Clinical Science (1983) 64,527-535
527
A study of zinc metabolism in alcoholic cirrhosis
P E T E R R . M I L L S , G O R D O N S. F E L L * , R O D N E Y G. B E S S E N T t S ,
L E S L E Y M. N E L S O N A N D R O B I N I. R U S S E L L
Gastroenterology Unit, and Departments of *Biochemistryand ?Nuclear Medicine, Glasgow Royal Idrmary, and $ West of
Scotland Health Boards Department of Clinical Physics and Bioengineering,Glasgow, Scotland, UX.
(Received 30 July119 October 1982; accepted 30 November 1982)
Summary
1. Zinc metabolism was studied in 11 patients
with alcoholic cirrhosis and 13 healthy volunteers
using the isotope tracer 65Zn.
2. Intestinal absorption, whole-body content
and total daily elimination of zinc were all
increased in alcoholic cirrhosis, but the biological
half-life of zinc did not differ from controls.
3. Hepatic zinc concentration was reduced in
alcoholic cirrhosis and correlated with changes in
hepatic alcohol dehydrogenase activity.
4. Patients with alcoholic cirrhosis in this
study were not demonstrated to be zinc-deficient.
Key words: zinc, alcoholic cirrhosis, 65Zn isotope, alcohol dehydrogenase, intestinal absorption, whole-body counting.
Introduction
Patients with alcoholic cirrhosis are reported to
have reduced serum zinc levels [1-31 and
increased urinary zinc excretion [4-61. In addition, decreased hepatic zinc concentration [4,7,
81 and leucocyte zinc content [9, 101 have also
been demonstrated. These findings, taken
together, have tended to suggest that alcoholic
cirrhosis may be associated with a state of zinc
deficiency [lll. It has been postulated that
alcoholism might lead to zinc deficiency, which in
turn may result in decreased activity of two
hepatic zinc metalloenzymes, alcohol dehydrogenase and glutamate dehydrogenase, thus possibly rendering the liver more susceptible to
damage from continued alcohol consumption
[121. Attempts to correct possible zinc deficiency
Correspondence: Dr R. I. Russell, Gastroenterology Unit, Royal Infirmary, Glasgow G4 OSF,
Scotland, U.K.
in alcoholic cirrhosis by giving oral zinc sulphate
supplementation had disappointing results. Two
double-blind clinical trials of zinc supplementation have shown a rise in serum zinc concentration in the treated group but no change in
markers of hepatic function [ 13, 141.
The evidence for zinc deficiency in alcoholic
cirrhosis is rather indirect. Zinc is almost exclusively an intracellular metal, being concentrated in muscle, bone and liver, the serum
pool accounting for less than 1% of whole-body
zinc. Serum zinc is non-specifically lowered in
many common illnesses [151 and reduction of
protein synthesis in alcoholic cirrhosis will lower
plasma zinc-binding proteins [3]. There are a few
reports of direct measurement of tissue zinc in
alcoholic cirrhosis which do suggest a degree of
zinc deficiency, but no estimates of whole-body
zinc content have been made.
A study of zinc metabolism was therefore
undertaken in patients with alcoholic cirrhosis.
Measurements included intestinal zinc absorption, the biological half-life of zinc in the
body, whole-body zinc content and the daily loss
of zinc from the body using the isotope tracer
65Zn. In addition, the functional importance of
any hepatic zinc deficiency was assessed by
measurement of hepatic zinc concentration and
alcohol dehydrogenase (EC 1.1.1.1) activity
and the distribution of zinc between the main
serum protein fractions was also investigated.
Patients and methods
Patients
The patients and controls studied were all
males and were divided into three groups. Group
A comprised 13 fit out-patients with histologically proven compensated alcoholic cirrhosis.
0143-5221/83/050527-09%2.00 @ 1983 The Biochemical Society and the Medical Research Society
528
P. R . Mills et al.
The study period lasted 32 weeks and only 1 1
patients with a mean age of 55 years (SD9, range
37-67) completed the study. Only two of these
1 1 patients were known to be still drinking
heavily, all were taking a normal diet and none
showed clinical evidence of nutritional deficiency.
Group B comprised 13 healthy hospital staff
volunteers, with a mean age of 43 years (SD 9,
range 33-60), who took part in the 65Znisotope
study. Group C comprised 10 healthy patients,
with a mean age of 51 years (SD 17, range
2 1-70), who did not abuse alcohol and agreed to
undergo Trucut-needle liver biopsies during elective surgery for a duodenal ulcer (eight patients)
or gallstones (two patients).
Groups A and B had serum and urinary zinc
measured and took part in the 65Znisotope study.
Groups A and C had Trucut-needle liver biopsies.
All the individuals in groups B and C had
normal liver-function tests. Permission to administer the isotope 65Zn was obtained from the
Administration of Radioactive Substances Advisory Committee of the Department of Health
and Social Security in November 1979 and
approval of the study was granted by the Ethical
Committee of Glasgow Royal Infirmary in
November 1980. The estimated whole-body and
liver radiation doses were 140 mrad and 460
mrad respectively. All patients gave consent prior
to entering the study.
Serum and urinary zinc measurements
Patients fasted overnight and 10 ml of serum
was collected between 09.00 and 10.00 hours in
zinc-free bottles. Four 24 h urine collections were
made in zinc-free plastic containers at the times
stated below. Total serum zinc and urinary zinc
were estimated by atomic-absorption spectrophotometry 1161. Total serum protein and
albumin concentrations were determined by
standard methods and the difference taken as
total serum globulins.
An estimate of the fraction of zinc bound to
albumin was made by selective precipitation of
the high-molecular-weight zinc metalloprotein
a,-macroglobulin in the following manner. A
0.5 ml portion of serum was added to 0.5 ml
of poly(ethy1ene glycol) 6000 (240 g/l) in
Tris/HCI buffer (0.5 mol/l). After mixing, the
solution was left at room temperature for 30 min
and then centrifuged at 10 000 g for a further 30
min. Zinc was determined in the supernatant by
atomic-absorption spectrophotometry, using zinc
standards in 12% poly(ethy1ene glycol) 6000.
The difference between total serum zinc and
albumin-bound zinc was termed 'non-albumin-
bound zinc'. The concentration of zinc found in
the supernatant fluid was considered to be mainly
albumin-bound zinc, but also included a small
amount of zinc complexed with amino acids. The
precipitation technique gives values for albuminbound zinc which are in agreement with other
reports and those found by a more selective
gel-chromatography procedure [ 171.
Liver biopsy measurements
Each patient had two liver biopsies taken with
a Trucut needle from adjacent sites on the liver
using the percutaneous method in group A and
under direct vision at laparotomy in group C. A
small portion of one biopsy from patients in
group C was sent for histological assessment and
confirmed normal liver architecture in all cases.
Preliminary studies on a post-mortem liver had
shown that Trucut needles caused no zinc
contamination of the small liver biopsies. The
liver biopsies were inserted into small airtight
zinc-free plastic containers, frozen at the bedside
in a solid CO,/methanol mixture and stored at
-2OOC. All the biopsies were collected within a
2-month period and then analysed as a single
batch of 21 samples. At the time of analysis the
wet weight of the biopsies (mean 25.5 mg) was
recorded.
The first biopsy from each patient was then
dried overnight in a furnace at 100°C, the dry
weight was recorded and the sample ashed at
55OOC. The sample was dissolved in 0.25 ml of
Aristar nitric acid and made up to 10 ml with
distilled water. Zinc, magnesium and copper
content were measured by atomic-absorption
spectrophotometry and expressed as ,ug/g dry
weight.
The second biopsy was homogenized in sucrose solution (0.25 mmol/l) containing 1% Triton
X-100and then centrifuged at 10000 g for 30
min to prepare a supernatant for analysis of
alcohol dehydrogenase activity and total protein
content [ 181. Alcohol dehydrogenase activity was
measured at pH 10-1 and expressed as units/g of
protein (1 enzyme unit = 1 p n o l of NADH
produced/min at 25 O C ) .
As it was anticipated that the number of
hepatocytes obtained in the cirrhotic biopsies
would be reduced, protein and magnesium
content of the biopsies were measured as an index
of the number of hepatocytes. Zinc is almost
exclusively intracellular and was therefore expressed in terms of mg of protein or as a
zinc/magnesiurn ratio. The limited amount of
liver tissue prohibited the use of DNA or
potassium as estimates of intracellular content.
529
Zinc status in alcoholic cirrhosis
65Znisotope study
Fasting subjects were given 5 pCi (185 kBq) of
6SZn orally in 5 ml of ZnSO, solution, which
contained 10 mg of elemental zinc, between 09.00
and 10.00 hours, and nothing was eaten until
lunch. Whole-body radioactivity was measured
after 15 min using a scanning-couch shadowshield whole-body monitor, and after background subtraction this was taken as the 100%
count. Two tablets of Senokot were taken on day
5 to ensure that no unabsorbed 65Znremained in
the colon at 1 week. Subsequent whole-body
counts were taken 1,4,24,28 and 32 weeks after
administration and corrected for decay and
include the initial two rapid-turnover components. In only two cases did the data allow the
definition of a double exponential with any degree
of certainty, and in these cases the long-term
exponents were not significantly different from
the single exponents of the other cases.
The 1-week whole-body retention of 65Zn was
taken as a measure of intestinal zinc absorption
[201. Whole-body zinc content was estimated
from whole-body activity and urinary specificactivity measurements at weeks 24, 28 and 32
when 65Zn is thought to be fully in equilibrium
with whole-body stores. The whole-body zinc
content is calculated using the isotope dilution
principle:
Urine zinc (mg/24 h urine sample)
Whole-body zinc (mg)
Whole-body 6sZn (% of administered dose) Urine 65Zn(% of administered dose in 24 h urine sample)
sensitivity changes by normalizing against a 6SZn
standard. Single 24 h urine collections were made
at 4, 24, 28 and 32 weeks and 65Zn content
estimated on the whole-body monitor with
reference to a standard of the same geometry.
Stable zinc content of the urine was measured as
lcribed above.
Whole-body percentage-retention data from
week 1 onwards were found to be a good fit to a
single exponential decay of the form:
R = Ae-(ln 2)1/T
-
4
where R is retention, A is amplitude, t is time in
days and T4is the biological half-life in days. An
iterative least-squares procedure was used to fit
the exponential function to the data. This
long-term decay component corresponds to the
third and final exponential function as described
by Aamodt et al. in 1982 [191 and does not
65Zn dynamics have previously been investigated using a two-compartment model, when
it was shown that total uniformity of specific
activity throughout both compartments was
never achieved [211. However, for all subjects, the
ratio of whole-body specific activity to specific
activity in the rapidly exchanging compartment
(sampled by urine) tended to a final value of 1.3,
passing through the value of 1.0 at between 100
and 140 days. From this earlier work we have
derived the divisor 1* 13 to correct the simple
isotope-dilution results obtained at 24-32 weeks
for the differences between specific activity in the
whole body and in the rapidly exchanging pool
(sampled by urine) as demonstrated by the
two-compartment model. The total daily loss of
zinc from the body was calculated from the
product of whole-body zinc content and the
biological decay constant [(ln 2)/7J.
TABLE1. Summary of serum and urine zinc results in controls and patients with
alcoholic cirrhosis (mean f SD)
Abbreviation used: N.S.,not significant.
-
Controls (n = 13)
Cirrhosis (n = 11)
Mean
SD
Mean
SD
Total serum zinc (pmolll)
Albumin-bound zinc (pmolll)
Percentageof total zinc (%)
Non-albumin-boundzinc (pmolh)
Percentage of total zinc (%)
Serum albumin (g/I)
Serum globulins (gh)
13.9
9.6
69.2
4.2
30.8
41.8
28.1
2.3
1.9
4.8
0.72
4.8
3.7
2.3
11.8
7.2
60.1
4.63
39.9
37.0
37.4
3.8
2.7
7.1
1.52
7.1
7.4
24 h urine zinc
pmol/day
(mglday)
9.s
(0.62)
2.9
(0.19)
15.3
(1.0)
-
6.S
6.6
(0.4)
P
N.S.
N.S.
<0.02
N.S.
(0.02
N.S.
<0.002
<0.02
.
P . R Mills et al.
530
volunteers (group B), and the results are listed in
Table 1. Total serum zinc was lower in the
patients with cirrhosis, but this was not statistically significant (probably owing to the small
numbers studied). Urinary zinc excretion was
significantly increased in the cirrhotic patients
and remained so throughout the period of study.
Serum albumin was lower in the patients with
cirrhosis, and the percentage of total serum zinc
bound to albumin was significantly reduced. In
the patients with cirrhosis there was a good
correlation between serum albumin and both total
Statistical comparisons were made using the
Maim-Whitney test. Correlations were assessed
by linear-regression analysis or the Spearman
rank correlation coefficient as appropriate.
Results
Serum and urinary zinc measurements
These were performed in the 11 patients with
alcoholic cirrhosis (group A) and the 13 healthy
500
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Cirrhosis
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Controls
Cirrhosis
Controls
Cirrhosis
FIG. 1. Liver zinc content in 11 patients with alcoholic cirrhosis and 10 controls. The horizontal
bar represents the mean. Results are expressed as means f 1 SD ih two different units (a, b) and as
a zinc/magnesium ratio (c). (a) pg/g dry weight: controls, 265.6 f 84.5; cirrhosis, 95.7 f 35.2
(P< 0.001). (b) pg/mg of protein: controls, 1.05 f 0.38;cirrhosis, 0.38 f 0.18 (P< 0.005). (c)
Zinc/magnesium ratio (pg/g dry weight): controls, 0.48 f 0.14; cirrhosis, 0.20 f 0.06 (P <
0.001).
Zinc status in alcoholic cirrhosis
serum zinc (r = +0.79, P < 0.01) and albuminbound zinc (r = +0.76, P < 0.01). Serum
globulins were significantly elevated in the
patients with cirrhosis, as was the percentage of
total serum zinc not bound to albumin. However,
in these patients there was a negative correlation
between serum globulins and total serum zinc
(r = -0.61, P < 0.05) and no correlation with
non-albumin-bound zinc (r = -0-24,not significant).
531
Liver biopsy measurements
Measurements were made on biopsy material
from patients with alcoholic cirrhosis (group A,
n = 11) and controls undergoing elective abdominal surgery (group C , n = 10).All measurements are reported as a mean & 1 SD. Liver
protein (controls 90.7 k 20.7; cirrhosis 68.9 &
11.8 pg/mg wet weight, P < 0.05) and liver
magnesium (controls 557.9 & 94.6; cirrhosis
463.3 & 58 pg/g dry weight, P < 0402) were
measured as an index of the number of hepatocytes in the biopsy and, as expected, both were
significantly reduced in the cirrhosis group. Liver
zinc content (Figs. la, lb and lc) was signifi-
0
m e
+
om
*
Controls
,
.
Cirrhosis
FIG.2. Liver alcohol dehydrogenaseactivity in units/g
of protein at pH 10.1. The horizontal bar represents
the mean. Results are expressed as means f 1 SD:
controls, 5.2 f 2.47; cirrhosis, 1.92 f 1.42 (P <
0.01).
Cirrhosis
Controls
FIG.3. Intestinal absorption of zinc, as measured by
the percentage whole-body retention of 65Zn 7 days
after oral ingestion (%). The horizonal bar represents
1 SD:
the mean. Results are expressed as means
controls, 26.9 f 14; cirrhosis, 43.1 f 16 (P< 0.05).
TABLE
2. Summary of sJZnisotope results (mean ? SD)
Abbreviation used: NS, not significant.
Controls (n = 13)
Percentage absorption of zinc "lday retention (%)I
Whole-body zinc content (g)
Biologicalhalf-lifeof zinc (days)
Total daily loss of zinc from the body (mg/day)
Cirrhosis (n = 11)
Mean
SD
MW
SD
26.9
0.79
278
1.92
14
0.4
51
0.87
43.1
1.5
302
3.72
16
0.49
87
1.74
P
(0.05
<0-005
N.S.
<0.01
532
P. R . Mills et al.
cantly reduced in patients with cirrhosis whether
measured as pg/g dry weight of tissue (P <
O.OOl), pglmg of protein (P < 0.005)or as a
zinc/magnesium ratio (P < 0.001). Liver copper
content (controls 145.7 & 91.1; cirrhosis 113.4
f 71.6 pglg of protein) was not significantly
different between the two groups. Liver alcohol
dehydrogenase activity, measured in units/g of
protein, was significantly reduced (P < 0.01) in
the patients with cirrhosis (Fig. 2) and there was
a positive correlation between liver alcohol
dehydrogenase activity (unitslg of protein) and
liver zinc content (pg/g dry weight), which was
significant at the 1% level ( T = +0.63, n = 21).
6’Zn isotope study
Patients with alcoholic cirrhosis (group A, n =
11) and healthy volunteers (group B, n = 13)
took part in this study and the results are
summarized in Table 2. The percentage intestinal
absorption of zinc, as measured by the percentage whole-body retention of 6’Zn at 7 days, was
significantly increased (P < 0.05)in the patients
with cirrhosis (Fig. 3). Whole-body zinc content,
measured in grams, was also significantly
increased (P < 0.005) in the patients with
cirrhosis (Fig. 4). Expressed in terms of body
0
00
h
0
0
I
I
Controls
Cirrhosis
FIG. 4. Whole-body zinc content in grams. The
horizontal bar represents the mean. Results are
0.4;
expressed as means f 1 SD: controls, 0.79
cirrhosis, 1.50 f 0.49 (P< 0.00s).
weight, the whole-body zinc content (controls
11.3 f 6; cirrhosis 20.5 f 6.8 mg/kg body
weight, P < 0.005) remained significantly
elevated. The biological half-life of zinc in the
body, measured in days, was not significantly
different between the two groups. Calculated total
daily loss of zinc from the body was significantly
increased (P < 0.001) in the patients with
cirrhosis at a mean of 3.72 mg/day compared
with a mean of 1.92 mg/day in the controls.
Discussion
This study of zinc metabolism in patients with
alcoholic cirrhosis did not confirm evidence of a
zinc-deficient state. Intestinal absorption of zinc,
whole-body zinc content and total daily loss of
zinc from the body have all been demonstrated to
be increased in alcoholic cirrhosis. Hyperzincuria and diminished hepatic zinc concentration have been confirmed and a correlation
shown between hepatic zinc concentration and
activity of the hepatic zinc metalloenzyme alcohol dehydrogenase. The possible mechanisms
behind these observed changes will be discussed.
Low serum zinc concentration in patients with
cirrhosis has been recorded by many laboratories
and has led to the belief that a state of zinc
deficiency may exist [ 1-31. However, serum zinc
is lowered in acute illnesses such as infection or
myocardial infarction 1151 and in chronic disorders such as nephrotic syndrome or neoplastic
disease, when alteration in circulating plasma
proteins are of importance 1221. Cirrhosis may be
an example of the latter change. The distribution
of zinc among the plasma proteins is normally
such that 3 0 4 0 % of the total is firmly bound to
a,-macroglobulin and 60-70% more loosely
bound to albumin, which is in equilibrium with a
much smaller amount (1-2%) of ultrafilterable
zinc complexed with low-molecular-weight ligands such as amino acids. Our study has
confirmed previous findings of a decrease in
albumin-bound zinc and an increase in a,macroglobulin-bound zinc in alcoholic cirrhosis
[31 and, in addition, has demonstrated a good
correlation between serum albumin and total
serum zinc. The reduction in total serum zinc
probably reflects the dominant role of albumin in
zinc transport. It is clear that alterations in liver
protein synthesis in cirrhosis will profoundly
affect zinc metabolism.
An increased urinary excretion of zinc has
been confirmed in this study and remains difficult
to explain. The effect of alcohol consumption on
urinary zinc excretion has been studied and
Zinc status in alcoholic cirrhosis
shown not to induce zincuria in normal individuals 1231 and not to alter hyperzincuria in
patients with cirrhosis [241. This study has shown
persistent hyperzincuria in patients with alcoholic
cirrhosis, nine of whom were not thought to be
consuming further alcohol, and therefore did not
confirm that hyperzincuria may be transient and
clear in the majority within 2 weeks of abstention
[251. The finding of increased whole-body zinc
content and increased total daily loss of zinc from
the body are both reflected in the persistent
hyperzincuria, although the actual renal mechanism of increased zinc excretion is not established.
We found hepatic zinc concentrations in
alcoholic cirrhosis to be diminished, despite an
increase in whole-body zinc content. Hepatic zinc
concentration will be influenced by the number of
hepatocytes in the biopsy sample. Allowance for
this was made by expressing zinc levels in terms
of protein and magnesium, as markers of intracellular content, and the concentration was low
whatever method was adopted. Others have also
shown an absolute reduction in hepatic zinc
concentration in cirrhosis, which was independent of the amount of collagen present 171.
Hepatic zinc concentration alone does not allow
estimation of whole-liver zinc content. We are not
aware of any autopsy studies which record
whole-liver zinc content in alcoholic cirrhosis,
and as many of these livers may be greatly
enlarged, this is an important omission. However,
if it is accepted that there is likely to be a
diminished whole-liver zinc content in alcoholic
cirrhosis, how can this be explained in the face of
an increase in whole-body zinc content? Several
mechanisms may be responsible. Firstly, cirrhosis
may produce portal hypertension and portosystemic venous shunting, hence reducing the
quantity of absorbed zinc reaching the liver in the
portal circulation and increasing the zinc load
distributed into the systemic circulation. It has
been estimated that 60% of absorbed zinc is
normally initially extracted by the liver from the
portal circulation before being gradually released
into the systemic circulation [261. Recently,
arteriovenous hepato-intestinal extraction of zinc
has been shown to be markedly diminished in
patients with alcoholic cirrhosis [271. Evidence
for portal hypertension, as judged by the endoscopic or radiological demonstration of oesophageal varices, was found in only two out of
eleven patients with alcoholic cirrhosis in our
series and their hepatic zinc concentrations at
0.29 and 0.33 pg/mg of protein were both very
low. Secondly, hepatocyte damage may reduce
the ability of the liver to manufacture the
intracellular zinc-binding protein metallo-
533
thionein, which normally contributes to hepatic
zinc storage [281. Thirdly, necrosis of hepatocytes, as may be found in alcoholic liver disease,
may lead to rupture of cells and release of storage
zinc into the systemic circulation. It is of interest
that no correlation was found between hepatic
and muscle zinc concentrations in healthy individuals or patients with liver disease [291.
Diminished activity of the hepatic zinc metalloenzyme alcohol dehydrogenase was demonstrated in this study. While the degree of hepatic
damage found in cirrhosis may be largely
responsible for this reduced activity, it was
possible to show a correlation between hepatic
zinc concentration and the enzyme activity,
suggesting that the reduced hepatic zinc content
may be of functional importance. A previous
study has demonstrated reduced hepatic alcohol
dehydrogenase activity in alcoholic liver disease,
the enzyme activity tending to fall off with
increasing severity of liver disease [ 181. While
regular alcohol ingestion may accelerate alcohol
elimination in the chronic alcoholic, this effect is
transient and the alcohol-elimination rates in
non-drinking patients with cirrhosis are in the
low-normal range or decreased [30,3 11.
The most interesting finding of this study is the
demonstration of increased intestinal zinc absorption in patients with alcoholic cirrhosis. The
increase in zinc absorption is matched by an
increase in zinc elimination but no change in the
rate of zinc turnover. Therefore, the whole-body
zinc stores must also be increased, as has been
demonstrated. Presumably, the increase in zinc
absorption is of prime importance, the other
findings being secondary events. The range of
intestinal zinc absorption in the controls was wide,
ranging from 7 to 56%, with a mean of 27%. The
5 pCi of oral 65Zn was given with a 10 mg
elemental zinc load, which is equivalent to the
daily oral intake of zinc, although clearly the
circumstances are not physiological. The use of
7-day whole-body retention of 65Zn as a measure
of intestinal zinc absorption is valid, provided all
unabsorbed intestinal 6’Zn has been excreted in
the faeces. The value obtained is a slight
underestimate of actual zinc absorption, because
of intestinal and urinary excretion of a small
proportion of absorbed 65Zn within the 7-day
period. However, the rate of zinc turnover was
not different between controls and cirrhotics, and
with a mean biological half-life of 278 days the
actual loss is negligible. Estimation of actual zinc
absorption on day 0 by extrapolation of a
logarithmic plot of the whole-body retention data
back to day 0 produced values within +2% of the
percentage 7-day retention data in all patients.
534
P.R.Mills et al.
Understanding of the mechanism of intestinal
zinc absorption is still far from complete, but zinc
is thought to be maximally absorbed in the
duodenum, under the influence of an ATPdependent transport system 128,321. Dietary zinc
is thought to bind to low-molecular-weight
ligands in the intestinal lumen, which may control
its bioavailability. Picolinic acid, released by the
pancreas, has been suggested to act as such a
zinc ligand 1331. Zinc then enters the intestinalcell zinc pool from where it may pass directly into
plasma, where it binds to albumin and is
transported via the portal vein to the liver, or it
may bind to high-molecular-weight proteins or
metallothionein in the cell. Metallothionein has
been demonstrated to be rapidly inducible in the
intestinal cell, under the influence of excess
intestinal zinc, to limit zinc absorption [281.
Possible mechanisms producing an increase in
zinc absorption in alcoholic cirrhosis are as
follows. There might be concomitant pancreatic
damage resulting in failure to produce sufficient
picolinic acid which may normally partially
inhibit zinc absorption, and here there may be an
analogy with the increase in iron absorption also
seen in alcoholic cirrhosis [341. In the presence of
cirrhosis, or during continued alcohol ingestion,
there might be failure of induction of metallothionein in the intestinal cell, thus allowing more zinc
to pass directly into plasma. The low plasma zinc
levels found in alcoholic cirrhosis may somehow
stimulate an inappropriate increase in the intestinal cellular transit of zinc. The two patients
with alcoholic cirrhosis in this study who were
known to have a continuing high alcohol intake
both had increased absorption at 55 and 53%
respectively and high whole-body zinc contents at
2.29 and 2.11 g.
Information concerning whole-body zinc content in the literature is very limited. Chemical
analysis of three adult cadavers revealed wholebody zinc contents of 0.99 g in a female suicide
case, 1.24 g in a male dying of infective
endocarditis and 2.39 g in a male dying from
chronic renal failure 1351. Twelve patients with
rheumatoid arthritis had a mean whole-body zinc
content of 1.1 g measured by the same technique
as in this study 1211.
In conclusion, the findings of diminished
serum, leucocyte and hepatic zinc concentrations appeared to suggest that patients with
alcoholic cirrhosis might be zinc-deficient.
Appropriate clinical trials of zinc supplementation, however, showed no clinical benefit.
This study of zinc metabolism in fit patients with
compensated alcoholic cirrhosis has demonstrated increased intestinal zinc absorption,
increased whole-body zinc and increased zinc
elimination. The paradox of tissue zinc
deficiency and whole-body zinc excess might be
explained by an alteration in zinc distribution. It
is possible that there may be a block to tissue
utilization of zinc in alcoholic cirrhosis, thus
leading to an increase in absorption and excretion
of zinc. Very recent preliminary evidence suggests that the excess whole-body zinc in cirrhotic
patients may be accumulating in the skeleton
1361, from where it may not be readily available
for tissue use. Oral zinc supplements may
therefore be ineffective despite an increased
requirement for zinc. Our findings should not be
extrapolated to the malnourished acutely ill
patient with decompensated alcoholic cirrhosis
who may in addition suffer from dietary zinc
deficiency.
Acknowledgments
We should like to acknowledge the assistance of
Professor D. C. Carter, Mr C. W. Imrie, Mr C. S.
McArdle and Mr D. Gilmour in providing liver
biopsy specimens in patients undergoing elective
abdominal surgery. In particular, we are very
grateful to Mrs Elizabeth Scott of the Department of Nuclear Medicine, Glasgow Royal
Infirmary, for her excellent organization and
consideration for patients, which contributed
largely to the successful completion of the study.
Finally, we should like to thank patients and staff
who volunteered so readily to take part in the
study.
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