Assessment of Liver Morbidity in Breast Cancer Patients Receiving Chemotherapy in Suez Canal University Hospitals

Background and study aim: In Egypt, breast cancer, representing 18.9% of total cancer cases and 35.1% of cancer in women. Potential interactions between the liver and chemotherapy fall into direct chemotherapy-induced hepatotoxicity and Potentiation of preexisting liver disease, especially viral hepatitis.The aim of the study is to assess liver morbidity in breast cancer patients before and 3 months after chemotherapy to assess reactivation of viral hepatitis. Subjects and Methods: This study is prospective study; It included 88 female patients who received chemotherapy for breast cancer. Results: Before chemotherapy 9 patients (10.2%) & 11 patients (12.5%) had elevated ALT & AST respectively which increased after chemotherapy to 32 patients (36.4%) & 29 patients (33%) respectively. Two patients (2.3%) had low serum albumin which increased after chemotherapy to 18 patients (20.5%). None of the patients had elevated S. bilirubin, ascites or jaundice, while after chemotherapy 10 patients (11.4%) had elevated S. bilirubin, 5 patients (5.6%) and 6 patients (6.8%) developed ascites and jaundice respectively. Regarding Child score: None of the patients had Child B/C score before treatment, while after chemotherapy 6 patients (6.8%) developed Child B/C score. Regarding viral hepatitis, 2 of ten patients (20%) who were HBcIgG positive, HBsAg negative with undetectable HBV DNA by PCR developed evidence of HBV reactivation in form of positive PCR for both & reversion of HBsAg for one patient. Conclusion: Chemotherapy for breast cancer carries high risk for hepatotoxicity and reactivation of viral hepatitis.

Background and study aim: In Egypt, breast cancer, representing 18.9% of total cancer cases and 35.1% of cancer in women.Potential interactions between the liver and chemotherapy fall into direct chemotherapy-induced hepatotoxicity and Potentiation of preexisting liver disease, especially viral hepatitis.The aim of the study is to assess liver morbidity in breast cancer patients before and 3 months after chemotherapy to assess reactivation of viral hepatitis.

Subjects and Methods:
This study is prospective study; It included 88 female patients who received chemotherapy for breast cancer.
Results: Before chemotherapy 9 patients (10.2%) & 11 patients (12.5%) had elevated ALT & AST respectively which increased after chemotherapy to 32 patients (36.4%) & 29 patients (33%) respectively.Two patients (2.3%) had low serum albumin which increased after chemotherapy to 18 patients (20.5%).None of the patients had elevated S. bilirubin, ascites or jaundice, while after chemotherapy 10 patients (11.4%) had elevated S. bilirubin, 5 patients (5.6%) and 6 patients (6.8%) developed ascites and jaundice respectively.Regarding Child score: None of the patients had Child B/C score before treatment, while after chemotherapy 6 patients (6.8%) developed Child B/C score.Regarding viral hepatitis, 2 of ten patients (20%) who were HBcIgG positive, HBsAg negative with undetectable HBV DNA by PCR developed evidence of HBV reactivation in form of positive PCR for both & reversion of HBsAg for one patient.

INTRODUCTION
In Egypt, breast cancer (BC) is the most common cancer among women, representing 18.9% of total cancer cases and 35.1% of cancer in women.Breast cancer patients receiving therapy require supportive care for the prevention and management of physical and psychosocial adverse effects of cancer and its treatments [1].Patients undergoing cytotoxic chemotherapy require careful assessment of liver function both prior to and during therapy.Potential interactions between the liver and chemotherapy fall into two categories: Direct chemotherapy-induced hepatotoxicity and potentiation of preexisting liver disease, especially viral hepatitis [2].Druginduced liver injury (DILI) has an estimated annual incidence between 10 and 15 per 10,000 to 100,000 persons exposed to prescription medications.DILI accounts for approximately 10% of all cases of acute hepatitis, and it is the most common cause of acute liver failure in the United States [3].
Viral hepatitis reactivation is one of the major challenges encountered during a variety of chemotherapy treatments.In the literature, there is a well-established association between hepatitis B virus (HBV) reactivation and some anti-cancer drugs, especially monoclonal antibodies.On the other hand, there is limited data concerning the reactivation of hepatitis C virus (HCV) with chemotherapeutic drugs and targeted therapies [4].

Aim of the work:
To assess liver morbidity in breast cancer patients before and 3 months after chemotherapy to assess reactivation of viral hepatitis.

Patients:
After approval of our ethics committee, this prospective study was performed in Oncology & nuclear medicine department at Suez Canal University hospital, Ismailia from June 2011 to December 2012.It included 88 breast cancer patients who consecutively attended the Oncology & Nuclear Medicine Department to receive chemotherapy during the study period.

Methods:
The chemotherapeutic regimens of each patient were given according to the standard protocol for the specific tumor type.6. Hepatitis was attributed to HBV reactivation when there was an increase in HBV DNA levels of ≥10fold when compared with baseline HBV DNA levels or the appearance of HBV DNA from an undetectable level at baseline or an absolute increase of HBV DNA level that exceeded 1,000,000,000 genome equivalents/ml (GE/ml) during chemotherapy [9,10].

RESULTS
This study revealed a significant liver morbidity in breast cancer patients who were treated with chemotherapy.

Regarding socio-demographic characteristics:
Mean age of patients was 50±11.1 years.Most of the patients (74 patients (84%)) are married.66 patients (75%) came from urban areas, and 72 patients (82%) were un-employed.Regarding to their special habits, only one patient was smoker and no one was alcoholic (Table 1).Also total S. bilirubin elevated in 11.4% of patients, the mean value of total S. bilirubin increased from 0.61 mg/dl before starting chemotherapy to 1.07 mg/dl after chemotherapy, in agree with Chauhan et.al. who reported the mean value of total bilirubin was 0.30±1.3mg/dlbefore the starting of the treatment which increased after chemotherapy to 1.12 mg/dl [5].

Regarding HBV & HCV
While percentage of patients who had low level of s. albumin markedly increased from 2.3% to 20.5% after chemotherapy and the mean value of S. albumin decreased from 4.07 gm/dl before chemotherapy to 3.77 gm/dl after chemotherapy, in agreement with authors found that low levels of serum albumin may be related to many factors as biological stress, liver dysfunction, and decrease mass of visceral protein or ability of albumin synthesizing.Also association with marked malnutrition [5,16,  , this difference explained by the higher prevalence of HBV in community of these studies than our community.
Ten patients (11.3%) were HBsAg negative/anti-HBc positive which is slightly lower than that (12%) reported by Pattullo [11].while markedly lower than that reported by Kawsar et al., in a survey performed in Greece, who found HBsAg negative/anti-HBc positive in 40% of cancer patients [12,13].
Two of ten patients (20%) who were HBsAg negative/anti-HBc positive before chemotherapy developed HBV reactivation with positive HBV DNA PCR during follow up after chemotherapy, In comparison with other studies, Alessandro et.al. reported that none of the patients who were inactive HBsAg carrier or had an occult HBV infection presented with HBV reactivation [12], while Tang et.al. reported that the rate of HBV reactivation is higher in patients with breast cancer (41-56%) than in those treated for other solid tumors (14-21%), also Yoo et.al. reported high rates of HBV reactivation, 38%-54% in HBV positive patients who undergo hematopoietic stem-cell trans-plantation and treatment for hematological malignancy, especially malignant lymphoma.These numerical differences are possibly due to the type or intensity of chemotherapy used for these conditions, rather than the nature of the malignancy itself and to the type of HBV infection [14,15].
Regarding HCV patients: Nine patients (10.2%) had positive result for HCV Ab, before treatment from whom 1 patient completed antiviral therapy with DAAS since 3 years and achieved SVR, 2 patients had negative HCV RNA by PCR, while the other 6 patients had positive HCV RNA by PCR with mean of 698352 IU/ ml which increased to 2609409 IU/ ml after chemotherapy.While Miura et.al. in a retrospective survey of patients diagnosed with breast cancer in Japan reported that 20 patients (2%) were HCV Ab positive; this difference may be due to difference of HCV prevalence between Egypt & Japan [7].Also Miura et.al. reported no difference in HCV RNA PCR before after chemotherapy with median serum HCV-RNA level at baseline and after chemotherapy was 6.4 and 6.5 log IU/ml, respectively.While Coppola et.al. showed that rituximab-based chemotherapy resulted in an increase in HCV-RNA at least 1.5 log IU/ml followed by hepatic flare among patients with lymphoma [8].These numerical differences are possibly due to the type or intensity of chemotherapy used for these conditions, rather than the nature of the malignancy itself and to the type of HCV infection [15].

CONCLUSION
Chemotherapy for breast cancer carries high risk for hepatotoxicity.Hepatotoxicity and liver morbidity is more common in patients with viral hepatitis and liver disease before starting chemotherapy, with probability of reactivation of HBV and HCV infections after chemotherapy.Prophylactic antiviral therapy by Tenofovir 300 mg once daily decreases risk of HBV reactivation.

7 . 8 .
Hepatitis was defined as a threefold or greater increase in serum ALT that exceeds the reference range (>45 IU/L) or an absolute increase of ALT to >100 IU/L [5,7].All patients who developed HBV reactivation received Tenofovir as a therapeutic measure [11-15].

9 .
Morbidity related to HBV or HCV reactivation was recorded.

Table 4 ). Regarding Liver morbidity in HCV patients:
Regarding Child score: None of the patients had child B/C score before treatment, while after chemotherapy 6 patients (6.8%) developed child B/C score (Table2).Regarding Child score: None of the patients had Child B/C score before treatment, while after chemotherapy 2 patients (18.2%) developed child B/C score (Table5).

Table (
2) : Comparison between patients before and after chemotherapy regarding liver morbidity

Table ( 3
): Group comparison between patients before and after chemotherapy according their clinical presentation Fig1.Shows different clinical presentation in breast cancer patients before and after receiving chemotherapy