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Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.
285
Address for correspondence
Dr. Shagufta Anwar, Department of Dermatology, Bahawal-Victoria Hospital, Quaid-e-Azam Medical College, Bahawalpur.
Email: [email protected]
Original Article
Frequency of cutaneous manifestations in patients of hepatitis C infection
Introduction
The hepatitis C virus (HCV) is an RNA virus
that belongs to the family flaviviridae.1 HCV
replicates in the cytoplasm of hepatocytes, but
is not directly cytopathic. Persistent infection
appears to rely on rapid production of virus
and continuous cell-to-cell spread, along with
a lack of vigorous T-cell immune response to
HCV antigens. The HCV turnover rate can be
quite high with replication ranging between
10 10
to 10 12
virions per day and a predicted
viral half-life of 2 to 3 hours.2 The rapid viral
replication and lack of error proofreading by
the viral RNA polymerase are reasons why the
HCV RNA genome mutates frequently.3 There
are six known genotypes (numbered 1 through
6) and more than 50 subtypes (e.g., 1a, 1b,
2a...).4 Frequent HCV mutations and numerous
subtypes have made the search for an HCV
vaccine challenging. Chronic hepatitis C is the
most common cause of chronic liver disease
and cirrhosis, and the most common indication
for liver transplantation in the United States
(U.S.), Australia, and most of Europe.5,6
Approximately 170 million people are affected
with HCV worldwide, comprising ~3% of the
global population.4 Hepatitis C virus (HCV) is
the most common chronic blood borne
infection in the U.S., and is involved in 40%
of chronic liver disease.4,5
Shagufta Anwar, Muhammad Khalid, Jamil Ahmad Shaheen
Department of Dermatology, Quaid-e-Azam Medical College, Bahawal-Victoria Hospital, Bahawalpur
Abstract Objective To determine the frequency of cutaneous manifestations in patients suffering from hepatitis C infection. Methods In this cross-sectional study, one hundred diagnosed patients of hepatitis C, admitted in medical units of Bahawal-Victoria Hospital, Bahawalpur, Quaid-e-Azam Medical College, Bahawalpur were registered over a period of six months. Cutaneous manifestations in these patients were recorded and analyzed.
Results Out of 100 patients, 51 (51%) were males and 49 (49%) were females. Majority of the patients (73%) were 20 to 59 years old. Most of the patients had more than one cutaneous manifestation. These included generalized pruritus 30%, lichen planus 30%, urticaria 26%, leukocytoclastic vasculitis 25%, necrolytic acral erythema 20% and porphyria cutanea tarda 4%. Conclusion Cutaneous manifestations of hepatitis are not uncommon. These may be the first clinical sign of chronic hepatitis C infection. Generalized pruritus, lichen planus, urticaria, leukocytoclastic vasculitis, necrolytic acral erythema and porphyria cutanea tarda were the important cutaneous manifestations recorded. Screening such patients on the basis of these dermatoses and investigating accordingly may help in early diagnosis and prevention of complications of this grave disease.
Key words Hepatitis C, HCV, cutaneous manifestations.
Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.
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Hepatitis C virus infection is one of the
commonest chronic
viral infections in the
world, with about 300 million people
chronically infected worldwide. Chronic HCV
infection leads to cirrhosis of liver if not
treated properly. 8 Physicians know hepatic
cirrhosis and its complication since the time of
Hippocrates. W.H.O. has estimated that
cirrhosis is responsible for 1.1% of all deaths
worldwide. About 175 million people in the
world have cirrhosis of liver. Cirrhosis
comprises 10 th most common cause of death in
USA. About 30% patients of cirrhosis die in
hepatic coma.
Hepatitis C infection is very common in this
southern area of Punjab. It is associated with
many cutaneous manifestations. These skin
manifestations may lead to screening and early
diagnosis of this chronic disease. To determine
the frequency of these skin changes among
hepatitis C patients was the objective of this
study.
Methods
Patients of both genders having positive anti-
HCV antibodies on the basis of BIOTEC
Latex Kit method® and presence of HCV
RNA by polymerase chain reaction (PCR)
(Qualitative), were included in the study.
Patients having age less than 15 years, known
alcoholics, patients of primary biliary cirrhosis
and patients with HBsAg-positive test were
excluded from the study.
Cases of hepatitis C with positive HCV
evidence, according to inclusion criteria,
admitted in medical units of Bahawal-Victoria
Hospital, Bahawalpur were considered. One
hundred cases of positive HCV were
registered in the study. Informed consent was
taken from the patients and all the information
was collected on pre-designed proforma, with
two parts, part-I comprising sociodemographic
details like age, sex, occupation and
educational status while part-II consisting
study variables. The cutaneous manifestations
were observed in each patient and
dermatological diagnosis was re-confirmed by
senior consultant dermatologist (MK and JAS)
and investigated where needed. The patients
who had anti-HCV antibodies in their serum
were subjected to HCV RNA by PCR
(Qualitative). Cryoglobulins and the levels of
complement were analyzed in patients who
had positive serologic tests for rheumatoid
factor (RF). Patients with co-existent liver
diseases (co-infection with hepatitis B virus),
alcoholic liver disease and primary biliary
cirrhosis were excluded.
All the information collected on the proforma
was analyzed using statistical package for
social sciences (SPSS) version 10.0.
Frequencies for individual cutaneous
manifestations and their percentages were
calculated in hepatitis C patients in general, as
well as, with respect to sex and age. Account
was also taken of the cutaneous features with
or without history of antiviral therapy. Mean
and standard deviation was calculated for age.
Results
One hundred diagnosed patients of hepatitis C,
on the basis of positive anti-HCV antibodies
and PCR, were included in this study. Out of
these, 51 (51%) were male and 49 (49%) were
female, with male to female ratio of 1.04:1.00.
The age ranged from 15 years to above 70
years. Majority of the patients (73%) were 20
to 59 years old while only 8% were less than
20 years and 19% were older than 59 years.
Most of the patients were relatively in middle
age i.e. 80% of patients were of the ages 54
years (range 23-76 years). Among these 100
patients, 17 had a history of previous surgery,
11 had received blood transfusions, four
patients had dental procedures, two underwent
hemodialysis for chronic renal failure, and one
patient had a history of intravenous drug
abuse. In 65 of 100 cases, the route of
transmission was not ascertained.
Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.
287
Figure 1 Frequency of different cutaneous manifestations in 100 HCV patients.
Figure 1 shows the frequency of different
cutaneous manifestations seen in the study
population. Out of 100 patients, generalized
pruritus was seen in 30% (18 male and 12
female), lichen planus in 30% (17 male and 13
female), urticaria in 26% (13 male and 13
female), leukocytoclastic vasculitis in 25% (14
male and 11 female), necrolytic acral erythema
in 20% (12 male and 8 female) and porphyria
cutanea tarda in 40% (3 male and 1 female),
Generalized pruritus was seen in 30 (30%)
cases. On examination, 6 had dry skin, and 2
excoriated papules, the skin in the remaining
was normal. In 5 of 30 patients with pruritus, a
moderate cholestasis was present.
Cutaneous and mucosal lichen planus (LP),
confirmed by histopathological examination,
were noted in 30 (30%) patients, 17 males and
13 females. These patients presented with
cutaneous lesions of various sized pruritic
papules and plaques mostly over the
extremities. 14 patients had cutaneous lesions
only and 4 patients had cutaneous, as well as,
oral lesions and oral lichen planus alone was
present in 12 patients. In some cases there
were whitish streaks over the oral mucosa,
while in others painful erosive lesions were
seen over the tongue. The LP lasted more than
one year.
25 patients of leukocytoclastic vasculitis,
presented with palpable purpura, erythematous
plaques, erosions and ulcers over the feet and
lower legs. Histopathology revealed a
cutaneous leukocytoclastic vasculitis. In 5 of
these, RF was positive, the complement levels
were low and cryoglobulinemia was detected.
Necrolytic acral erythema was reported in 20%
patients as erythematous, scaly plaques on
hands and feet. Histopathology was suggestive
of the disease. In 4 patients of PCT, there was
history of photosensitivity and blistering on
face and hands, hyperpigmentation,
hypertrichosis and scarring but the
biochemical diagnosis could not be confirmed
due to unavailability of laboratory tests.
The serum levels of ALT and AST were
normal in 22 of the 100 chronic HCV infected
patients (22%). Fifty-five patients (55%)
showed mild to severe elevations of the serum
transaminases. RF was positive (>20 IU/ml) in
44 of 100 patients (44%). In 5 serum samples
from the RF positive patients,
cryoglobulinemia and altered complement
levels were detected. Forty patients (40%) had
received or were on antiviral therapy, which
was a combination of interferon and ribavirin.
None of the patients were on interferon
therapy alone or on ribavirin therapy only. All
30 30
26 25
20
4
0
5
10
15
20
25
30
35
40
Gen. pruritus Lichen planus Ch urticaria Leucocytoclastic
vasculitis
Necrolytic acral
erythema
Porphyria cutanea
tarda
Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.
288
the patients were on supportive/symptomatic
therapy.
Discussion
In the present study, total one hundred patients
were included. 51 (51%) were male and 49
(49%) were female. The male predominance
has been observed in various studies
conducted in Pakistan, as well as,
internationally previously, so is the case in this
study. This male to female difference may be
due to delayed consultation by female patients
and gender inequality in utilization of health
care facilities in Pakistan. The other factor
may be that, as compared to females, males are
relatively more exposed to the risk factor for
the transmission of HCV i.e. transmission
through barbers and intravenous drug abuse.
Fifty seven percent patients were illiterate.
Epidemiological studies have revealed that
HCV infection is uncommon in age groups
younger than 20 years and prevalent in persons
older than 40 years. 5
Our results show only 8
patients of less than 20 years with a frequency
of 8%, hence an almost similar scenario but
we found the infection also common in the age
range of 40-49 years. This may indicate that in
our region younger persons are becoming a
victim to the disease.
Pruritus was found more often in patients with
severe fibrosis and cirrhosis. Pruritus with
non-specific excoriations was a common
finding with a frequency of 30%. Several
etiologies can be considered. Pruritus could be
a direct effect of HCV infection or related to
IFN therapy. Cholestasis alone could be
another cause.10 The prevalence of pruritus in
HCV infected patients varies from one country
to another, and the epidemiology of HCV
differs substantially between countries. It is,
therefore, difficult to compare the results. For
example, the HCV rate in patients with
pruritus was 0.7% in a study from France11
while in another French study, pruritus was
found in 15% of HCV positive patients.12
The relationship between LP and HCV is
debatable and several studies have been
conducted. A retrospective study by Beaird et
al. 13
reported 70% frequency of HCV in
patients of LP. Another case-control study on
340 LP patients revealed 55% frequency. 14
Epidemiological study by Tameez-ud-Deen et
al. 15
on patients of LP have reported an
association of 32.7% while Mahboob et al. 16
reported a frequency of 23.5%. All these
studies were conducted on patients of LP
while in our study HCV positive patients were
examined for features of LP. We found a
frequency of 30%. This difference in
frequency could be due to our detection of LP
in HCV patients rather than HCV detection in
LP patients.
In several studies, a possible link between
urticaria and HCV infection was mentioned. A
Japanese study by Kanazawa et al.17 in 1996,
showed a statistically significant association
between urticaria and hepatitis C. A study, in
Pakistan, on patients of chronic urticaria by
Ahmed et al.18 showed a frequency of 13.16%
cases positive for anti-HCV antibodies.
The
demographic data revealed an almost equal
gender distribution. A study carried out by
Umar et al.19 in Pakistan showed a similar
male to female ratio.
Cutaneous vasculitis has been associated with
HCV infection. Karlsberg et al.20
did a
systematic dermatological evaluation of 408
patients with hepatitis C and vasculitis was
found in 10 (3%) patients. In a comparative
study on essential mixed cryoglobulinemia in
HCV infected vs. noninfected patients, 21% of
HCV infected patients presented with
cutaneous features of palpable purpura.21
Our
findings of 25% vasculitis are almost similar.
Palpable purpura was a feature seen in all our
cases of cutaneous vasculitis. Cryoglobulins
are immunoglobulins that undergo reversible
precipitation at low temperatures. These
consist of IgG and IgM polyclonal rheumatoid
factors. There is a strong association between
Journal of Pakistan Association of Dermatologists. 2015;25 (4):285-290.
289
type II and type III mixed cryoglobulinemia
and HCV infection. The initial observation
was by Pascual et al.21 in 1990 who found anti-
HCV antibodies in patients with type II
cryoglobulinemia.
Porphyria cutanea tarda was
seen in 4 (4%) of our cases and it is frequently
associated with HCV infection.22
Chronic HCV is a leading cause of cirrhosis in
Bahawalpur. As there is no vaccine yet
available against hepatitis C virus and it is the
commonest cause of cirrhosis in this part of
world hence needs more meticulous approach
to prevent its transmission, through avoidance
of risk factors and early detection, if a patient
presents with cutaneous manifestation. Even if
the cirrhosis develops, early detection and
prompt treatment of these viral infections
improve the overall outcome of the patients
and prevent from development of
hepatocellular carcinoma. Once the cirrhotic
process has begun, the incidence of
hepatocellular carcinoma ranges from 1% to
4%. Hepatitis C is reaching epidemic
proportions and is a significant cause of
morbidity worldwide. Timely intervention can
stabilize the disease and positively impact
morbidity and mortality. This underscores the
importance of detecting individuals infected
with HCV. Since dermatologic manifestations
may be the only and most apparent sign of
chronic HCV, it is important that health care
professionals be aware of these dermatologic
manifestations. The cutaneous features are not
only themselves a cause of morbidity, but they
can also provide an indirect clue for the
underlying disease. Such an observation leads
to early detection and initiation of therapy.
Accurate and timely diagnosis of HCV is
critical to prevent the life threatening
complications. Antiviral therapy for HCV may
also be effective in curing the cutaneous
disease for example, cryoglobulinemia.
Moreover, such identification can help to
prevent further transmission of the disease.
Conclusion
Cutaneous manifestations may be the first
clinical sign of chronic HCV infection.
Screening for HCV infection in certain
dermatological conditions may lead to
antiviral treatment being effective in curing
cutaneous diseases. Moreover, such
identification will help prevent further
transmission of HCV.
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