBT)
(n ⫽ 117) and (B) those who have abnormal LBT (n ⫽ 53). Numbers in parentheses represent numbers of subjects in each group. Horizontal
bars represent mean HIC.
day (P ⬍ 0.001; Figure 1). In addition, 75% (88 of 117)
of subjects with elevated hepatic iron and normal liver
blood tests who did not consume excess alcohol, had no
fibrosis on liver biopsy.
When age was taken into consideration via the calculation of the HII (Figure 5), the mean HII of cirrhotic
subjects who consumed less than 60 g alcohol per day
was higher (8.1 ⫾ 4.0) than those subjects who drank
more than 60 g per day (6.0 ⫾ 4.2), and after adjusting
for age and sex, this difference approached significance
(P ⫽ 0.09). This further indicated that subjects who
consume excess alcohol are likely to develop cirrhosis at
lower HIC than those who do not.
Irrespective of whether subjects consumed excess alcohol or not, 98 of the 206 subjects in the study had
serum ferritin levels less than 1000 ␮g/L and normal
liver blood tests. None of these subjects had severe
fibrosis/cirrhosis present on liver biopsy. One hundred
eleven subjects (65.3%) who drank less than 60 g alcohol
per day irrespective of liver blood tests did not have any
hepatic fibrosis despite elevated HIC (mean 151 ␮mol/g
dry weight) compared with only 17% in those who drank
60 g or more per day.
Characteristics of Cirrhotic Subjects
The clinical characteristics of HHC subjects with
cirrhosis are shown in Table 2. Twelve subjects (7.1%) in
the low alcohol consuming group developed cirrhosis,
compared with 61.1% percent in the group who drank
more than 60 g per day (P ⬍ 0.001). Male subjects
predominated in both groups. The mean age, HIC, and
HII were lower in subjects who consumed alcohol in
excess (P ⬍ 0.05); however, the mean serum ferritin was
similar in both groups. Sixty-one percent of the heavy
alcohol consumers had cirrhosis, and 77.8% had abnormal liver blood tests. Twenty-two of the 35 (62.3%)
Figure 5. Relationship between HII and fibrosis in (A ) all subjects who consume less than 60 g alcohol per day (n ⫽ 170) and (B) those subjects
who drink more than 60 g per day (n ⫽ 36). Numbers in parentheses represent numbers of subjects in each group. Horizontal bars represent
mean HII.
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FLETCHER ET AL.
GASTROENTEROLOGY Vol. 122, No. 2
Table 2. Clinical Characteristics of HHC Subjects With Severe Fibrosis/Cirrhosis
N (% of group)
Male:female
Age ( yr )
Serum ferritin (␮g/L)
HIC (␮mol/g dry wt) (range)
HII
Elevated ALT and/or AST/GGT
Alcohol ⬍ 60 g/da
Alcohol ⱖ 60 g/da
P value
Adjusted
P valueb
12 (7.1%)
11:1
53.7 ⫾ 11.9
2916 ⫾ 939
406 ⫾ 125 (233–675)
8.1 ⫾ 3.9
10/13 (76.9%)
22 (61.1%)
22:0
46.5 ⫾ 10.5
2667 ⫾ 1017
271 ⫾ 186 (22–847)
6.0 ⫾ 4.2
28/36 (77.8%)
⬍0.001
0.353
0.048
0.439
0.003
0.042
0.279
0.494
0.045
0.049
0.343
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, ␥-glutamyltransferase.
shown as mean ⫾ SD where applicable.
bAdjusted for age and sex.
aData
cirrhotic subjects consumed alcohol in excess, confirming
that alcohol is a significant co-factor in the pathogenesis
of fibrosis in HHC. Eighty percent of the cirrhotic
subjects had serum ferritin levels in excess of 2000 ␮g/L.
The prevalence of abnormal liver blood tests, steatosis,
fibrosis, and HCC in those subjects who consumed less
than 60 g alcohol per day compared with those who
drink more than this amount is shown in Figure 6. With
the exception of the percentage of subjects with fibrosis,
which was not significantly different between the 2
groups, significantly more subjects who consumed alcohol in excess had abnormal liver blood tests, steatosis,
cirrhosis, and HCC. Only 17% of heavy drinkers showed
no fibrosis present on liver biopsy, compared with 65%
of subjects who consumed less than 60 g alcohol per day
(P ⬍ 0.001). There was a lack of histologic features of
alcoholic liver disease in those subjects who consumed
alcohol in excess, and only 25% had steatosis.
Discussion
We have investigated the prevalence of cirrhosis
in 2 groups of subjects with C282Y-associated HHC
Figure 6. The prevalence of abnormal liver blood tests, steatosis,
fibrosis, cirrhosis, and HCC in relation to alcohol consumption in
hereditary hemochromatosis (䊐, alcohol consumption ⬍60 g per day;
1, alcohol consumption ⱖ60 g per day). Numbers refer to number of
subjects in each group. AbnLBT, abnormal liver blood tests; HCC,
hepatocellular carcinoma.
distinguished on the basis of exposure to excess alcohol.
Our study showed that cirrhosis was relatively uncommon (7%) in subjects who consumed less than 60 g
alcohol per day and present in only 1.7% of subjects in
this group who had normal liver blood tests, despite
elevated hepatic iron. In contrast, 61% of HHC individuals who had a history of exposure to alcohol in excess of
60 g per day had cirrhosis. This indicates that HHC
subjects who consume alcohol in excess are almost 9
times more likely to develop cirrhosis than those who
drink less than 60 g alcohol per day. The lowest HIC
associated with cirrhosis in the low alcohol group was
233 ␮mol/g, whereas 11 of 22 cirrhotic subjects in the
high alcohol group had an HIC below this value. Thus,
although severe fibrosis/cirrhosis is uncommon in HHC
patients with low alcohol intake, excess alcohol consumption can significantly influence the development of
cirrhosis even at modestly elevated HIC.
None of the subjects in this study with normal liver
blood tests and serum ferritin levels below 1000 ␮g/L
had cirrhosis, thus our study confirms the recommendation of Guyader et al.28 that liver biopsy was not recommended in such patients. However, we have highlighted
the importance of also noting the alcohol history. Population screening studies for C282Y-associated HHC are
being conducted in many centers throughout the world.
Given this development, it is probable that practicing
clinicians will see many more subjects who are otherwise
well (i.e., normal liver blood tests and no risks for
intercurrent liver disease), but who will have biochemical
evidence of increased body iron stores. This study provides some insights into the most appropriate clinical
management of such patients. Cirrhosis in C282Y homozygous patients has important clinical and prognostic
significance, but in general those patients with normal
liver blood tests and an alcohol consumption of less than
60 g per day can be reassured that the risk of underlying
cirrhosis is small (⬍2% in this population). The 2 subjects who consumed less than 60 g alcohol per day who
February 2002
had liver cirrhosis but normal liver blood tests, were
elderly males (67 and 63 years of age) who had high
hepatic iron stores (HIC 516 and 380; HII 7.7 and 6.0)
and serum ferritin concentrations greater than 2000
␮g/L. This suggests the threshold for liver biopsy in such
patients could be a serum ferritin of 2000 ␮g/L. However, some caution should be exercised because of the
small number of cirrhotic subjects in the group in which
excess iron was the only toxic insult and studies of larger
groups of patients are required to define more precisely
their risk of cirrhosis and the appropriate threshold for
liver biopsy.
Our data also indicate that duration of exposure of the
liver to high iron stores (and patient age) may be important in determining the risk of developing cirrhosis,
particularly if liver blood tests are not elevated. Although duration of exposure to toxic insult from excessive hepatic iron was probably a significant determining
factor of development of fibrosis in 2 subjects, fibrosis
was absent in 4 other subjects aged greater than 60 years,
with normal liver blood tests and elevated HIC (302,
322, 408, and 429 ␮mol/g dry weight). It is possible
that these subjects and indeed other subjects with elevated HIC but no fibrosis (65% subjects had no fibrosis),
may have as yet undetermined factors that offer some
protective effect against the development of fibrosis. In
contrast, of the 22 subjects with cirrhosis who consumed
60 g alcohol per day or more, only one was older than 60
years, one subject was 60 years old at the time of diagnosis, whereas 20 others were aged 54 years or less. The
mean age of cirrhotic patients who consumed excess
alcohol was 46.5 ⫾ 10.5 years compared with 53.7 ⫾
11.9 years in those cirrhotic patients who consumed less
than 60 g of alcohol per day (Table 2, P ⫽ 0.048),
indicating that cirrhosis develops at a significantly earlier
age in HHC subjects who consume alcohol in excess of
60 g per day. We found a substantial overlap between
HICs in cirrhotic alcoholic patients and cirrhotic patients
with low alcohol intake. As suggested, individual susceptibility to fibrogenic stimuli—possibly related to age,
gender, and other unidentified host factors—may all
contribute to this overlap. The mean HIC was not decreased in the high alcohol group with mild/moderate
fibrosis compared with the low alcohol group. This may
be a result of the relatively small number of high alcohol
users in the mild to moderate fibrosis group, and further
studies with larger numbers of patients with milder
degrees of fibrosis are necessary.
Oxidative stress has been implicated as playing an
important role in initiating the complex series of events
involving interplay between parenchymal cells and non-
IRON, ALCOHOL, AND CIRRHOSIS IN HEMOCHROMATOSIS
287
parenchymal cells that eventually results in hepatic stellate cell activation in subjects with iron overload.29,30
Many groups have found evidence of enhanced oxidative
stress in liver tissue of iron-loaded subjects, and Houglum et al.2 showed that markers of oxidative stress
decreased after venesection treatment in serum and liver
samples from HHC patients. Many subjects in our study
in which iron was the only toxin had no evidence of
fibrosis, despite HIC within the range associated with
cirrhosis. Clearly, elevated HIC does cause oxidative
stress, but high concentrations of hepatic iron alone may
be insufficient to overwhelm the antioxidant protective
systems and/or stimulate hepatic fibrogenesis in many
patients. Reactive oxygen species have been associated
with stellate cell activation in other forms of hepatocellular disease such as hepatitis C. Hepatitis C patients
who also drink alcohol to excess have more aggressive
disease, and it is likely that the level of inflammation in
these diseases may be important in this context.16,17 The
progression of fibrosis to cirrhosis in different hepatocellular diseases may therefore be multifactorial. It has been
suggested that an inflammatory response in association
with increased tumor necrosis factor ␣ is an important
component in the activation of stellate cells and subsequent fibrogenesis.31 The absence of a significant inflammatory infiltrate in HHC where iron is the only insult
may also explain, in part, the reduced frequency of
cirrhosis in uncomplicated HHC. Our observations are
supported by findings in animal models of hemochromatosis whereby, despite intensive iron loading, significant
fibrosis is not usually shown in iron-loaded rodents.32,33
A number of other reports have also implicated excessive alcohol consumption in more severe disease expression in iron overload disease,20 –22,25,34 and the severity of
disease is attenuated by venesection therapy.9,35 The
present study differs from earlier studies by including
only C282Y homozygous individuals and excluding
complicating factors contributing to fibrogenesis, apart
from excess alcohol consumption, in the analysis. This
more clearly identified the contribution of iron alone and
the additive effect of alcohol to the development of
fibrogenesis. In an experimental model of alcoholic liver
disease, the addition of small amounts of iron to the diet
of rats fed a high fat alcoholic diet resulted in significant
fibrosis compared with those fed the high fat alcohol diet
alone, where only mild fibrosis was reported.36 These
small amounts of iron markedly exacerbated the oxidative stress and thus contributed to the pathogenesis of
the liver disease. Just how much alcohol ingestion is
required in hemochromatosis to initiate significant fibrosis is difficult to determine. We have chosen 60 g per day
288
FLETCHER ET AL.
as a cutoff in the present study, and re-analysis of results
using 40 g per day did not significantly alter our results.
Bassett et al.24 suggested that the critical iron concentration at which fibrosis/cirrhosis occurred in homozygous hemochromatosis subjects approximated 400
␮mol/g dry weight. This was based on the fact that all
6 HLA-linked homozygous hemochromatosis subjects
with an HIC of ⬎400 ␮mol/g dry weight had cirrhosis.
In our study, 11 subjects in the group who consumed less
than 60 g/day had HICs above this level; however, only
4 of these subjects had cirrhosis. In the report by Bassett
et al., a further 3 subjects with HIC below 400 ␮mol/g
dry weight had cirrhosis, and this was attributed to high
alcohol consumption, indicating that alcohol indeed may
lower the threshold for development of fibrosis. Adams37
revisited the question of a specific hepatic iron threshold
for cirrhosis in HHC after the cloning of the HFE. One
hundred C282Y homozygotes were evaluated, and he
concluded that an HIC in excess of 283 ␮mol/g was
associated with cirrhosis. However, the low sensitivity of
this threshold suggested that other cofactors contribute
to the development of cirrhosis in HHC. Loreal et al.25
(in a study before the cloning of HFE that included
patients with concomitant disease) also could not demonstrate a threshold of HIC above which fibrosis occurred.25 Thus, there is general agreement that although
the mean HIC is higher in HHC patients with cirrhosis
compared with those without cirrhosis, it is unlikely that
there exists a discrete threshold value of hepatic iron for
cirrhosis. Rather, it is likely that there is a range of the
HIC above which the risk of cirrhosis is increased and
below which the risk of cirrhosis is low. In the present
study, the lowest HIC associated with cirrhosis in the
nonalcoholic patients was 233 ␮mol/g. This value is
remarkably similar to the 283 ␮mol/g that Adams proposed as an important cut point—albeit with limited
sensitivity. It is likely that factors such as age, gender,
and individual susceptibility to cirrhosis may all contribute to the pathogenesis of cirrhosis in this disease.
Of interest, we did not find a strong correlation between HIC and age in either of our 2 groups, and this is
consistent with findings of others38 – 40 who could not
find a correlation between HIC and age. These results
differ from those of Bassett et al.,24 who found that HIC
correlated with age in the predominantly male population, and Loreal et al.,25 who reported an HIC correlation
with age in males less than 40 years old.
We conclude that a daily alcohol intake of greater than
60 g per day increases the risk of cirrhosis in HHC by
approximately ninefold. These subjects are more likely to
progress to cirrhosis at an earlier age than those who do
GASTROENTEROLOGY Vol. 122, No. 2
not drink excess alcohol. The range of HIC associated
with cirrhosis in the absence of alcohol and other profibrogenic factors was 233– 675 ␮mol/g dry weight.
Nevertheless, venesection therapy is recommended in all
cases of elevated body iron stores irrespective of alcohol
consumption to minimize the risk of disease progression.
In addition, all HHC patients should be encouraged to
severely curtail alcohol consumption.
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Received December 28, 2000. Accepted October 8, 2001.
Address requests for reprints to: Linda M. Fletcher, Ph.D., Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. e-mail: Lin_Fletcher@health.qld.gov.au; fax: 61-7-3240 5111.
This project was supported, in part, by the National Health and
Medical Research Council of Australia.