World Journal of Cardiovascular Diseases, 2013, 3, 499-505 WJCD
http://dx.doi.org/10.4236/wjcd.2013.38079 Published Online November 2013 (http://www.scirp.org/journal/wjcd/)
Hyperhomoysteinemia as a risk factor for coronary heart
diseases in chronic hepatitis C patients
Ali Raza Kazmi1, Andleeb Hanif1,2, Muhammad Ismail1, Javaria Qazi2
1Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan
2Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan
Email: drsakazmi@gmail.com
Received 20 August 2013; revised 28 September 2013; accepted 15 October 2013
Copyright © 2013 Ali Raza Kazmi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Hepatitis C virus is one of the major health problems
worldwide. It affects mainly the liver but several ex-
trahepatic manifestations are also accounted. Chronic
hepatitis C patients are at an increased risk of devel-
oping hepatic steatosis, which share many clinical fea-
tures with the metabolic syndrome. Hepatic steatosis
has also been associated with elevated levels of mark-
ers of inammation such as homocysteine, identified
as hyperhomocysteinemia (HHC). HHC due to Me-
thylenetetrahydrofolate Reductase (MTHFR) gene, in
particular the C677T polymorphism, was recently as-
sociated with coronary heart diseases (CHD) in chro-
nic hepatitis C (CHC) patients. Homocysteine is an
intermediate in methionine metabolism, which takes
place mainly in the liver metabolism. Deficiencies of
micronutrients (folate, vitamin B 6 and possibly vita-
min B 12) along with mild hyperhomocysteinemia,
perhaps, act synergistically with other classical risk
factors to further increase the risk of CHD. Clinical
data indicate that HHC is associated with an increa-
sed incidence of CHD as well as with the severity of
the disease in CHC patients. In conclusion, HHC
might be a potential aetiological factor of CHD in
CHC patients. The aim of this review is to investigate
the progression of coronary heart diseases in chronic
hepatitis C patients and correlate with levels of homo-
cysteine in concurrence to genetic defects and nutri-
ent deficiencies. However, future studies need to clari-
fy the mechanistic role of HHC in CHD and CHC as a
useful paradigm with most interesting therapeutic im-
plications.
Keywords: Hepatitis C Virus; Hyperhomocysteinemia
(HHC); Coronary Heart Diseases (CHD); Chronic
Hepatitis C (CHC)
1. INTRODUCTION
Chronic infection with hepatitis C virus (HCV) is one of
the leading causes of chronic liver disease; about 170
million people worldwide are estimated to be infected.
Hepatitis C virus infection causes acute symptoms in
only 15% of patients exposed to HCV infection while
about 80% patients develop chronic infection [1]. Chro-
nic hepatitis C results in formation of high levels of free
radicals in the liver cells, which put serious oxidative
stress depleting protective antioxidants and eventually
kill the liver cells. A hepatitis screen is recommended for
patients whereby the disease can be diagnosed by the
presence of antibodies for hepatitis C or by the direct
presence of the virus or viral products in the blood [2].
2. ASSOCIATED RISKS: CHRONIC
HEPATITIS C
Hepatitis C virus (HCV) infection is a major cause of
chronic liver disease. HCV infection frequently does not
resolve, leading to chronic hepatitis with increasing risk
of developing hepatic fibrosis, steatosis, liver cirrhosis,
hepatocellular carcinoma, metabolic syndromes, arthro-
sclerosis and extrahepatic diseases [3]. The combination
of pegylated interferon (IFN)-a and ribavirin is the only
treatment for chronic HCV infections with proven effi-
cacy.
Unfortunately, this therapeutic strategy results in a low
sustained virologic response (SVR), defined as an ab-
sence of detectable serum HCV-RNA at six months after
completion of antiviral therapy; SVR is achieved in less
than 50% of treated patients that have HCV genotype 1
and a high viral load [4]. There is evidence indicating
that SVR is associated with long-term clearance of HCV
infection and lower HCV-related complications [5,6].
However, IFN-a in combination with ribavirin is gene-
rally not well tolerated, and the adverse side effects may
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A. R. Kazmi et al. / World Journal of Cardiovascular Diseases 3 (2013) 499-505
500
lead to interruption or cessation of therapy. The major
adverse effects are anemia, fatigue, hair loss, depression,
insomnia, vertigo, anorexia, nausea, nasal congestion,
cough, dyspnea, pruritus, and growth delay [7].
3. HEPATITIS C VIRUS AND CARDIAC
RISK
Chronic hepatitis C virus (CH-C) infection is associated
with metabolic conditions such as insulin resistance and
type 2 diabetes (T2DM) and may increase the risk of
coronary heart diseases. Coronary artery disease is the
most common heart disease with multifactorial etiology.
Atherosclerosis being the principal cause has plagued
human kind since ancient times. Its understanding has
much evolved over centuries, traditionally being viewed
as degenerative disease, is now considered a dynamic in-
flammatory and fibroproliferative process, triggered by
cytokines and growth factors [8-12]. In addition to other
conventional atherogenic risk factors (Age, Sex, Smok-
ing, Hypertension, Diabetes Mellitus and Dyslipidaemia),
one of the most interesting development in the recent
years has been the idea that infective agents may induce
a pro-inflammatory state and have a crucial role in athe-
rothrombosis [12-14].
4. INADEQUATE VITAMINS AND HCV
Patients with chronic HCV infection have significantly
lowered plasma vitamin B1, B2, B6, C, and folic acid
levels [15]. These patients were also observed to have
significantly higher plasma homocysteine (a sulfur-con-
taining amino acid, which is influenced by vitamin B2, 6,
12, and folic acid) concentrations and lower concentra-
tions of folic acid and vitamin B12 [16]. The plasma ho-
mocysteine levels were inversely correlated with the con-
centrations of folic acid in HCV-infected patients. SVR
patients have been observed to have lower plasma homo-
cysteine levels than non-SVR patients [17]. Pre-treat-
ment with IFN-a and ribavirin in chronic HCV-infected
patients, serum vitamin B12 levels are positively corre-
lated to end-of-treatment response [18].
Several infectious etiologies for coronary heart dis-
eases (CHD) have been proposed in recent years on the
basis of epidemiological associations, but there is no
consensus regarding a causative role [19-21]. The asso-
ciation between hepatitis C virus (HCV) infection and
CHD is less clear. A small number of reported studies
have shown conflicting results; some have reported no
association between HCV infection and CHD [22-25],
whereas others have reported an increased risk [26] or an
increase in measures of subclinical atherosclerosis (e.g.,
carotid intima-media thickness) [26-28]. Many of the
studies showing no association between HCV infection
and CHD used a case-control design in which subjects
with known CHD were compared with control subjects
without CHD and the prevalence of HCV infection was
compared between the 2 groups without adjustment for
all Coronary artery diseases (CAD) risk factors. However,
Persons with HCV infection are at an increased risk of
developing hepatic steatosis, which shares many clinical
features with the metabolic syndrome [29,30]. Hepatic
steatosis has also been associated with elevated levels of
markers of inflammation and endothelial dysfunction
[31]. Hepatitis C virus increases the risk of coronary ar-
tery disease, a large American study published in the Cli-
nical Infectious Diseases [32]. These factors suggest a
biologically plausible mechanism of increased risk of
CHD in at least a subset of HCV-infected persons.
The main rationale of this review is shown in Figure
1.
5. HOMOCYSTEINE METABOLISM
Homocysteine (Hcy) belongs to a group of molecules
known as cellular thiols. It is considered a “bad thiol”
because its association with a variety of health conditions
including cardiovascular disease, [33] end-stage renal di-
sease, [34] neural tube defects, [35]. Recently, homo-
cysteine has also been implicated in the pathogenesis of
alcoholic liver injury [36].
The 5,10-methylenetetrahydrofolate reductase (MTHFR)
is a key enzyme in the folate cycle and contributes to the
metabolism of the amino-acid homocysteine. It irreversi-
bly catalyzes the reduction of 5,10-methylene-tetrahy-
drofolate to 5-methyltetrahydrofolate, the major circula-
tory form of folate in the body and a carbon donor for
conversion of homocysteine to methionine, precursor of
S-adenosyl-L-methionine [37].
6. HOMOCYSTEINE AND CHRONIC
HEPATITIS C
Homocysteine levels are also altered in chronic liver di-
sease. Homocysteine is a sulphur containing amino acid
belonging to the group of intracellular thiols. Numerous
Figure 1. Rationale of study.
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A. R. Kazmi et al. / World Journal of Cardiovascular Diseases 3 (2013) 499-505 501
clinical and epidemiological studies have reported that
elevated plasma homocysteine concentrations reflect im-
paired cellular metabolism [38] and may be considered
as an independent risk factor for atherosclerotic vascular
disease and thromboembolism [39]. Experimental data in
transgenic mice deficient in homocysteine metabolism
enzymes have shown the presence of severe liver steato-
sis with occasional steatohepatitis. In human beings, many
studies have found a correlation between homocysteine
and steatosis [40]
Homocysteine is mainly synthesized and metabolized
in the liver, since metabolism of majority of dietary me-
thionine occurs in this organ, where about 85% of the
whole body capacity for transmethylation resides. There-
fore, genes involved in methionine and homocysteine
metabolism are expressed in a specific pattern in the liver
[41]. Homocysteine is formed as an intermediate in me-
thionine metabolism; therefore, impaired liver function
leads to altered methionine and homocysteine metabo-
lism [42]. Plasma homocysteine levels were significantly
elevated in HCV infected patients in both sexes com-
pared with control values. These findings are in accor-
dance with the results of many studies observed elevated
plasma homocysteine levels in patients with liver cirrho-
sis secondary to hepatitis C virus infection [38]. Some of
the studies have attributed this condition to reduced ex-
pression of genes involved in Hcy metabolism. The de-
gree of reduced expression of these genes was related to
the severity of liver disease [40].
Alterations in Hcy metabolism in human liver cirrho-
sis can be ascribed in part to a marked reduction in the
expression of the main genes involved in its metabolism,
namely methionine synthase (MS) and betaine-homo-
cysteine methyltransferase (BHMT), which convert ho-
mocysteine back to methionine, and cystathionine-syn-
thase (CBS), the first enzyme in the transsulfuration
pathway[41]. The expression of these genes was always
more compromised than that of HSA and was related to
the severity of the disease, expressed as the Child-Pugh
score. We observe reduced expression of Hcymetaboliz-
ing genes, both in alcoholism and hepatitis C virus cir-
rhosis. It has been suggested that impairment of Hcy
metabolism in cirrhosis most possibly can be also related
to decreased availability or utilization of vitamins B6,
B12, or folates, [43].
7. HYPERHOMOCYSTEINEMIA
Elevated levels of homocysteine, Hyperhomocysteinemia
(HHC), may result from defects in homocysteine-me-
tabolizing genes; (such as MTHFR, Methylene tetrahy-
drofolate Reductase gene) vitamin B6, B12, or folate de-
ficiencies resulting from nutritional conditions; or chro-
nic alcohol consumption [40]. The hyperhomocysteine-
mia is known as atherogenic and thrombotic risk factor
for cardiovascular disease. It might also be a risk factor
for cirrhotic patients but the direct effect of Hcy on liver
injury is not well known [44].
Hyperhomosysteinemia was correlated with elevated
levels of ALT, ALP, TGs and cholesterol. This might be
related to progression of liver injury. Some other studies
have also reported a correlated elevation of plasma Hcy
levels with ALT, ALP, TGs and cholesterol [45,46]. It is
evident that homocysteine-induced endoplasmic reticu-
lum stress leaves a dysregulated endogenous sterol re-
sponse pathway, which leads to increased hepatic bio-
synthesis and uptake of cholesterol and triglycerides
[47].
8. GENETIC DEFECTS IN
HOMOCYSTEIN METABOLISM
Elevations in plasma homocyst(e)ine are typically caused
either by genetic defects in the enzymes involved in ho-
mocysteine metabolism or by nutritional deficiencies in
vitamin cofactors. Homocystinuria and severe hyperho-
mocyst(e)inemia are caused by rare inborn errors of me-
tabolism resulting in marked elevations of plasma and
urine homocyst(e)ine concentrations. Cystathionine b-
synthase deficiency is the most common genetic cause of
severe hyperhomocyst(e)inemia. The homozygous form
of this disease—congenital homocystinuria—can be as-
sociated with plasma homocyst(e)ine concentrations of
up to 400 mmol per liter during fasting [48]. The homo-
zygous trait is rare (occurring in 1 in 200,000 births), and
clinical manifestations include ectopialentis, skeletal de-
formities, mental retardation, thromboembolism, and se-
vere, premature atherosclerosis [49]. Atherothrombotic
complications frequently develop in young adulthood in
homozygotes and are often fatal, as first shown in a study
by Carey and colleagues as early as 1968 [49]. Mudd and
colleagues [50] have estimated that approximately 50
percent of untreated patients with homocystinuria will
have a thromboembolic event before the age of 30 and
that overall, the disease-related mortality is approxima-
tely 20 percent.
Heterozygotes typically have much less marked hy-
perhomocyst(e)inemia, with plasma homocyst(e)ine con-
centrations in the range of 20 to 40 mmol per liter, ap-
proximately two to four times greater than the normal
concentration of homocyst(e)ine in plasma [49,51-53]. A
homozygous deficiency of N5, N10-methylenetetra hy-
drofolatereductase, the enzyme involved in the vitamin
B12-dependent remethylation of homocysteine to me-
thionine, may also lead to severe hyperhomocyst(e)ine-
mia [54]. Patients with this type of deficiency tend to
have a worse prognosis than those with cystathionine
b-synthase deficiency, in part because of the complete
lack of effective therapy [55,56]. In addition, studies
(Kang and colleagues) [57] have reported a thermolabile
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A. R. Kazmi et al. / World Journal of Cardiovascular Diseases 3 (2013) 499-505
502
variant of N5, N10-methylene-tetrahydrofolate reductase
that is caused by a point mutation (MTHFR_C677T) in
the coding region for the N 5, N 10-methylene-tetrahy-
drofolate binding site, leading to the substitution of va-
line for alanine [58].
9. MTHFR: CT POLYMORPHISM
A single nucleotide polymorphism (SNP) in the MTHFR
gene, which is located in the chromosome 1p36.3, has
been identified. A C-to-T transition at the nucleotide 677
(C677T) in exon four results in an alanine to valine ex-
change which affects the catalytic domain of the enzyme;
as a consequence, a thermo-labile variant of MTHFR,
called t-MTHFR, is synthesized, which possesses redu-
ced enzyme activity [59].
One of the most common mutations, or polymor-
phisms, that are associated with a mild increase in
plasma homocysteine (hyperhomocysteinemia) is the
677CT substitution (an alanine to valine change) in the
enzyme methylenetetrahydrofolate reductase (MTHFR).
The MTHFR is an enzyme of the folate metabolism that
reduces 5,10-metilenetetraidrofolate (5,10-mTHFR) to
5-metiltetraidrofolate (5-mTHF), an important co-factor
to homocysteine (Hcy) methylation. Mutations in MTHFR
gene like C677T result in amino acids substitutions that
lead to a decreased enzyme activity [60,61]. As a conse-
quence of the MTHFR dysfunctions, an increased Hcy
level in plasma has been expected which, in turn, produ-
ces a cytotoxic effect [62].
10. CONCLUSION
Hepatitis C virus infection is a major cause of progres-
sive liver damage whose long term sequelae includes cir-
rhosis and primary hepatocellular carcinoma. HCV main-
ly affects the liver, but several tissues outside the liver
have been reported to be involved, resulting in a wide
spectrum of extrahepatic manifestations. Despite having
fewer risk factors for cardiovascular disease, the hepatitis
C-infected individuals were more likely to have been
diagnosed with coronary artery disease. Multiple pro-
spective and case-control studies have shown that a
moderately elevated plasma homocysteine concentration
is an independent risk factor for atherothrombotic vascu-
lar disease. Homocysteine concentrations are consistent-
ly higher in patients with peripheral, cerebrovascular, and
coronary artery disease than in those without such disea-
ses. Homocyst(e)ine promotes atherothrombogenesis by
a variety of mechanisms; however, it is not yet clear
whether homocysteine itself or a related metabolite or
cofactor is primarily responsible for the atherothrombo-
genic effects of hyperhomocyst (e)inemia in vivo. How-
ever, it is biologically plausible that hepatitis C may in-
crease the risk of disease such as heart attack and stoke
as hepatitis steatosis (fatty liver), a common complica-
tion of hepatitis C infection, has been associated with in-
creased levels of homocysteine and metabolic syndrome.
Though, the reason(s) and mechanism(s) of this associa-
tion need further study.”
11. ACKNOWLEDGEMENTS
We are thankful to the head of Department of Biotechnology, Quaid-i-
Azam University, Islamabad, Pakistan for support.
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