Frequency of Dermatological Disorders Associated with Hepatitis C Virus Infection in Sharkia Governorate , Egypt

Background and study aim: Egypt has the highest HCV prevalence in the world. Cutaneous lesions are found in some patients of HCV infection. This study was conducted to determine frequency and types of dermatological disorders present in chronic HCV infection in Sharkia governorate, Egypt. 
Patients and Methods: 157 Patients of chronic hepatitis C divided into 2 groups; group 1: Includes 117 patients with chronic HCV infection who didn’t receive antiviral treatment group 2: Includes 40 patients with chronic HCV infection who received antiviral treatment (peg- interferon and ribavirin). Detailed history taking, clinical and dermatological examination was carried out. Biochemical profile including complete blood count, platelet count, and cryoglobulins were done. 
Results: The percentage of dermatological manifestations increase with the severity of liver cirrhosis. Pruritus was the predominant dermatological manifestation in untreated and treated patients (37.9%) and (52.9%) respectively. There was significant statistical difference between positive and negative cryoglobulineamic patients in the untreated group regarding different dermatological manifestations with high percentage of pruritus, vasculitis and purpura in patients with cryoglobulin positivity (p= 0.04). 
Conclusion: Skin manifestations are present in 61% of chronic HCV patients and less frequent in treated group. The frequency of skin manifestations increases with the advancement of liver disease. Pruritis is the most frequent manifestation in all patients.


INTRODUCTION
Although the hepatitis C virus (HCV) was identified only in 1989, it has emerged as major cause not only of liver disease, but also of numerous extrahepatic conditions [1].According to different studies, 40-74% of patients infected with HCV might develop at least one extrahepatic manifestation during the course of the disease [2,3].In fact as many as 17% to 46% of all HCV-infected patients have at least one skin manifestation [2,4].This study was conducted to determine frequency and types of dermatological disorders present in chronic HCV infection in Sharkia governorate, Egypt.

Study design: Cross sectional study
Site and Time of study: This study was carried out in Tropical Medicine, Internal Medicine Departments and Dermatology outpatient clinic, Zagazig University Hospitals in the period from August 2016 to August 2017.

Patients:
The sample size was 157 patients, which were divided into two groups: group (I): Includes 117 patients with chronic HCV infection who didn't receive antiviral treatment (79 patients with skin manifestations and 38 patients without skin manifestations).Group(II): Includes 40 patients with chronic HCV infection who received anti viral treatment (peg interferon and ribavirin) (17 patients with skin manifestations and 23 patients without skin manifestations).allpatients in the second group received antiviral treatment before the year 2015.
Inclusion criteria: All patients with chronic liver disease due to HCV either on treatment or not.The drugs used for treatment of chronic HCV were pegylated interferon and ribavirin.
Exclusion criteria: Any patient with: hepatitis B or auto immune hepatitis or diabetes mellitus or renal failure or diagnosed malignancy, were excluded from the study.

Patient assessment
All patients of the study were subjected to the following: 1-Complete history taking: History of present dermatological disease including: onset, course, duration, site, and its relation to antiviral treatment in the second group.2-Full clinical examination: general examination.
Full dermatological examination of the present lesion as regard site, size, and shape was done.

RESULTS
There was no statistically significant difference between both groups regarding sex distribution, while the treated patients were significantly younger than the untreated group.There was a highly statistically significant difference between both groups regarding duration of illness (p<0.001), while there were no significant statistical differences between them regarding pruritus and fall of hair (Table 1).There was a highly statistical significant difference between both groups regarding liver and spleen size, presence of ascites, skin manifestations and Child Pugh classes (p<0.001)(Table 1).
Pruritus was the predominant dermatological manifestation in untreated and treated patients (37.9%) and (52.9%) respectively regarding all skin manifestations (Table 2).
There was significant statistical difference between all patients regarding their dermatological manifestations and the severity of the liver disease by Child Pugh class (P<0.05).The percentage of dermatological manifestations increases with the advancement of the severity of liver cirrhosis (Table 3).
There were no statistically significant difference between all patients with or without skin manifestation as regard viral load, degree of viraemia and cryoglobulin (P> 0.05) (Table 4).
Pruritus, hair falling, vasculitis, oral lichen planus, alopecia and purpura occur more frequently in patients with severe viraemia (Table 5).
The common skin lesions in untreated patients with positive cryoglobulin were purpura, pruritus and vasculitis while with negative cryoglobulin were hair falling, psoriasis and lichen planus (Table 6).
The common skin lesions in treated patients with positive cryoglobulin were present in patients with vitiligo and pruritus while with negative cryoglobulin was lichen planus and alopecia (Table 7).Various types of skin lesions have been reported due to HCV infection, as well as anti-HCV treatment.Some skin lesions improve with anti-HCV treatment, whereas others worsen, necessitating the discontinuation of the treatment This study was designed to assess the frequency of dermatological manifestations associated with chronic HCV infection and its treatment.To reach this purpose, 157 patients with chronic HCV infection were recruited.They were divided into 2 groups, the first included 117 patients who didn't receive anti-HCV treatment and the second included 40 patients who received treatment in the form of peg-interferon and ribavirin before the year 2015.
In this study, the treated patients were significantly younger than the untreated patients.This may be due to the significantly longer duration of illness of untreated group that exposes the patients to decompensation making them non-candidates for treatment.There was no statistically significant difference between both groups regarding sex distribution and this is in agreement with Asim and Wahid and In our study, the most frequent skin manifestations associated with cryopositivity in untreated patients were; purpura (100%), pruritus (67%) and vasculitis (60%).The three most common symptoms of patients with mixed cryoglobulinemia are palpable purpura, arthralgia, and weakness, which were named as the core symptoms of cryoglobulinemia [38].The intravascular precipitation of immunoglobulins in lower temperatures causes reversible mechanical obstruction in the small vessels of skin and immune-complex mediated vasculitis and chronic ulcers may also occur [39].The obstructive immune complexes may also cause pruritus and urticaria [40].
In treated group, there was no any patient with vasculitic lesions.This may be due to the effect of treatment of antiviral therapy against HCV which is the mainstay of treatment for cryoglobulinemic disorders associated with HCV infection.There is good evidence that treatment leads to reduction of cryoglobulins, improve cutaneous vasculitis and rashes [33].
Limitations of our study were that patients included in this study received treatment with peg-interferon plus ribavirin before the year 2015 and it did not include cases treated by Direct Acting Antivirals (DAAs).This was simply because by the time this study was carried outwe did not find cases with skin lesions related to DAAs but we found cases with skin lesions previously treated with interferon, so further studies are needed to rule out relation between DAAs and skin lesions in HCV patients.

CONCLUSION
Skin manifestations are present in 61% of chronic HCV patients and less frequent in treated group.The frequency of skin maniestations increases with the advancement of Child-Pugh class.Pruritis is the most frequent manifestation in all patients and more frequent in treated group.Alopecia is frequent in treated than untreated patients.
With sever viremia; pruritis, hair falling, vasculitis, oral lichen planus, alopecia and purpura are frequent skin manifestations.Purpura, pruritus and vasculitis are frequently associated with cryoglobulinemia.

Research ethics considerations:
The protocol of this study was reviewed and approved by Zagazig University ethical committee.Written and informed consent was obtained from all participants.

Table ( 1
): Demographic, clinical, ultrasonographic, child classification of both groups HS; highly significant, NS; non-significantTable (2):Comparison between treated and untreated patients with different skin manifestations regarding frequency and type

Table ( 6
): Relationship between cryoglobulin and different skin lesions in untreated patients Cryoglobulin

Table ( 7
): Relationship between cryoglobulin and different skin lesions in treated patients Cryoglobulin