Neglected tropical diseases as a cause of chronic liver disease: the case of Schistosomiasis and Hepatitis C Co‐infections in Egypt
Year: 2012
Type: article
Abstract: The year 2011 will be remembered as an important one for highlighting the global burden of diseases that result from chronic non-communicable diseases (CNCDs). Several landmark events occurred, including a high-level United Nations General Assembly meeting in September 2011 that addressed the prevention and control of CNCDs. To date an important emphasis on CNCDs has been lifestyle changes leading to rapidly increasing rates of obesity, diabetes and heart disease in developing countries. However, we believe that neglected tropical diseases (NTDs) also represent important hidden factors underlying the emergence of CNCDs in developing countries 1. The NTDs are chronic and disabling conditions that include all of the highly prevalent helminthic and protozoan infections as well as selected bacterial, viral and fungal infections 2. Several NTDs contribute to the burden of chronic gastrointestinal and liver disease in low- and middle-income countries (LMICs), including trichuriasis now recognized as an important cause of inflammatory bowel disease, Chagas disease as a cause of megacolon and megaesophagus, amebiasis and echinococcosis as causes of liver cysts, and schistosomiasis as a leading cause of liver fibrosis 1. High rates of co-infections from two leading diseases affecting the liver have been recognized in Egypt: schistosomiasis caused by Schistosoma mansoni and hepatitis C virus (HCV) infection. We have found that these two co-infections and their synergies in promoting liver disease in Egypt represent an illustrative example of a burden of a CNCD in LMICs. Schistosomiasis has plagued Egypt and other African countries along the Nile River since antiquity 3. During the first half of the 20th century, up to 80% of the populations of impoverished Egyptian villages were infected with schistosomes, leading one writer to declare that 'no other people on earth suffer the ravages of bilharzia to the extent of the Egyptian fellaheen (farmers)' 3. Factors favouring schistosomiasis endemicity include improper water and sanitation facilities along with bodies of freshwater, which are often contaminated with infected snails. Chronic morbidities associated with repeated infection include impaired child growth and development, chronic inflammation of liver, anaemia and other nutritional deficiencies with some estimates of up to 56 million disability-adjusted life years (DALYs) lost annually, a value that exceeds the estimated global burden of malaria 4. Prior to the availability of praziquantel, the primary treatment of schistosomiasis in Egypt was with parenteral administration of tartar emetic (potassium antimony tartrate) 3. Hundreds of thousands of Egyptian fellaheen received the medication following World War I, which was often effective in curing schistosomiasis although it was also highly toxic. The mechanism of action of tartar emetic is inhibition of DNA synthesis 5 with a side effect profile including nausea, vomiting, coughing, acute circulatory failure and electrocardiographic changes 6. Sadly, it was often dispensed without due attention to sterilization of needles between patients leading to an unanticipated consequence of an epidemic of HCV infections 7-13. It was unknown during this period of administration that infectious agents could be transmitted via syringes and human blood 13. As tartar emetic was administered parenterally, both HCV and hepatitis B virus (HBV) were also transmitted through this process 14. It has also been proposed that Egyptians are particularly susceptible to both schistosomiasis and HCV co-infections 15, 16. Today, the prevalence of chronic HCV infections and seropositivity in Egypt has been reported as high as one in 10 people, compared with the global rate of one in 50 people 17. In contrast, the seroprevalence of HCV and schistosomiasis in neighbouring Sudan seem to be much lower, the basis of which is still not clear 18. The epidemic of schistosome (past or present infection) and HCV infections in Egypt also revealed synergies in liver disease progression resulting from these two pathogens. Several studies have shown that patients co-infected with schistosomiasis and HCV infections suffer from an increased rate of liver fibrosis than would be present with either disease alone ultimately leading to a more advanced liver disease 19-28; although, other studies have not illustrated a direct causal linkage between the two infections 29-31. One possible reason for the elevated fibrosis is from the shift in immune response and corresponding cytokine release. Typically, a successful immune response to HCV infection would promote a Th1 immunological profile, which in general triggers a robust antiviral response and a reduction in host fibrosis. However, schistosomiasis triggers a Th2 cytokine response, which not only suppresses Th1 cytokine release, thereby hindering cellular and antiviral immunity, but also promotes Th2 host responses and fibrogenesis 16, 23, 24, 32-37. The shift in immune response from Th1 to Th2 can be confirmed by high plasma levels of profibrotic cytokines IL-4 and IL-13 and antiinflammatory cytokine IL-10 32-34, 38-42. Other key cytokines involved in inflammation and fibrosis include tumour necrosis factor-α (TNF-α) and tumour necrosis factor-β (TNF-β) 25. In addition, it has also been reported that immunosuppression of Th1 cytokine release may not require the schistosomiasis co-infection to be active (i.e. having viable adult worms) 26. Egypt's hepatitis C epidemic may be further intensified by additional fibrogenic factors unique to the country and region, including host genetic factors 43. Chromosome 6q23 carries a gene that encodes a connective tissue growth factor (CTGF), which stimulates strong fibrogenic molecules leading to severe hepatic fibrosis 44. Furthermore, single nucleotide polymorphism (SNP) rs9402373 is localized near the CTGF gene and is independently associated with elevated liver fibrosis 44. In addition, a SNP rs1327475 in the interferon gamma receptor locus (INFGR1 gene) has been linked to schistosomal hepatic fibrosis 15. In another study, Egyptians were found to harbour a SNP in lymphotoxin-α (LTα) gene, which is involved with inflammatory processes and increases susceptibility to HCV infection regardless of schistosomiasis co-infection 16. Additional mediators of fibrosis include serum laminin and serum activin A, which are increased in co-infected patients 45. Insulin-like growth factor (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are also found to be decreased in co-infected patients, which is associated with hepatocellular carcinoma progression 46. Furthermore, a statistically significant elevation of serum fibrosis markers YKL-40, transforming growth factor-β (TGF-β) and N-terminal propeptide of collagen III (PIIINP) are seen in co-infected individuals, but not in HCV alone 25. Fibrosis markers YKL-40 and TGF-β are efficient to early detection and in monitoring progression of fibrosis 25. These studies could lead to the development of biomarkers to predict severity of fibrosis, staging of disease, progression of liver disease and essential chemotherapy 25, 44. In addition, while the United States and Europe are affected primarily with genotype 1 HCV, genotype 4a predominates in Egypt 11, 12. Genotype 4a results in higher HCV RNA viral titres when compared with genotype 1 along with having a higher incidence of cirrhosis and fibrosis 11, 12, 22, 37. In a longitudinal cohort study, intermittent liver biopsies were taken to assess the histological changes occurring in patients with HCV alone and co-infected individuals 25. A statistically significant increased rate of progression of liver fibrosis was noted in patients co-infected with schistosomiasis and HCV when compared with HCV alone 25. Histologically, co-infected patients were found to have significantly higher total inflammatory scores, hepatitis and periportal necrosis 25. Furthermore, patients with schistosomiasis infection alone developed portal hypertension with splenomegaly and oesophageal varices; however, these clinical changes occur much later in disease progression 25. In conclusion, an escalated rate of progression of liver fibrosis is seen in patients co-infected with HCV and schistosomiasis when compared with HCV alone 25. Most of the studies are limited by small sample sizes and require additional larger studies to confirm each of the findings; however, the serum markers and information gathered thus far seem promising. Future endeavours should include larger, well-designed cohort studies to confirm the preliminary findings in the studies cited. However, the Ministry of Health in Egypt has embarked on a schistosomiasis elimination programme using praziquantel since 1988 in regular annual treatments in schools, and so the current level of schistosomiasis prevalence has been significantly reduced from previously reported levels. The combination of virus, parasite and host factors appears to have created a 'perfect storm' of factors leading to an epidemic of severe liver fibrosis and disease in Egypt (Box 1). Complications of liver fibrosis include portal hypertension, cirrhosis and hepatocellular carcinoma, ultimately progressing to death 20, 47-49. Despite improved results with current medication practices, many Egyptians infected with HCV and currently or previously with schistosomes are presenting with severe disease. Current medication regimen for HCV therapy consists of pegylated interferon (IFN) in combination with ribavirin 50-52. Individuals co-infected with HCV and schistosomiasis should initially be treated with praziquantel 40 mg/kg single dose, which can be repeated with up to three weekly consecutive doses prior to the initiation of antiviral treatment 37. It has been noted that co-infected patients respond poorly to IFN therapy and have increased relapse rates when compared with HCV alone 53. In addition, the imported medications for the treatment of HCV are beyond the economic capability of many patients to pay for the treatments on their own, despite the assistance programmes available. Resources are limited and sometimes inaccessible, thus illustrating that an added hindrance in curing HCV is a sometimes-inadequate healthcare infrastructure in Egypt 26. Finally, chronic infection of HCV remains an ongoing public health threat in Egypt as transmission is further propagated with continued evidence of inadequate sterilization practices in clinics and hospitals 17. In summary, Egypt's co-infection epidemic is an illustrative example of how NTDs served as an important underlying factor to the emergence of a CNCD in LMIC. The continued plague of HCV infections seen in Egypt is secondary to the high prevalence of chronic HCV infections that partly resulted from tartar emetic treatment, as well as overall increased co-infection susceptibility. Accelerated fibrosis, higher HCV RNA titres, predominance of genotype 4a and higher histological activity have been noted in patients with co-infection of HCV and schistosomiasis from not only downregulation of Th1 cytokines and upregulation of Th2 cytokines but also host genetic factors 27. There is a need for additional research to follow, detect and ultimately to halt disease progression. More importantly, preventive measures, including health education to thwart ongoing transmission in clinics, hospitals and elsewhere, need to be fully supported to arrest the Egyptian epidemic. As the importance of CNCDs becomes fully realized, it will be important to consider the role of NTDs as aetiologies of these conditions. Box 1. Key factors underlying progression of hepatitis C disease in Egypt
Source: Liver International
DOI: 10.1111/liv.12052
Authors: Menka M. Sanghvi, Peter J. Hotez, Alan Fenwick
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1984537785