Zinc and Liver Disease

Abstract

Zinc is an essential trace element required for normal cell growth, development, and differentiation. It is involved in DNA synthesis, RNA transcription, and cell division and activation. It is a critical component in many zinc protein/enzymes, including critical zinc transcription factors. Zinc deficiency/altered metabolism is observed in many types of liver disease, including alcoholic liver disease (ALD) and viral liver disease. Some of the mechanisms for zinc deficiency/altered metabolism include decreased dietary intake, increased urinary excretion, activation of certain zinc transporters, and induction of hepatic metallothionein. Zinc deficiency may manifest itself in many ways in liver disease, including skin lesions, poor wound healing/liver regeneration, altered mental status, or altered immune function. Zinc supplementation has been documented to block/attenuate experimental ALD through multiple processes, including stabilization of gut-barrier function, decreasing endotoxemia, decreasing proinflammatory cytokine production, decreasing oxidative stress, and attenuating apoptotic hepatocyte death. Clinical trials in human liver disease are limited in size and quality, but it is clear that zinc supplementation reverses clinical signs of zinc deficiency in patients with liver disease. Some studies suggest improvement in liver function in both ALD and hepatitis C following zinc supplementation, and 1 study suggested improved fibrosis markers in hepatitis C patients. The dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc taken with a meal to decrease the potential side effect of nausea.

Full text

Invited Review
Nutrition in Clinical Practice
Volume 27 Number 1
February 2012 8-20
© 2012 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533611433534
http://ncp.sagepub.com
hosted at
http://online.sagepub.com
Zinc and Liver Disease
Mohammad K. Mohommad, MD1; Zhanxiang Zhou, PhD2; Matthew Cave, MD3;
Ashutosh Barve, MD, PhD3; and Craig J. McClain, MD4
Abstract
Zinc is an essential trace element required for normal cell growth, development, and differentiation. It is involved in DNA synthesis, RNA
transcription, and cell division and activation. It is a critical component in many zinc protein/enzymes, including critical zinc transcription
factors. Zinc deficiency/altered metabolism is observed in many types of liver disease, including alcoholic liver disease (ALD) and
viral liver disease. Some of the mechanisms for zinc deficiency/altered metabolism include decreased dietary intake, increased urinary
excretion, activation of certain zinc transporters, and induction of hepatic metallothionein. Zinc deficiency may manifest itself in many
ways in liver disease, including skin lesions, poor wound healing/liver regeneration, altered mental status, or altered immune function.
Zinc supplementation has been documented to block/attenuate experimental ALD through multiple processes, including stabilization of gut-
barrier function, decreasing endotoxemia, decreasing proinflammatory cytokine production, decreasing oxidative stress, and attenuating
apoptotic hepatocyte death. Clinical trials in human liver disease are limited in size and quality, but it is clear that zinc supplementation
reverses clinical signs of zinc deficiency in patients with liver disease. Some studies suggest improvement in liver function in both ALD and
hepatitis C following zinc supplementation, and 1 study suggested improved fibrosis markers in hepatitis C patients. The dose of zinc used
for treatment of liver disease is usually 50 mg of elemental zinc taken with a meal to decrease the potential side effect of nausea. (Nutr Clin
Pract. 2012;27:8-20)
Keywords
zinc; liver diseases; liver diseases, alcoholic; liver cirrhosis; hepatitis
From 1University of Louisville, Louisville, Kentucky; 2University of
North Carolina Greensboro, Greensboro, North Carolina; and 3University
of Louisville Medical Center, Louisville, Kentucky.
Financial disclosure: none declared.
Received for publication September 9, 2011; accepted for publication
October 29, 2011.
Correspondence Author: Craig J. McClain, University of Louisville Medi-
cal Center, 550 S Jackson St, ACB 3rd Floor, Louisville, KY 40292, USA;
E-mail: craig.mcclain@louisville.edu.
Zinc is the second most prevalent trace element in the body.
It is integrally involved in the normal life cycle and has
many important regulatory, catalytic, and defensive func-
tions. Zinc was shown to be an essential trace nutrient for
rodents in the 1930s and in humans in 1963, and it plays a
catalytic role in a host of enzymes. Zinc plays a major role
in the regulation of gene expression through metal-binding
transcription factors and metal response elements in the
promoter regions of the regulated genes. Zinc also plays a
critical role in zinc-finger motifs. Zinc fingers typically
have 4 cysteines within the protein that allow zinc to be
bound in a tetrahedral complex.
Liver disease, especially alcoholic liver disease (ALD),
has been associated with hypozincemia and zinc deficiency
for more than half a century.1,2 These early ALD observations
were confirmed by multiple investigators, and tissue concen-
trations of zinc have been demonstrated to be decreased in
alcoholic cirrhosis as well as animal models of liver dis-
ease.3-11 This article updates these early observations on dys-
regulated zinc metabolism in liver disease with new advances
in this area and will review (1) clinical manifestations of zinc
deficiency and their relevance to liver disease, (2) zinc
metabolism, (3) zinc and ALD, (4) zinc and viral liver dis-
ease, (5) zinc and other liver diseases, and (6) general
recommendations concerning zinc supplementation and
overall conclusions.
Much of our knowledge concerning the metabolic func-
tions of zinc in humans is derived from manifestations
of zinc deficiency in zinc-deficient animals, in patients
with acrodermatitis enteropathica (a hereditary disease of
impaired zinc absorption), or in patients with acquired zinc
deficiency due to an underlying disease process.12 It is also
becoming clear that clinical and biochemical manifestations
of zinc deficiency often occur when some stress is placed on
the organism.13,14 In liver disease, this stress may occur
through increased gut permeability with endotoxemia, infec-
tions such as spontaneous bacterial peritonitis, or release of
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Zinc and Liver Disease / Mohommad et al 9
stress hormones. Selected potential clinical manifestations of
zinc deficiency in liver disease are shown in Table 1.
Clinical Manifestations of Zinc
Deficiency in Liver Disease
Skin Lesions
The effects of zinc deficiency are particularly obvious on the
skin, as manifested by an erythematous rash or scaly plaques.
Many common dermatological conditions (eg, dandruff, acne,
diaper rash) have been associated with zinc deficiency or
effectively treated with zinc.15 Acrodermatitis enteropathica
(AE) is a rare hereditary disease characterized by skin lesions,
alopecia, failure to thrive, diarrhea, impaired immune function
with frequent infections, and, in some cases, ocular abnormali-
ties.16-19 The skin lesions (acrodermatitis) tend to occur around
the eyes, nose, and mouth; over the buttocks and perianal
regions; and sometimes in an acral distribution. The signs and
symptoms of AE are caused by zinc deficiency due to impaired
intestinal absorption of zinc. AE is caused by mutations of the
SLC39A4 gene on the chromosome band 8q24.3, encoding a
zinc transporter in humans (Zip4).19
Patients with ALD and other forms of liver disease are pre-
disposed to develop the skin lesions of zinc deficiency because
of marginal underlying total body zinc stores. Several cases of
acrodermatitis also have been reported in alcoholics with or
without liver disease who were not receiving zinc in their
hyperalimentation solutions or who had inadequate dietary
intake of zinc (Figure 1).20-24
Zinc deficiency is also associated with necrolytic acral ery-
thema (NAE).25 NAE is a recently recognized dermatosis, pre-
senting in the form of pruritic, symmetric, well-demarcated,
hyperkeratotic, erythematous-to-violaceous, lichenified
plaques with a rim of dusky erythema on the dorsal aspects of
the feet and extending to the toes. NAE is associated with
decreased serum and skin zinc levels and is almost always
associated with HCV infection, thereby serving as a cutaneous
marker for underlying HCV infection.26 Use of oral zinc ther-
apy is highly effective and leads to NAE resolution in combi-
nation with treatment of the underlying HCV infection.27
Depressed Mental Function and
Encephalopathy
Early studies by Henkin et al28 reported that experimentally
induced zinc deficiency in humans may be accompanied by
apathy or irritability, which is reversed with zinc supplementa-
tion. Similarly, children with AE may have apathy or confu-
sion, which responds to zinc supplementation. We have
observed patients receiving parenteral nutrition (PN) who
developed severe depression or confusion and severe hypoz-
incemia. Marked improvement in mental status coincided with
zinc supplementation in these patients.20,21
Portal systemic (hepatic) encephalopathy (PSE) is a
derangement of mental function caused by liver disease or
Figure 1. Classic skin lesions around the eyes, nose, and
mouth in 2 alcoholics with extremely low serum zinc levels
(a, b). Skin lesions rapidly resolved in both patients with zinc
supplementation. Patient 1b had encephalopathy that was initially
believed to be hepatic encephalopathy. However, this resolved
with zinc supplementation, documenting how zinc deficiency can
cause mental disturbances. From McClain et al20 and McClain.21
Table 1. Clinical Manifestations of Zinc Deficiency
1 Skin lesions
2 Depressed mental function, encephalopathy
3 Impaired night vision; altered vitamin A metabolism
4 Anorexia (with possible alterations in taste and smell
acuity)
5 Hypogonadism
6 Depressed wound healing
7 Altered immune function
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10 Nutrition in Clinical Practice 27(1)
shunting of blood around the liver.29-31 This disordered mental
state ranges in severity from intellectual impairment detect-
able only by careful psychometric testing to frank coma.29
Gut-derived toxins such as ammonia, mercaptans, short-chain
fatty acids, false neurotransmitters, metabolites of tryptophan,
and others are postulated to play an etiological role in this
disordered mental status.29 Patients with cirrhosis have
depressed serum zinc levels, and those with hepatic encepha-
lopathy have statistically reduced serum zinc concentra-
tions.32,33 Zinc is integrally involved in the metabolism of
ammonia. Zinc deficiency markedly decreases activity of the
urea cycle enzyme, ornithine transcarbamylase, and zinc sup-
plementation corrects this.34 Similarly, zinc deficiency has
been reported to impair activity of muscle glutamine synthe-
tase, which causes hyperammonemia.35 Glutamine synthetase
activity has also been reported to be decreased in patients with
encephalopathy.36 Several trials have reported using zinc sup-
plementation in various stages of PSE with somewhat incon-
sistent results. In the most recent large randomized clinical
trial, polaprezinc supplementation plus standard therapy for 6
months (compared with standard therapy alone, protein-
restricted diet with branched-chain amino acids and lactulose)
was associated with a significant improvement in encepha-
lopathy grade, blood ammonia levels, serum albumin levels,
and a variety of psychomotor performance tests.37 Last, overt
hepatic encephalopathy has been induced in a subject by cre-
ating zinc deficiency, and encephalopathy was then reversed
with zinc supplementation.38
Impaired Night Vision
Impaired night vision has been recognized in alcoholic cirrhot-
ics since the late 1930s, and this has been confirmed in recent
studies in many types of cirrhosis.39-41 This is usually associ-
ated with vitamin A deficiency, and vitamin A supplementation
improved night vision. Several groups, including our own,
have shown that some individuals with cirrhosis require not
only vitamin A but also zinc supplementation to correct or
improve their dark adaptation.42,43 Zinc and vitamin A interact
on many different levels, including production of retinol-bind-
ing protein and activity of retinol dehydrogenase. Studies in
zinc-deficient experimental animals also demonstrated pro-
gressive anatomic deterioration of the retina.44,45 Similar reti-
nal degeneration was observed in a patient with AE.46 Thus,
there is strong clinical and experimental evidence that zinc
affects retinal function, and zinc supplementation may improve
dark adaptation in some patients with liver disease.
Anorexia With Altered Taste/Smell
A major and initial manifestation of zinc deficiency is anorexia
with subsequent weight loss.47 The mechanism(s) by which
zinc deficiency produces anorexia is unknown. Initially,
alterations in taste acuity and in circulating amino acids were
implicated as etiologic factors.48,49 We showed that zinc defi-
ciency in the rat affected catecholamine levels in total brain
and in specific regions of the hypothalamus. We demonstrated
that zinc-deficient animals are resistant to the central adminis-
tration of known inducers of food intake such as norepineph-
rine and muscimol.50 Zinc is extremely important for normal
membrane structure and function.51 We speculated that there is
a decrease in receptor responsivity in the zinc-deficient ani-
mal, possibly secondary to alterations in membrane fluidity,
which may explain, at least partially, the severe anorexia noted
in these animals.
Patients with alcoholic liver disease frequently complain of
anorexia and have decreased food consumption.52,53 Patients
with acute liver disease also frequently complain of unpleasant
olfactory and gustatory sensations, and this usually improves
as the liver disease resolves. Burch et al54 reported decreased
taste and smell acuity in cirrhotics with hypozincemia. Smith
et al55 demonstrated objective disordered gustatory acuity in
both viral hepatitis patients and patients with chronic liver
disease (both groups had hypozincemia).
Hypogonadism
Zinc deficiency is a well-recognized cause of hypogonadism
in experimental animals and humans.56 Chronic alcoholics
with and without liver disease and other patients with liver
disease of multiple etiologies may have hypogonadism.57 The
hypogonadism of zinc deficiency appears to be primarily a
gonadal defect.56,58 Adequate levels of gonadotrophins and
intact gonadotrophin response to luteinizing hormone–releas-
ing hormone have been demonstrated in zinc-deficient ani-
mals. Zinc-deficient animals have reduced basal testosterone
levels and depressed weights of testes and other androgen-
sensitive organs compared with zinc-sufficient controls.58
Humans fed a zinc-deficient diet developed decreased libido,
depressed serum testosterone levels, and marked reduction in
sperm counts.59,60 Moreover, zinc supplementation signifi-
cantly increased serum testosterone in elderly men with mar-
ginal zinc deficiency. Zinc is also required for maintenance
of sperm cells, progression of spermatogenesis, and sperm
motility.61,62
Depressed Wound Healing
The role of zinc in nucleic acid metabolism, in the synthesis of
structural proteins such as collagen, and in a host of enzymatic
pathways makes zinc balance important for wound healing. A
clinical role for zinc in wound healing was initially postulated
by Pories et al63 with the observation of improved healing of
pilonidal sinuses with zinc administration. Subsequent con-
trolled studies by Hallböök and Lanner64 demonstrated that zinc
supplementation improved wound healing in patients with both
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Zinc and Liver Disease / Mohommad et al 11
venous leg ulcers and decreased serum zinc concentrations.
Several investigators then reported depressed wound healing in
experimental animal models (eg, thermal and excised wounds,
gastric ulcers) in zinc-deficient compared to zinc-sufficient ani-
mals.65,66 Recent studies have supported the important clinical
role of zinc in wound healing, especially in leg ulcers.
Hepatocyte regeneration after liver injury represents a form
of wound healing. After partial hepatectomy or liver injury,
hepatocytes undergo a synchronized, multistep process con-
sisting of priming/initiation, proliferation, and termination.
These steps are essential for restoring the structure and func-
tions of the liver. The regenerating liver requires a large amount
of zinc over a short period of time. This demand is met, in part,
by induction of the zinc/copper binding protein metallothio-
nein.67 Metallothionein can transfer zinc to various metalloen-
zymes and transcription factors, and metallothionein knockout
mice have impaired liver regeneration.68 Thus, zinc is essential
for wound healing at peripheral sites as well as for liver
regeneration.
Altered Immune Function
The effect of zinc deficiency on immune function in humans
was initially studied in children with AE.69 Leukocyte function
and cell-mediated immunity were impaired in these children
and corrected with zinc supplementation. Golden et al70
described thymic atrophy in children with protein energy mal-
nutrition and zinc deficiency, and this thymic atrophy reversed
with zinc supplementation. We reported 2 patients who devel-
oped severe zinc deficiency with acrodermatitis while on PN.
These patients had cutaneous anergy and markedly depressed
T cell response to phytohemaglutinin,71 which corrected with
zinc supplementation alone.
Results from these early human studies have been sup-
ported by a variety of in vitro and animal research document-
ing a critical role for zinc in multiple aspects of innate and
adaptive immunity. Well-established effects of zinc deficiency
include thymic atrophy, alterations in thymic hormones, lym-
phopenia, and compromised cellular and antibody-mediated
responses, which can result in increased rates and duration of
infection.72-74
Recent studies in experimental animals and humans support
the concepts of dysregulated zinc metabolism during infec-
tions and zinc deficiency increasing morbidity and mortality
following infection. Work from Knoell’s laboratory showed
that zinc deficiency increases systemic inflammation, organ
damage, and mortality in a small animal model of sepsis.75
Using a cecal ligation and puncture model, they showed that
zinc-deficient animals had increased bacterial burden,
enhanced nuclear factor–κB (NF-κB)–binding activity,
increased expression of NF-κB-targeted genes such as tumor
necrosis factor (TNF)-α and ICAM-1, and increased acute-
phase proteins. Similarly, genome-level expression profiling in
patients with pediatric septic shock demonstrated that altered
zinc homeostasis predicted poor outcome.76 Of the genes most
prominently up- or downregulated, many play important roles
in zinc homeostasis. We postulate that patients with liver dis-
ease who have underlying dysregulated zinc homeostasis will
have this altered zinc metabolism exacerbated by infection or
inflammation, potentially leading to poor outcome.
Zinc Metabolism
Zinc is an essential nutrient for a broad range of biological
activities. In the United States, the Recommended Dietary
Allowance (RDA) is 8 mg/d for women and 11 mg/d for men
older than age 19. Red meats, especially beef, lamb, and liver,
as well as certain sea foods (eg, oysters), have some of the
highest concentrations of zinc in food. Zinc and dietary protein
directly correlate with each other. Patients with liver disease,
especially ALD, often have poor diets that are low in protein
and low in zinc. Moreover, some dietary fibers/phytates can
reduce zinc absorption. Absorption of zinc is concentration
dependent and occurs throughout the small intestine (mainly
the jejunum). Absorption may be impaired in cirrhosis, and
typically there is increased urinary excretion of zinc in
cirrhosis.12
Zinc absorption, transfer, and excretion are accomplished
by 2 large classes of transporters that tend to have opposing
effects (ZnT proteins and Zip transporters).73,77-79 The Zip fam-
ily of transporters move zinc from the extracellular space into
the cellular cytoplasm. Indeed, Zip4 plays a major role in intes-
tinal zinc absorption, and a lack of this transporter causes acro-
dermatitis enteropathica. The ZnT proteins generally work in
opposition to the Zip transporters.
Zinc status and the serum zinc level drop with low dietary
zinc intake. There normally are multiple mechanisms in place
to protect against zinc deficiency, including increased absorp-
tion and decreased excretion via modification of zinc trans-
porters.77,79 Zinc status is typically assessed by plasma/serum
zinc concentration. However, inflammation/stress hormones
may cause a decrease in serum zinc level, with an internal
redistribution of the zinc (Figure 2).13,14,79 This stress response
is often associated with hypoalbuminemia. Albumin is a major
binding protein for zinc, but the serum zinc concentration will
decrease with an inflammatory stimulus even in the absence of
hypoalbuminemia (Figure 2).13 This is mediated at least in part
by changes in zinc transporters, especially induction of Zip14
and induction of hepatic metallothionein.73 Metallothionein is
a metal-binding protein that serves many functions, including
zinc transport, antioxidant activity, and modulation of zinc
absorption.8,77,79 Indeed, ingestion of pharmacologic amounts
of zinc causes induction of intestinal metallothionein, which
then inhibits intestinal copper uptake and induces negative
copper balance in the treatment of Wilson disease (discussed
subsequently).
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12 Nutrition in Clinical Practice 27(1)
Although we are beginning to learn about the role of zinc
transporters in experimental inflammation and in human infec-
tions, no studies to date in human cirrhosis have evaluated this
important topic. Expanded knowledge of intracellular zinc
metabolism and the role of zinc transporters in liver disease
will enhance our understanding concerning altered zinc metab-
olism and zinc therapeutic effects in liver disease.
Zinc and Alcoholic Liver Disease
ALD continues to be a major cause of morbidity and mortality
in the United States. Two-thirds of Americans consume alco-
hol, and an estimated 14 million Americans are alcoholics.80 It
has been estimated that 15%–30% of heavy drinkers develop
advanced ALD. Alcoholic cirrhosis accounts for more than
40% of all deaths from cirrhosis and for 30% of all hepatocel-
lular carcinomas.80-82 Significant advances have been made in
our understanding of the pathophysiologic mechanisms of
ALD. However, there is still no Food and Drug Administra-
tion (FDA)–approved therapy for this common and often dev-
astating disease. Interactions between the bowel, immune
system, and the liver are critical components of ALD. In this
model, chronic alcoholism results in changes to the intestinal
epithelial barrier, leading to increased gut permeability.83 Sub-
sequently, endotoxin or lipopolysaccharide (LPS), a compo-
nent of the gram-negative bacterial cell wall, translocates
across the disrupted intestinal barrier and enters the portal
venous circulation to stimulate primed Kupffer cells. This
results in both proinflammatory cytokine production and gen-
eration of reactive oxygen species, key mediators of ALD
(Figure 3).81-83 Zinc deficiency is well documented in both
humans with alcoholic cirrhosis and in animal models of
ALD.8 In a representative human study, the serum zinc con-
centration in alcoholic patients was 7.52 µmol/L, which was
significantly lower than 12.69 µmol/L in control subjects.84
Moreover, the decrease in serum zinc correlates with progres-
sion of liver damage. Patients with alcoholic cirrhosis had a
lower serum zinc level (80 µg/dL) than noncirrhotic patients
(97 µg/dL), decreased by –37% and –24%, respectively, com-
pared with healthy individuals (127 µg/dL).85 We have dem-
onstrated that zinc supplementation attenuates ethanol-induced
liver injury in murine models.8,86-90 Importantly, zinc pro-
tected intestinal barrier function to prevent endotoxemia,
reducing both proinflammatory cytokine production and oxi-
dative stress (Figure 4). These data provide a strong rationale
for zinc supplementation in human ALD. Below, we discuss
in greater detail the effects of zinc deficiency/zinc supplemen-
tation on specific pathways for ALD.
Alcohol, Gut Permeability, Endotoxemia, and
Proinflammatory Cytokine Production
As noted above, endotoxemia plays an important role in the
development of ALD through stimulating proinflammatory
cytokine production.83 Disruption of the intestinal barrier
has been suggested to be a leading cause of alcohol-induced
endotoxemia.83 Alcoholic patients showed increased gut per-
meability to a variety of permeability markers, such as
polyethyleneglycol, mannitol/lactulose, or 51CrEDTA.91-94 In
Time (Hours)
0122436486072
Zinc
(µg/dL)
0
20
40
60
80
100
120
LPS-1 LPS-2
Saline controls (n=12)
LPS volunteers (n=12)
Figure 2. Healthy volunteers were injected intravenously with
low-dose endotoxin or lipopolysaccharide (LPS). There was a
marked reduction in the serum zinc level, which nearly normalized
by 24 hours. A second dose of LPS caused a similar reduction in
serum zinc. Injection of vehicle caused no significant reduction
in zinc. Importantly, this very low dose of endotoxin caused no
changes in the serum albumin.13 Thus, the hypozincemia was not
secondary to a drop in the serum albumin level.
Altered Gut Flora
Increased gut permeability
Increased LPS/Gut derived toxins
Increased TLR4 activation
Increased TNF production
Liver injury
Figure 3. This graph depicts the gut-liver axis in alcoholic
liver disease (ALD), beginning with altered gut flora and gut
leakiness, leading to endotoxin-stimulated cytokine production,
and, ultimately, liver injury and systemic inflammation. LPS,
lipopolysaccharide; TLR, toll-like receptor; TNF, tumor necrosis
factor.
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Zinc and Liver Disease / Mohommad et al 13
animal studies, gut permeability to macromolecules such as
horseradish peroxidase (HRP) was increased in association
with alcohol-induced plasma endotoxemia and liver dam-
age.95-98 We showed that orally administrated LPS can be
detected in the plasma of alcohol-intoxicated mice but not in
control mice,99 providing direct evidence that alcohol increases
gut permeability to endotoxin. Animal studies also showed that
preventing gut leakiness results in suppression of alcohol-
associated endotoxemia and liver damage, suggesting that gut
leakiness is a causal factor in the development of alcoholic
endotoxemia and liver injury.96,97,99
Because of the above-noted findings, we carried out a
series of studies to determine whether zinc deficiency is
related to the deleterious effects of alcohol on the intestinal
barrier. We fed mice an alcohol or isocaloric liquid diet
for 4 weeks, and liver injury was detected in association
with elevated blood endotoxin level.100 Alcohol exposure
significantly increased the permeability of the ileum.
Reduction of tight-junction proteins in the ileal epithelium
was observed in alcohol-fed mice. Alcohol exposure signifi-
cantly reduced the ileal zinc concentration in association with
accumulation of reactive oxygen species. Using in vitro stud-
ies, Caco-2 cell cultures demonstrated that alcohol exposure
increased the intracellular free zinc because of oxidative
stress. Zinc deprivation caused epithelial barrier disruption in
association with disassembling of tight junction proteins in
the Caco-2 monolayer cells.100 Furthermore, minor zinc
deprivation exaggerated the deleterious effect of alcohol on
the epithelial barrier.100 In summary, alcohol disrupts intesti-
nal barrier function and induces endotoxemia, in part, by
causing alterations in intestinal zinc homeostasis. Zinc sup-
plementation partially protects against this increased perme-
ability, endotoxemia, increased cytokine production, and
subsequent liver injury.
Figure 4. Zinc deficiency can disrupt intestinal-barrier function in vitro (a), and zinc deficiency can enhance alcohol-induced intestinal-
barrier dysfunction (b). (a) Effect of zinc deprivation on the epithelial barrier of Caco-2 cells. Caco-2 cells were cultured on inserts and
treated with N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) at 2, 3, and 4 µM or 4 µM TPEN plus 100 µM zinc for 24
hours. The epithelial barrier function was assessed by measuring transepithelial electrical resistance (TEER) and FD-4 permeability.
Results are means ± SD (n = 8). Significant differences (P < .05, analysis of variance [ANOVA]) are identified by different letters, a–e. T,
TPEN. (b) Sensitizing effect of zinc deprivation on alcohol-induced epithelial barrier dysfunction. Caco-2 cells were cultured on inserts
and treated with TPEN at 2 µM for 24 hours, followed by treatment with 5% (vol/vol) ethanol for 5 hours. The epithelial barrier function
assessed by measuring TEER and FD-4 permeability. Results are means ± SD (n = 8). Significant differences (P < .05, ANOVA) are
identified by different letters, a–c. From Zhong et al.100
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14 Nutrition in Clinical Practice 27(1)
Oxidative Stress
Zinc can attenuate oxidative stress through introduction
of metallothionein and through multiple other mechanisms,
such as inhibiting TNF and modulating multiple enzymes. Zinc
supplementation in a mouse model of ALD attenuated alcohol-
induced liver injury as measured by histopathological and ultra-
structural changes, serum alanine transferase activity, and
hepatic TNF-α levels. Zinc supplementation inhibited accumu-
lation of ROS as indicated by dihydro-ethidium fluorescence
and the subsequent oxidative damage as assessed by immuno-
histochemical detection of 4-hydroxynonenal and nitrotyrosine
and quantitative analysis of malondialdehyde and protein car-
bonyl in the liver.101 Zinc supplementation suppressed alcohol-
elevated CYP 2E1 activity but increased the activity of alcohol
dehydrogenase in the liver. Zinc supplementation also pre-
vented alcohol-induced decreases in glutathione (GSH) con-
centration and glutathione peroxidase activity and increased
glutathione reductase activity in the liver.8,101
Apoptosis
Apoptosis is a major mechanism of hepatocyte death in ALD.
We evaluated the possible beneficial effects of zinc therapy in
experimental ALD. Adult male mice fed an alcohol liquid diet
for 6 months developed hepatitis as indicated by neutrophil
infiltration and elevation of the chemokines, keratinocyte che-
moattractant, and monocyte chemoattractant protein-1. Apop-
totic cell death was detected in alcohol-exposed mice by a
terminal deoxynucleotidyl transferase dUTP nick end labeling
(TUNEL) assay and confirmed by the increased activities of
caspase-3 and -8. Zinc supplementation attenuated alcoholic
hepatitis and reduced the number of TUNEL-positive cells in
association with inhibition of caspase activities.90 The mRNA
levels of TNF-α, TNF-R1, FasL, Fas, FAF-1, and caspase-3 in
the liver were upregulated by alcohol exposure and were atten-
uated by zinc supplementation.89,90 Zinc supplementation also
prevented elevated serum and hepatic TNF-α levels and TNF-α
R1 and Fas proteins in the liver associated with alcohol feed-
ing. Thus, zinc supplementation attenuated the increase in fac-
tors known to be associated with hepatic apoptosis.8,90
Zinc Supplementation and Human ALD
There have been multiple studies showing that zinc supple-
mentation reverses known manifestations of zinc deficiency in
ALD, such as impaired night vision, skin lesions, and, in some
cases, encephalopathy and immune dysfunction.12 Studies
have been performed to determine the duration and amounts of
zinc necessary to improve serum and hepatic zinc in patients
with ALD. Alcoholic patients without cirrhosis received zinc
sulfate at 600 mg/d for 10 days and alcoholic cirrhotics for 10,
30, and 60 days.102 Serum zinc concentrations increased to
normal values in all groups of patients during 10 days to 2
months of zinc supplementation. Zinc concentrations in the
liver biopsies were significantly increased in patients with cir-
rhosis after zinc supplementation for 10 and 60 days, but some
patients remained under normal values, particularly those with
cirrhosis. No adverse reactions of zinc supplementation were
observed in this short-term study.
A long-term oral zinc supplementation (200 mg tid
for 2–3 months) in cirrhotic patients, including alcoholics, pro-
duced beneficial effects on both liver metabolic function and
nutrition parameters.103 Quantitative liver function tests,
including galactose elimination capacity and antipyrine clear-
ance, improved following oral zinc supplementation. Similarly,
the Child-Pugh score, an overall clinical estimation of hepato-
cellular failure, was improved by zinc supplementation on
average by greater than 1 point. Zinc supple-mentation also
significantly improved nutrition parameters, such as serum
prealbumin, retinol-binding protein, and insulin-like growth
factor 1 (IGF-1). Indeed, the serum IGF-1 increased approxi-
mately 30% after zinc therapy. However, the nutrition param-
eters remained on average below the lower limit of the normal
range.103 Studies evaluating specific mechanisms of action of
zinc in ALD and long-term outcome studies are needed.
Zinc and Viral Liver Disease
HCV
Approximately 3% (~170 million) of the world’s population
has been infected with HCV. For most countries, the preva-
lence of HCV infection is <3% (2% in United States).104,105
Approximately 70% of acute HCV infection progresses to
chronic liver disease. The current standard of care for chronic
HCV infection is based on the combination of pegylated inter-
feron and ribavirin. Approximately 40%–50% of genotype 1,
by far the most frequent HCV genotype in the United States, is
cured with this type of therapy. Specific protease inhibitors,
telaprevir and boceprevir, became available in 2011, and this
new addition to the interferon and ribavirin regimen should
substantially increase the cure rate of both naive patients and
many individuals who have already been treated.104,105
Similar to ALD, the serum levels of zinc are often decreased
in HCV patients, and serum levels also tend to negatively cor-
relate with hepatic reserve and to decrease with interferon-
based therapy.105-108 Serum zinc levels are not only decreased
in many patients with hepatitis C, but there are functional cor-
relations with the reduced serum zinc levels. For example,
patients have reduced taste sensitivity that correlates with their
reduced serum zinc levels. Moreover, it is increasingly recog-
nized that some patients with hepatitis C have decreased skin
levels of zinc as well as serum zinc levels.106 HCV patients
may present with necrolytic acral erythema, which responds to
zinc supplementation (discussed above).
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Zinc and Liver Disease / Mohommad et al 15
There are many therapeutic reasons why zinc may be ben-
eficial in the treatment of hepatitis C, including (1) antioxidant
function, (2) regulation of the imbalance between TH1 and
TH2 cells, (3) zinc enhancement of antiviral effects of inter-
feron, (4) inhibitory effects of zinc in the HCV replicon sys-
tem, and (5) hepatoprotective effects of metallothionein.105,109
Several studies have evaluated the role of zinc as an adjunct
therapy for eradication of the HCV. Initial studies indicated
that administration of zinc in combination with interferon was
more effective than interferon alone.110,111 However, in subse-
quent studies, when pegylated interferon and ribavirin were
used in combination, the addition of zinc generally produced
limited benefits on viral clearance.112 Some of these combina-
tion studies have shown improved transaminases or fewer
medication side effects while on zinc therapy.113-115
Although the beneficial effects of zinc as an adjunct antivi-
ral therapy for hepatitis C appear to be limited, there is promis-
ing evidence that zinc may decrease liver injury and provide
antifibrotic effects in patients with chronic HCV. Himoto and
coworkers107 used polaprezinc as an antifibrotic therapy in
patients with chronic hepatitis C and showed a decrease in
noninvasive fibrosis markers. Subsequently, Matsuoka and
coworkers116 treated chronic HCV patients for 3 years with
polaprezinc 150 mg bid. Zinc therapy was associated with
improvement of aspartate aminotransferase (AST) and alanine
aminotransferase (ALT). Interestingly, patients with lower zinc
concentrations showed later reduction in liver enzymes follow-
ing zinc supplementation. There was also a suggestion that the
risk for hepatocellular carcinoma (HCC) may also be lower in
zinc-supplemented patients.
Hepatitis B Virus
Hepatitis B virus (HBV) is an even more serious public health
problem, with more than 350 million infected people world-
wide. Serum zinc levels are significantly decreased in patients
with acute hepatitis B infection and are frequently depressed
with HBV cirrhosis (similar to HCV cirrhosis).117,118 Specifi-
cally designed zinc finger proteins had been used in an attempt
to inhibit HBV viral transcription with some success, and this
is a potential therapeutic target for new HBV drugs.119 Impor-
tantly, marginal zinc deficiency appears to impair the efficacy
of hepatitis B vaccination.120 This is another example of how
zinc deficiency may impair immune function with special rel-
evance to liver disease.
Zinc and Other Liver Diseases
Wilson Disease
Wilson disease is an autosomal recessive disorder of copper
metabolism. Zinc was first used to treat Wilson disease in
the Netherlands as early as the 1960s. Zinc acetate was
approved for maintenance therapy by the FDA in 1997,
based on research that showed that zinc caused a negative cop-
per balance, controlled urine and plasma copper levels,
removed stored copper, and protected the liver, at least in part,
by inducing the expression of intestinal and hepatic
metallothionein.121-123
Metallothionein is mainly a cytosolic peptide with a high
cysteine content that binds metals such as zinc and copper
quite avidly (copper having a higher affinity). In the cytosol of
enterocytes, metallothionein binds newly absorbed copper and
prevents it from passing from the intestine into the circulation.
Shed enterocytes with copper still bound to metallothionein
then result in a high fecal copper content and loss of copper
from the body.121-123 The dose that is frequently used for adults
with Wilson disease is 50 mg elemental zinc 3 times a day. The
multiple dosing regimen is critical to impair copper absorp-
tion. Many investigators have also used zinc therapy for pri-
mary treatment of Wilson disease. However, recent
communications have suggested that some patients are resis-
tant to zinc therapy.124-126 Moreover, compliance is often an
issue, especially in asymptomatic patients on long-term ther-
apy.124-126 Thus, if zinc is to be used for Wilson disease therapy
(especially primary therapy), careful patient monitoring and
documentation of compliance are critical. Zinc therapy is an
attractive therapeutic agent because it is inexpensive and rela-
tively nontoxic compared to chelation therapy.
Hepatocellular Carcinoma
HCC is the third leading cause of cancer mortality worldwide
and the ninth leading cause of cancer deaths in the United
States.127 Its incidence and mortality rates in the United States
are increasing. The survival rate continues to be dismal with an
overall 5-year survival of only 13%.128 The high mortality is
due to late-stage detection of this cancer when most of the
therapies available are not effective. Globally, 78% of HCC
can be attributed to chronic HBV and chronic HCV viral infec-
tion.129 In United States, alcoholism is the most common cause
of HCC.130
Several groups have reported decreased serum levels of
zinc in HCC patients. In a case-control study comparing
patients with HCC, cirrhosis, and benign digestive disease,
serum levels of Zn in patients with HCC were significantly
lower than in those patients with benign digestive disease and
similar to levels in cirrhotic patients.131 Nakayama et al132
reported depressed levels of zinc in patients with chronic hepa-
titis and hepatocellular carcinoma compared to healthy volun-
teers. They also tested the metallothionein levels of these
individuals and found that patients with cirrhosis and hepato-
cellular carcinoma had levels significantly lower than those in
patients with chronic hepatitis and controls. When levels of
zinc in HCC tumor tissue were studied, they were found to be
significantly decreased compared to surrounding nontumor tis-
sue, and levels in nontumor tissue were significantly lower
than normal liver tissue.133-141 Kubo et al142 investigated
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16 Nutrition in Clinical Practice 27(1)
metallothionein (MT) levels by high-performance liquid chro-
matography (HPLC) analysis in resected HCC tumors, sur-
rounding noncancerous but diseased hepatic tissue, and normal
liver tissue obtained from autopsies done on patients with no
liver disease. They found that MT existed mainly as Zn-MT in
normal hepatic tissue, whereas in the noncancerous paren-
chyma surrounding HCC, the Zn-MT was replaced to a signifi-
cant extent by Cu,Zn-MT. In the cancerous tissue, the Cu,Zn-
MT was largely displaced by Cu-MT, and Zn-MT was
undetectable.
It is unclear if these changes in serum and tissue zinc con-
centrations contribute to the initiation or promotion of HCC or
whether they are the effects of malignant transformation.
Studies are under way to try to elucidate the mechanisms under-
lying these phenomena. Somewhat conflicting data have
emerged. Most recently, Franklin et al143 have reported a down-
regulation of ZIP14 gene expression and the near absence of the
protein within hepatoma cells in core biopsy samples, which
could explain the decrease in intracellular zinc levels in HCC.
ZIP14 localizes to the cell membrane of normal hepatocytes
and is a functional transmembrane transporter involved in the
uptake of zinc into the cell.144,145 Thus, its downregulation may
explain the decreased zinc levels in hepatoma cells. Because Zn
has been proposed to have anticancer properties in multiple sys-
tems, the authors suggest that intracellular levels of zinc are
downregulated early in HCC to suppress its antitumor effect.
The human hepatoma cell line HepG2 does not lose the ZIP14
transporter. Interestingly, exposure of HepG2 cells to even
physiologic concentrations of Zn (5 µM) inhibits their growth
by about 80%.143 On the other hand, Weaver et al146 observed an
upregulation of the zinc transporter ZIP4 gene expression in
human and mouse HCC tissue compared with surrounding non-
cancerous tissue. In fact, ZIP4 protein was rarely found in non-
cancerous tissue, but it was abundant in the cancerous tissue.
They then inhibited ZIP4 in Hepa cells (mouse hepatoma cell
line) using a RNAi-expressing lentivirus vector, and this
increased apoptosis and modestly slowed progression from G0/
G1 to S phase when these cells were released from the hydroxy-
urea block into the zinc-deficient medium but not in the zinc-
adequate medium. Furthermore, migration of these cells
through a fibronectin-coated membrane was inhibited.146
Unfortunately, they did not measure zinc levels in these sam-
ples, so it is not known how the aberrant expression of ZIP4 in
HCC tissue noted in this study affected tumor zinc levels.
Conclusions and General Recommendations
Zinc deficiency occurs in many types of liver disease, espe-
cially more advanced/decompensated disease. Zinc supple-
mentation has been best studied in experimental models of
ALD where it blocks most mechanisms of liver injury, includ-
ing increased gut permeability, endotoxemia, oxidative stress,
excess TNF production, and hepatocyte apoptosis. Zinc may
have some limited antiviral effect in HCV therapy. Impor-
tantly, zinc therapy has shown some promising antifibrotic
effects in chronic HCV. The dose of zinc we currently admin-
ister is 50 mg of elemental zinc (220 mg zinc sulfate) per day
orally with a meal. Because of its effects on multiple targets
and its relative lack of toxicity, we tend to give zinc long-term
(months to years) or at least until the serum zinc level has nor-
malized. Multiple forms of zinc are available, with some of the
most widely used including zinc sulfate, zinc gluconate, zinc
acetate, zinc picolinate, and others. To our knowledge, zinc
acetate is the only zinc supplement requiring a prescription,
and extensive information on these supplements, including
tablet dosing, is available on the Internet.
Most forms of zinc salts have nausea and epigastric
distress as potential side effects. Consuming zinc with
a meal or switching types of supplements (eg, switch
from zinc sulfate to zinc gluconate or acetate) may lessen these
symptoms. We use a once-daily dose of 50 mg elemental zinc
to not inhibit copper absorption. In Wilson disease, split doses
(usually 50 mg of elemental zinc 3 times per day, separated
from meals) are required to cause appropriate reduction in cop-
per burden. Moreover, it appears that some patients may not be
zinc responsive, and adherence to therapy and careful monitor-
ing are absolutely critical.
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Nutrition in Clinical Practice
Volume 27 Number 2
April 2012 305
© 2012 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533612441470
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hosted at
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Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and liver disease. Nutr Clin Pract. 2012;27:8-20. (Original DOI
10.1177/0884533611433534)
The first author’s name was spelled incorrectly as Mohammad K. Mohommad. It should have been spelled Mohammad K.
Mohammad.
Erratum